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Entry
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- #188890 - TOBACCO ADDICTION, SUSCEPTIBILITY TO
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- OMIM
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<p>
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<span class="h4">#188890</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/188890"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=(TOBACCO ADDICTION) OR (GABBR2 OR CHRNA4 OR CYP2A6 OR SLC6A3)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/9410" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/chrna4" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=188890[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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188890
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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TOBACCO ADDICTION, SUSCEPTIBILITY TO
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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CIGARETTE HABITUATION, SUSCEPTIBILITY TO<br />
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SMOKING HABIT, SUSCEPTIBILITY TO<br />
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NICOTINE DEPENDENCE, SUSCEPTIBILITY TO<br />
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NICOTINE ADDICTION, SUSCEPTIBILITY TO<br />
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NICOTINE DEPENDENCE, PROTECTION AGAINST
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/5/24?start=-3&limit=10&highlight=24">
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5p15.33
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Nicotine dependence, protection against}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/188890"> 188890 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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SLC6A3
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/126455"> 126455 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/9/351?start=-3&limit=10&highlight=351">
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9q22.33
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Nicotine dependence, susceptibility to}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/188890"> 188890 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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GABBR2
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/607340"> 607340 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/9/351?start=-3&limit=10&highlight=351">
|
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9q22.33
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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{Nicotine dependence, protection against}
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/188890"> 188890 </a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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GABBR2
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/607340"> 607340 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/19/717?start=-3&limit=10&highlight=717">
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19q13.2
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Nicotine addiction, protection from}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/188890"> 188890 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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CYP2A6
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/122720"> 122720 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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- Smoking habit <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4505437&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4505437</a>]</span><br />
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<p>A number sign (#) is used with this entry because polymorphisms in several genes are believed to predispose to nicotine dependence and smoking behavior, including the gene encoding G protein-coupled receptor-51 (GPR51; <a href="/entry/607340">607340</a>) on chromosome 9q22.</p><p><a href="#17" class="mim-tip-reference" title="Li, M. D., Payne, T. J., Ma, J. Z., Lou, X.-Y., Zhang, D., Dupont, R. T., Crews, K. M., Somes, G., Williams, N. J., Elston, R. C. <strong>A genomewide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans.</strong> Am. J. Hum. Genet. 79: 745-751, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960812</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960812[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960812">Li et al. (2006)</a> found evidence of significant linkage of chromosome 10q22-q25 to smoking quantity (SQTL1; <a href="/entry/611003">611003</a>). <a href="#28" class="mim-tip-reference" title="Saccone, S. F., Pergadia, M. L., Loukola, A., Broms, U., Montgomery, G. W., Wang, J. C., Agrawal, A., Dick, D. M., Heath, A. C., Todorov, A. A., Maunu, H., Heikkila, K., Morley, K. I., Rice, J. P., Todd, R. D., Kaprio, J., Peltonen, L., Martin, N. G., Goate, A. M., Madden, P. A. F. <strong>Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples.</strong> Am. J. Hum. Genet. 80: 856-866, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436240">Saccone et al. (2007)</a> found evidence of linkage of chromosome 22q12 to a heavy smoking phenotype (SQTL2; <a href="/entry/611004">611004</a>). See also SQTL3 (<a href="/entry/612052">612052</a>), which is associated with polymorphisms in the nicotinic acetylcholine receptor gene cluster on chromosome 15q25.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16960812+17436240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Li, M. D. <strong>Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analysis.</strong> Hum. Genet. 123: 119-131, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18205015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18205015</a>] [<a href="https://doi.org/10.1007/s00439-008-0473-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18205015">Li (2008)</a> provided a review of susceptibility loci for nicotine dependence identified to date. Thirteen regions, located on chromosomes 3 through 7, 9 through 11, 17, 20, and 22 are suggestive or significant in at least 2 independent samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18205015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Evidence for moderate genetic influences on lifetime smoking practices was found by <a href="#3" class="mim-tip-reference" title="Carmelli, D., Swan, G. E., Robinette, D., Fabsitz, R. <strong>Genetic influence on smoking--a study of male twins.</strong> New Eng. J. Med. 327: 829-833, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1508241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1508241</a>] [<a href="https://doi.org/10.1056/NEJM199209173271201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1508241">Carmelli et al. (1992)</a> in an analysis of male twins in the National Academy of Sciences--National Research Twin Registry. The registry included male twins who were born in the United States between 1917 and 1927 and who were members of the Armed Forces during World World II. Information on smoking history was available for 4,775 pairs of twins who were first surveyed when they were in their forties and then resurveyed when they were aged 56 to 66. Eighty percent of the subjects had smoked at some time, 60% were still smokers in their forties, and 39% were smoking at the time of the resurvey. Monozygotic twins showed a higher concordance rate than dizygotic twins for having never smoked, for continuing to smoke, for quitting smoking, and for cigar or pipe smoking. For moderate smokers, there was no evidence of either familial or genetic influences; genetic factors seemed to contribute only in light smokers and heavy smokers. A metaanalysis of the data from 5 studies, each involving more than 1,000 twin pairs, showed an estimated heritability of 60% for the propensity to smoke (<a href="#8" class="mim-tip-reference" title="Heath, A. C., Madden, P. G. <strong>Behavior genetic approaches in behavioral medicine. In: Turner, J. R.; Cardon, L. R.; Hewitt, J. K. (eds.): Behavior Genetic Influences on Smoking Behavior.</strong> New York: Plenum 1995. Pp. 37-48."None>Heath and Madden, 1995</a>). Twin studies also showed that the genetic factors involved in the initiation and cessation of smoking are partially overlapping but mostly independent (<a href="#9" class="mim-tip-reference" title="Heath, A. C., Martin, N. G. <strong>Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence.</strong> Addictive Behav. 18: 19-34, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8465673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8465673</a>] [<a href="https://doi.org/10.1016/0306-4603(93)90005-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8465673">Heath and Martin, 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1508241+8465673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Gelernter, J., Liu, X., Hesselbrock, V., Page, G. P., Goddard, A., Zhang, H. <strong>Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking.</strong> Am. J. Med. Genet. Neuropsychiat. Genet. 128B: 94-101, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15211640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15211640</a>] [<a href="https://doi.org/10.1002/ajmg.b.30019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15211640">Gelernter et al. (2004)</a> completed a genomewide scan to map loci increasing the risk for cigarette smoking in a set of families originally identified because they segregated panic disorder. They studied 142 genotyped individuals in a total of 12 families. Of these, 69 individuals were affected with habitual cigarette smoking. The 3 highest multipoint Zlr scores (3.43, 3.04, and 3.01; p = 0.0003, 0.0012, and 0.0013, respectively) reflected suggestive evidence for linkage and were observed in multipoint linkage analyses on chromosomes 11p and 9. <a href="#6" class="mim-tip-reference" title="Gelernter, J., Liu, X., Hesselbrock, V., Page, G. P., Goddard, A., Zhang, H. <strong>Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking.</strong> Am. J. Med. Genet. Neuropsychiat. Genet. 128B: 94-101, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15211640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15211640</a>] [<a href="https://doi.org/10.1002/ajmg.b.30019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15211640">Gelernter et al. (2004)</a> noted that the chromosome 11 region has previously been linked to alcohol dependence and illegal drug abuse (e.g., <a href="#20" class="mim-tip-reference" title="Long, J. C., Knowler, W. C., Hanson, R. L., Robin, R. W., Urbanek, M., Moore, E., Bennett, P. H., Goldman, D. <strong>Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population.</strong> Am. J. Med. Genet. 81: 216-221, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9603607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9603607</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980508)81:3<216::aid-ajmg2>3.0.co;2-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9603607">Long et al., 1998</a>), while the chromosome 9 region has previously been identified as significantly linked to panic disorder in Icelandic pedigrees (see <a href="/entry/607853">607853</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15211640+9603607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a genomewide scan of 505 individuals consisting mostly of dizygotic twin pairs from 153 Finnish families ascertained for nicotine dependence, <a href="#22" class="mim-tip-reference" title="Loukola, A., Broms, U., Maunu, H., Widen, E., Heikkila, K., Siivola, M., Salo, A., Pergadia, M. L., Nyman, E., Sammalisto, S., Perola, M., Agrawal, A., Heath, A. C., Martin, N. G., Madden, P. A. F., Peltonen, L., Kaprio, J. <strong>Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background.</strong> Pharmacogenomics J. 8: 209-219, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17549066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17549066</a>] [<a href="https://doi.org/10.1038/sj.tpj.6500464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17549066">Loukola et al. (2008)</a> found suggestive evidence for linkage to chromosomes 7q31 and 11p15 (maximum lod scores of 2.50 at D7S486 and 2.25 at D11S4181, respectively). Both regions also showed evidence for linkage to the comorbid phenotype of smoking and alcohol use. A male-specific locus for isolated smoking and for the comorbid phenotype was also found at chromosome 7q35 (maximum 2-point lod scores of 2.90 and 2.74 at D7S661, respectively). <a href="#22" class="mim-tip-reference" title="Loukola, A., Broms, U., Maunu, H., Widen, E., Heikkila, K., Siivola, M., Salo, A., Pergadia, M. L., Nyman, E., Sammalisto, S., Perola, M., Agrawal, A., Heath, A. C., Martin, N. G., Madden, P. A. F., Peltonen, L., Kaprio, J. <strong>Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background.</strong> Pharmacogenomics J. 8: 209-219, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17549066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17549066</a>] [<a href="https://doi.org/10.1038/sj.tpj.6500464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17549066">Loukola et al. (2008)</a> suggested that these findings may represent shared genetic etiology for these traits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17549066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="The Tobacco and Genetics Consortium. <strong>Genome-wide meta-analyses identify multiple loci associated with smoking behavior. (Letter)</strong> Nature Genet. 42: 441-447, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418890">The Tobacco and Genetics Consortium (2010)</a> reported the findings of genomewide association studies for number of cigarettes smoked per day among 73,853 European individuals from multiple different cohorts, including those of <a href="#19" class="mim-tip-reference" title="Liu, J. Z., Tozzi, F., Waterworth, D. M., Pillai, S. G., Muglia, P., Middleton, L., Berrettini, W., Knouff, C. W., Yuan, X., Waeber, G., Vollenweider, P., Preisig, M., and 95 others. <strong>Meta-analysis and imputation refines the association of 15q25 with smoking quantity. (Letter)</strong> Nature Genet. 42: 436-440, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418889</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418889[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418889">Liu et al. (2010)</a> and <a href="#31" class="mim-tip-reference" title="Thorgeirsson, T. E., Gudbjartsson, D. F., Surakka, I., Vink, J. M., Amin, N., Geller, F., Sulem, P., Rafnar, T., Esko, T., Walter, S., Gieger, C., Rawal, R., and 83 others. <strong>Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.</strong> Nature Genet. 42: 448-453, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418888</a>] [<a href="https://doi.org/10.1038/ng.573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418888">Thorgeirsson et al. (2010)</a>. An association was also found for the G allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3733829;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3733829</a> in the EGLN2 gene (<a href="/entry/606424">606424</a>) on chromosome 19q13 (p = 1.04 x 10(-8)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20418888+20418889+20418890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>One part of this cohort was reported independently and simultaneously by <a href="#31" class="mim-tip-reference" title="Thorgeirsson, T. E., Gudbjartsson, D. F., Surakka, I., Vink, J. M., Amin, N., Geller, F., Sulem, P., Rafnar, T., Esko, T., Walter, S., Gieger, C., Rawal, R., and 83 others. <strong>Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.</strong> Nature Genet. 42: 448-453, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418888</a>] [<a href="https://doi.org/10.1038/ng.573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418888">Thorgeirsson et al. (2010)</a>, who conducted genomewide association metaanalyses for the number of cigarettes smoked per day among 31,266 individuals. Significant associations were found with the C allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4105144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4105144</a> on 19q13 (p = 1.2 x 10(-9)). When combined with the studies of <a href="#29" class="mim-tip-reference" title="The Tobacco and Genetics Consortium. <strong>Genome-wide meta-analyses identify multiple loci associated with smoking behavior. (Letter)</strong> Nature Genet. 42: 441-447, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418890">The Tobacco and Genetics Consortium (2010)</a> and <a href="#19" class="mim-tip-reference" title="Liu, J. Z., Tozzi, F., Waterworth, D. M., Pillai, S. G., Muglia, P., Middleton, L., Berrettini, W., Knouff, C. W., Yuan, X., Waeber, G., Vollenweider, P., Preisig, M., and 95 others. <strong>Meta-analysis and imputation refines the association of 15q25 with smoking quantity. (Letter)</strong> Nature Genet. 42: 436-440, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418889</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418889[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418889">Liu et al. (2010)</a> (n = 83,317), the p value for <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4105144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4105144</a> became 2.2 x 10(-12). <a href="#31" class="mim-tip-reference" title="Thorgeirsson, T. E., Gudbjartsson, D. F., Surakka, I., Vink, J. M., Amin, N., Geller, F., Sulem, P., Rafnar, T., Esko, T., Walter, S., Gieger, C., Rawal, R., and 83 others. <strong>Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.</strong> Nature Genet. 42: 448-453, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418888</a>] [<a href="https://doi.org/10.1038/ng.573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418888">Thorgeirsson et al. (2010)</a> also found an association with the T allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6474412;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs6474412</a> on chromosome 8p11 (p = 1.4 x 10(-8)) when combining the 3 studies. These 2 loci include genes involved in nicotine metabolism, such as CYP2A6 (<a href="/entry/122720">122720</a>) and CYP2B6 (<a href="/entry/123930">123930</a>) on 19q13, and nicotinic acetylcholine receptor subunits on 8p11 (CHRNB3; <a href="/entry/118508">118508</a>) and CHRNA6 (<a href="/entry/606888">606888</a>). No associations were found when considering smoking initiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20418888+20418889+20418890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Glutamate Transporters</em></strong></p><p>
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In a group of 23 individuals, including 5 nonalcoholic nonsmokers, 5 alcoholic nonsmokers, 7 nonalcoholic smokers, and 6 alcoholic smokers, <a href="#5" class="mim-tip-reference" title="Flatscher-Bader, T., Zuvela, N., Landis, N., Wilce, P. A. <strong>Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area.</strong> Hum. Molec. Genet. 17: 38-51, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17928304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17928304</a>] [<a href="https://doi.org/10.1093/hmg/ddm283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17928304">Flatscher-Bader et al. (2008)</a> found that expression levels of the glutamate transporters SLC1A2 (<a href="/entry/600300">600300</a>), SLC17A6 (<a href="/entry/607563">607563</a>), and SLC17A7 (<a href="/entry/605208">605208</a>) were robustly induced by smoking, an effect that was reduced by alcohol coexposure. Bonferroni post hoc analyses identified a relative increase in SLC1A2 mRNA levels by real-time PCR analysis in chronic smokers with and without alcohol abuse compared with nonsmoking alcoholics (3.99 times, p = 6 x 10(-3); 2.94 times, p = 6 x 10(-3), respectively), although this was not significant at the protein level. There was a striking induction of higher SLC17A6 relative expression in nonalcoholic smokers compared with controls (27.91 times, p = 2 x 10(-7)), as well as smoking chronic alcoholics (3.08 times, p = 3 x 10(-2)) and nonsmoking chronic alcoholics (13.27 times, p = 3 x 10(-6)). Additionally, relative SLC17A6 expression was significantly elevated in smoking chronic alcoholics compared with controls (9.06 times, p = 10(-4)) and nonsmoking alcohol abusers (4.31 times, p = 3 x 10(-3)). Relative SLC17A7 transcription was highly induced in heavy smokers compared with controls (18.64 times, p = 5 x 10(-3)), nonsmoking alcoholics, (15.16 times, p = 2 x 10(-3)), and smoking chronic alcoholics (9.97 times, p = 6 x 10(-4)). Glutamatergic transmission is vital for the control of the VTA and may also be critical to the weighting of novelty and importance of a stimulus, an essential output of this brain region. <a href="#5" class="mim-tip-reference" title="Flatscher-Bader, T., Zuvela, N., Landis, N., Wilce, P. A. <strong>Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area.</strong> Hum. Molec. Genet. 17: 38-51, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17928304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17928304</a>] [<a href="https://doi.org/10.1093/hmg/ddm283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17928304">Flatscher-Bader et al. (2008)</a> concluded that plasticity within the VTA may be a major molecular mechanism for the maintenance of smoking addiction and that alcohol, nicotine, and coabuse have distinct impacts on neuronal plasticity and glutamatergic transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17928304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Dopamine Transporter/Receptors</em></strong></p><p>
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<a href="#26" class="mim-tip-reference" title="Sabol, S. Z., Nelson, M. L., Fisher, C., Gunzerath, L., Brody, C. L., Hu, S., Sirota, L. A., Marcus, S. E., Greenberg, B. D., Lucas, F. R., IV, Benjamin, J., Murphy, D. L., Hamer, D. H. <strong>A genetic association for cigarette smoking behavior.</strong> Health Psychol. 18: 7-13, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925040</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925040">Sabol et al. (1999)</a> and <a href="#15" class="mim-tip-reference" title="Lerman, C., Caporaso, N. E., Audrain, J., Main, D., Bowman, E. D., Lockshin, B., Boyd, N. R., Shields, P. G. <strong>Evidence suggesting the role of specific genetic factors in cigarette smoking.</strong> Health Psychol. 18: 14-20, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925041</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925041">Lerman et al. (1999)</a> found a significant association between a particular polymorphism of the dopamine transporter gene SLC6A3 (<a href="/entry/126455">126455</a>) and smoking status. Individuals with the SLC6A3*9 allele were significantly less likely to be smokers, especially if they also had the DRD2*A2 genotype at the dopamine receptor D2 locus (DRD2; <a href="/entry/126450">126450</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9925041+9925040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The search for susceptibility loci for smoking-related behavior was discussed by <a href="#16" class="mim-tip-reference" title="Li, M. D., Ma, J. Z., Beuten, J. <strong>Progress in searching for susceptibility loci and genes for smoking-related behaviour.</strong> Clin. Genet. 66: 382-392, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15479180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15479180</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00302.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15479180">Li et al. (2004)</a>. The review included a metaanalysis of 12 reported studies showing a significantly higher prevalence of the DRD2 TaqI A1 allele in smokers than in nonsmokers. For other candidate genes, insufficient published studies were available to allow a metaanalysis to be performed, or metaanalysis showed no significant difference between smokers and nonsmokers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15479180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Huang, W., Ma, J. Z., Payne, T. J., Beuten, J., Dupont, R. T., Li, M. D. <strong>Significant association of DRD1 with nicotine dependence.</strong> Hum. Genet. 123: 133-140, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18092181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18092181</a>] [<a href="https://doi.org/10.1007/s00439-007-0453-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18092181">Huang et al. (2008)</a> found a significant association between nicotine dependence and a SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs686;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs686</a>) in the DRD1 gene (<a href="/entry/126449">126449</a>) among 1,366 African Americans. In a pooled sample of 1,366 African Americans and 671 European Americans, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs686;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs686</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4532;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4532</a> were both significantly associated with nicotine dependence. Several haplotypes related to these SNPs also suggested an association. In vitro functional expression studies indicated that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs686;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs686</a>, which is located in the 3-prime untranslated region, is functionally involved in the regulation of DRD1 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18092181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>DOPA Decarboxylase</em></strong></p><p>
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DOPA decarboxylase (DDC; <a href="/entry/107930">107930</a>) is involved in the synthesis of dopamine, norepinephrine, and serotonin, and is located on chromosome 7p11, which showed a 'suggestive linkage' to nicotine dependence (ND) in a genomewide scan in the Framingham Heart Study population. <a href="#23" class="mim-tip-reference" title="Ma, J. Z., Beuten, J., Payne, T. J., Dupont, R. T., Elston, R. C., Li, M. D. <strong>Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence.</strong> Hum. Molec. Genet. 14: 1691-1698, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15879433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15879433</a>] [<a href="https://doi.org/10.1093/hmg/ddi177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15879433">Ma et al. (2005)</a> tested 8 SNPs within DDC for association with ND, which was assessed by smoking quantity (SQ), heaviness of smoking index (HSI), and the Fagerstrom test for ND (FTND) score, in a total of 2,037 smokers and nonsmokers from 602 nuclear families of African American or European American ancestry. Association analysis for individual SNPs indicated that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs921451;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs921451</a> was significantly associated with 2 of the 3 adjusted ND measures in European Americans. Haplotype-based association analysis revealed a protective T-G-T-G haplotype for <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs921451;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs921451</a>-<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3735273;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3735273</a>-<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1451371;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1451371</a>-<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2060762;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2060762</a> in African Americans, which was significantly associated with all 3 adjusted ND measures after correction for multiple testing. In contrast, the authors found a high-risk T-G-T-G haplotype for a different SNP combination in European Americans, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs921451;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs921451</a>-<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3735273;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3735273</a>-<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1451371;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1451371</a>-<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3757472;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3757472</a>, which showed a significant association with the SQ and FTND score. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15879433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cholinergic Receptors</em></strong></p><p>
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Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine were logical candidates for vulnerability to nicotine addiction. <a href="#4" class="mim-tip-reference" title="Feng, Y., Niu, T., Xing, H., Xu, X., Chen, C., Peng, S., Wang, L., Laird, N., Xu, X. <strong>A common haplotype of the nicotine acetylcholine receptor alpha-4 subunit gene is associated with vulnerability to nicotine addiction in men.</strong> Am. J. Hum. Genet. 75: 112-121, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15154117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15154117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15154117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/422194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15154117">Feng et al. (2004)</a> studied 6 SNPs in the CHRNA4 gene (<a href="/entry/118504">118504</a>) on chromosome 20q13.2-q13.3 and 4 SNPs in the CHRNB2 gene (<a href="/entry/118507">118507</a>) on chromosome 1q21 in relation to nicotine dependence in a collection of 901 subjects (815 sibs and 86 parents) from 222 nuclear families with multiple nicotine-addicted sibs. Because only 5.8% of female offspring were smokers, only male subjects were included in the final analyses. Univariate (single-marker) family-based association tests (FBATs) demonstrated that variant alleles of 2 SNPs in exon 5 of the CHRNA4 gene (<a href="/entry/118504#0005">118504.0005</a>, <a href="/entry/118504#0006">118504.0006</a>) were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype. Furthermore, the haplotype-specific FBAT showed a common (22.5%) CHRNA4 haplotype that was significantly associated with a protective effect against nicotine addiction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15154117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The determination of gene-by-gene and gene-by-environment interactions represents one of the greatest challenges in genetics. Combinatorial approaches, such as the multifactor dimensionality reduction (MDR) method of <a href="#25" class="mim-tip-reference" title="Ritchie, M. D., Hahn, L. W., Roodi, N., Bailey, L. R., Dupont, W. D., Parl, F. F., Moore, J. H. <strong>Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer.</strong> Am. J. Hum. Genet. 69: 138-147, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11404819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11404819</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11404819[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/321276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11404819">Ritchie et al. (2001)</a>, are useful but have limitations such as not allowing for covariates that restrict their practical use. <a href="#21" class="mim-tip-reference" title="Lou, X.-Y., Chen, G.-B., Yan, L., Ma, J. Z., Zhu, J., Elston, R. C., Li, M. D. <strong>A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence.</strong> Am. J. Hum. Genet. 80: 1125-1137, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503330[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/518312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503330">Lou et al. (2007)</a> reported a generalized MDR (GMDR) method that permitted adjustment for discrete and quantitative covariates and was applicable to both dichotomous and continuous phenotypes in population-based studies of various designs. Computer simulations indicated that the GMDR method had superior performance in its ability to identify epistatic loci, compared with current methods in the literature. <a href="#21" class="mim-tip-reference" title="Lou, X.-Y., Chen, G.-B., Yan, L., Ma, J. Z., Zhu, J., Elston, R. C., Li, M. D. <strong>A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence.</strong> Am. J. Hum. Genet. 80: 1125-1137, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503330[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/518312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503330">Lou et al. (2007)</a> applied the method to a genetic study of 4 genes that were reported to be associated with nicotine dependence: CHRNA2 (<a href="/entry/118502">118502</a>), CHRNB4 (<a href="/entry/118509">118509</a>), BDNF (<a href="/entry/113503">113503</a>), and NTRK2 (<a href="/entry/600456">600456</a>). They found significant joint action between CHRNB4 and NTRK2. <a href="#21" class="mim-tip-reference" title="Lou, X.-Y., Chen, G.-B., Yan, L., Ma, J. Z., Zhu, J., Elston, R. C., Li, M. D. <strong>A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence.</strong> Am. J. Hum. Genet. 80: 1125-1137, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503330[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/518312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503330">Lou et al. (2007)</a> commented that ubiquity of joint actions appears to be a natural property of complex inherited traits and that the term 'epistasis,' coined for a specific type of gene-by-gene interaction, has evolved to have different meanings in biologic and statistical genetics. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17503330+11404819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Thorgeirsson, T. E., Geller, F., Sulem, P., Rafnar, T., Wiste, A., Magnusson, K. P., Manolescu, A., Thorleifsson, G., Stefansson, H., Ingason, A., Stacey, S. N., Bergthorsson, J. T., and 45 others. <strong>A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.</strong> Nature 452: 638-641, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385739</a>] [<a href="https://doi.org/10.1038/nature06846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385739">Thorgeirsson et al. (2008)</a> identified a common variant, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1051730;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1051730</a>, in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, nicotine dependence, and the risk of 2 smoking-related diseases (lung cancer and peripheral artery disease) in populations of European descent. The SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1051730;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1051730</a>, which resides in the CHRNA3 gene (<a href="/entry/118503#0001">118503.0001</a>), was strongly associated with smoking quantity (P = 5 x 10(-16)). The same variant was associated with nicotine dependence in a previous genomewide association study that used low-quantity smokers as controls (<a href="#27" class="mim-tip-reference" title="Saccone, S. F., Hinrichs, A. L., Saccone, N. L., Chase, G. A., Konvicka, K., Madden, P. A., Breslau, N., Johnson, E. O., Hatsukami, D., Pomerleau, O., Swan, G. E., Goate, A. M., and 10 others. <strong>Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.</strong> Hum. Molec. Genet. 16: 36-49, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17135278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17135278</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17135278[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddl438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17135278">Saccone et al., 2007</a>; <a href="#2" class="mim-tip-reference" title="Bierut, L. J., Madden, P. A., Breslau, N., Johnson, E. O., Hatsukami, D., Pomerleau, O. F., Swan, G. E., Rutter, J., Bertelsen, S., Fox, L., Fugman, D., Goate, A. M., and 10 others. <strong>Novel genes identified in a high-density genome wide association study for nicotine dependence.</strong> Hum. Molec. Genet. 16: 24-35, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17158188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17158188</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17158188[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddl441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17158188">Bierut et al., 2007</a>). With a similar approach, <a href="#30" class="mim-tip-reference" title="Thorgeirsson, T. E., Geller, F., Sulem, P., Rafnar, T., Wiste, A., Magnusson, K. P., Manolescu, A., Thorleifsson, G., Stefansson, H., Ingason, A., Stacey, S. N., Bergthorsson, J. T., and 45 others. <strong>A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.</strong> Nature 452: 638-641, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385739</a>] [<a href="https://doi.org/10.1038/nature06846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385739">Thorgeirsson et al. (2008)</a> observed a highly significant association with nicotine dependence. The authors also demonstrated an association with lung cancer in a gene-environment interaction; see <a href="/entry/612052">612052</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17158188+18385739+17135278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Keskitalo, K., Broms, U., Heliovaara, M., Ripatti, S., Surakka, I., Perola, M., Pitkaniemi, J., Peltonen, L., Aromaa, A., Kaprio, J. <strong>Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15.</strong> Hum. Molec. Genet. 18: 4007-4012, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19628476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19628476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19628476[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19628476">Keskitalo et al. (2009)</a> measured the number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level (a nicotine metabolite) in 516 daily smokers (aged 30-75 years; 303 males and 213 females) from an adult Finnish population. Association of 21 SNPs from a 100-kb region of chromosome 15q25.1 with cotinine and CPD were examined. The SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1051730;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1051730</a> showed the strongest association to both measures; however, this SNP accounted for nearly a 5-fold larger proportion of variance in cotinine levels than in CPD (R(2) 4.3% vs 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. <a href="#12" class="mim-tip-reference" title="Keskitalo, K., Broms, U., Heliovaara, M., Ripatti, S., Surakka, I., Perola, M., Pitkaniemi, J., Peltonen, L., Aromaa, A., Kaprio, J. <strong>Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15.</strong> Hum. Molec. Genet. 18: 4007-4012, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19628476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19628476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19628476[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19628476">Keskitalo et al. (2009)</a> concluded that variation at the CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19628476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Hong, L. E., Hodgkinson, C. A., Yang, Y., Sampath, H., Ross, T. J., Buchholz, B., Salmeron, B. J., Srivastava, V., Thaker, G. K., Goldman, D., Stein, E. A. <strong>A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction.</strong> Proc. Nat. Acad. Sci. 107: 13509-13514, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20643934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20643934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20643934[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1004745107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20643934">Hong et al. (2010)</a> found a significant association (p = 0.020) between the CHRNA5 D398N variant (<a href="/entry/118505#0001">118505.0001</a>) and smoking among 149 smokers and 148 nonsmokers (odds ratio of 1.84, p = 0.03 for 1 allele; odds ratio of 3.59, p = 0.032 for 2 alleles). The sample included individuals with psychiatric illnesses, which are associated with smoking; however, the D398N variant was not associated with psychiatric illness. Among 93 smokers and 79 nonsmokers who completed a functional MRI scan, smokers had significantly decreased functional connectivity between the dorsal anterior cingulate (dACC)-ventral striatum compared to nonsmokers, and the decrease was associated with the N389 risk allele. In addition, reduced connectivity of this circuit correlated with greater severity of nicotine addiction. Nonsmoker carriers of the N389 risk allele also showed reduced connectivity of this circuit, confirming a genetic effect independent of smoking status. <a href="#10" class="mim-tip-reference" title="Hong, L. E., Hodgkinson, C. A., Yang, Y., Sampath, H., Ross, T. J., Buchholz, B., Salmeron, B. J., Srivastava, V., Thaker, G. K., Goldman, D., Stein, E. A. <strong>A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction.</strong> Proc. Nat. Acad. Sci. 107: 13509-13514, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20643934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20643934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20643934[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1004745107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20643934">Hong et al. (2010)</a> postulated that variation in the nAChR alpha-4/beta-2/alpha-5 receptor may modulate dopamine release, which may regulate the reinforcing effects and addictive properties of nicotine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20643934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>G Protein-Coupled Receptor-51</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Beuten, J., Ma, J. Z., Payne, T. J., Dupont, R. T., Crews, K. M., Somes, G., Williams, N. J., Elston, R. C., Li, M. D. <strong>Single- and multilocus allelic variants with the GABA(B) receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence.</strong> Am. J. Hum. Genet. 76: 859-864, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15759211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15759211</a>] [<a href="https://doi.org/10.1086/429839" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15759211">Beuten et al. (2005)</a> concluded from findings in association studies that variants in the GABABR2 gene (<a href="/entry/607340">607340</a>), which encodes subunit 2 of the gamma-aminobutyric acid type B receptor, play an important role in the etiology of nicotine dependence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15759211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Serotonin Transporter</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Gerra, G., Garofano, L., Zaimovic, A., Moi, G., Branchi, B., Bussandri, M., Brambilla, F., Donnini, C. <strong>Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents.</strong> Am. J. Med. Genet. Neuropsychiat. Genet. 135B: 73-78, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15806583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15806583</a>] [<a href="https://doi.org/10.1002/ajmg.b.30173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15806583">Gerra et al. (2005)</a> examined the association of the serotonin transporter promoter polymorphism (SLC6A4; <a href="/entry/182138#0001">182138.0001</a>) with smoking behavior among adolescents. They genotyped 210 Caucasian high school students, including 103 nonsmokers and 107 tobacco smokers, aged 14 to 19 years. They also assessed aggressiveness levels, temperamental traits, and school performance. Short-short (SS) genotype frequency was higher among smokers compared to nonsmokers (p = 0.023). The odds ratio for the SS genotype versus the long-long (LL) genotype frequency was 1.17 (95% CI, 0.30-2.05) when smokers were compared with nonsmokers. The SS genotype frequency was higher among heavy smokers with early onset compared with moderate smokers with late onset (p = 0.042). Irritability scores and school failure frequency were significantly higher in the smokers than in the nonsmokers. Multivariate model-fitting analyses evidenced a significantly greater relationship of genotype with irritability levels (0.34, p less than 0.001) and temperament traits (0.36, p less than 0.001) than with school performance (rate of school underachievement, 0.18, p less than 0.05) and nicotine smoking (0.24, p less than 0.01). <a href="#7" class="mim-tip-reference" title="Gerra, G., Garofano, L., Zaimovic, A., Moi, G., Branchi, B., Bussandri, M., Brambilla, F., Donnini, C. <strong>Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents.</strong> Am. J. Med. Genet. Neuropsychiat. Genet. 135B: 73-78, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15806583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15806583</a>] [<a href="https://doi.org/10.1002/ajmg.b.30173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15806583">Gerra et al. (2005)</a> suggested that decreased expression of the SLC6A4 gene caused by the S allele may be associated with smoking behavior among adolescents and with increased risk for developing nicotine dependence, possibly in relationship to personality traits, temperamental characteristics, and school underachievement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15806583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Kremer, I., Bachner-Melman, R., Reshef, A., Broude, L., Nemanov, L., Gritsenko, I., Heresco-Levy, U., Elizur, Y., Ebstein, R. P. <strong>Association of the serotonin transporter gene with smoking behavior.</strong> Am. J. Psychiat. 162: 924-930, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15863794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15863794</a>] [<a href="https://doi.org/10.1176/appi.ajp.162.5.924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15863794">Kremer et al. (2005)</a> studied 330 families and 244 individuals who had ever smoked (54 past smokers, 190 current smokers) along with various personality measures by genotyping them for the serotonin transporter gene promoter polymorphism. In contrast to the findings of <a href="#7" class="mim-tip-reference" title="Gerra, G., Garofano, L., Zaimovic, A., Moi, G., Branchi, B., Bussandri, M., Brambilla, F., Donnini, C. <strong>Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents.</strong> Am. J. Med. Genet. Neuropsychiat. Genet. 135B: 73-78, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15806583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15806583</a>] [<a href="https://doi.org/10.1002/ajmg.b.30173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15806583">Gerra et al. (2005)</a>, they found a significant excess of the long allele of the SLC6A4 promoter polymorphism in current smokers, past smokers, and ever smokers compared to participants who had never smoked. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15863794+15806583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Taste Receptor Polymorphisms</em></strong></p><p>
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<a href="#24" class="mim-tip-reference" title="Mangold, J. E., Payne, T. J., Ma, J. Z., Chen, F., Li, M. D. <strong>Bitter taste receptor gene polymorphisms are an important factor in the development of nicotine dependence in African Americans.</strong> J. Med. Genet. 45: 578-582, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18524836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18524836</a>] [<a href="https://doi.org/10.1136/jmg.2008.057844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18524836">Mangold et al. (2008)</a> presented evidence suggesting that the 3 SNPs in the TAS2R38 gene (<a href="/entry/607751#0001">607751.0001</a>-<a href="/entry/607751#0003">607751.0003</a>) identified by <a href="#13" class="mim-tip-reference" title="Kim, U., Jorgenson, E., Coon, H., Leppert, M., Risch, N., Drayna, D. <strong>Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide.</strong> Science 299: 1221-1225, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12595690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12595690</a>] [<a href="https://doi.org/10.1126/science.1080190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12595690">Kim et al. (2003)</a> may play a role in the development of nicotine dependence among African Americans. The taster haplotype PAV was inversely associated (p = 0.0165), and the nontaster haplotype AVI was positively associated (p = 0.0120), with smoking quantity in a study of 1,053 African American smokers. The nontaster haplotype was positively associated with all measures of nicotine dependence in female African American smokers (p = 0.01-0.003). No significant associations were observed in a sample of 515 European smokers. <a href="#24" class="mim-tip-reference" title="Mangold, J. E., Payne, T. J., Ma, J. Z., Chen, F., Li, M. D. <strong>Bitter taste receptor gene polymorphisms are an important factor in the development of nicotine dependence in African Americans.</strong> J. Med. Genet. 45: 578-582, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18524836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18524836</a>] [<a href="https://doi.org/10.1136/jmg.2008.057844" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18524836">Mangold et al. (2008)</a> postulated that heightened oral sensitivity confers protection against nicotine dependence. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18524836+12595690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1093/hmg/ddl441" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199209173271201" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15154117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15154117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15154117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15154117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/422194" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17928304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17928304</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17928304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm283" target="_blank">Full Text</a>]
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Gerra, G., Garofano, L., Zaimovic, A., Moi, G., Branchi, B., Bussandri, M., Brambilla, F., Donnini, C.
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<strong>Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents.</strong>
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[<a href="https://doi.org/10.1016/0306-4603(93)90005-t" target="_blank">Full Text</a>]
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Hong, L. E., Hodgkinson, C. A., Yang, Y., Sampath, H., Ross, T. J., Buchholz, B., Salmeron, B. J., Srivastava, V., Thaker, G. K., Goldman, D., Stein, E. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20643934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20643934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20643934[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20643934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.1004745107" target="_blank">Full Text</a>]
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<a id="Huang2008" class="mim-anchor"></a>
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Huang, W., Ma, J. Z., Payne, T. J., Beuten, J., Dupont, R. T., Li, M. D.
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<strong>Significant association of DRD1 with nicotine dependence.</strong>
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Hum. Genet. 123: 133-140, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18092181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18092181</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18092181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-007-0453-9" target="_blank">Full Text</a>]
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<a id="Keskitalo2009" class="mim-anchor"></a>
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<strong>Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddp322" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1080190" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1037//0278-6133.18.1.14" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/508208" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-008-0473-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19980508)81:3<216::aid-ajmg2>3.0.co;2-u" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.tpj.6500464" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.057844" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1037//0278-6133.18.1.7" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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|
Saccone, S. F., Pergadia, M. L., Loukola, A., Broms, U., Montgomery, G. W., Wang, J. C., Agrawal, A., Dick, D. M., Heath, A. C., Todorov, A. A., Maunu, H., Heikkila, K., Morley, K. I., Rice, J. P., Todd, R. D., Kaprio, J., Peltonen, L., Martin, N. G., Goate, A. M., Madden, P. A. F.
|
|
<strong>Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples.</strong>
|
|
Am. J. Hum. Genet. 80: 856-866, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
|
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|
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[<a href="https://doi.org/10.1086/513703" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="{The Tobacco and Genetics Consortium}2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
The Tobacco and Genetics Consortium.
|
|
<strong>Genome-wide meta-analyses identify multiple loci associated with smoking behavior. (Letter)</strong>
|
|
Nature Genet. 42: 441-447, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20418890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.571" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
|
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<a id="30" class="mim-anchor"></a>
|
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<a id="Thorgeirsson2008" class="mim-anchor"></a>
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|
<div class="">
|
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<p class="mim-text-font">
|
|
Thorgeirsson, T. E., Geller, F., Sulem, P., Rafnar, T., Wiste, A., Magnusson, K. P., Manolescu, A., Thorleifsson, G., Stefansson, H., Ingason, A., Stacey, S. N., Bergthorsson, J. T., and 45 others.
|
|
<strong>A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.</strong>
|
|
Nature 452: 638-641, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18385739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature06846" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="31" class="mim-anchor"></a>
|
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<a id="Thorgeirsson2010" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Thorgeirsson, T. E., Gudbjartsson, D. F., Surakka, I., Vink, J. M., Amin, N., Geller, F., Sulem, P., Rafnar, T., Esko, T., Walter, S., Gieger, C., Rawal, R., and 83 others.
|
|
<strong>Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.</strong>
|
|
Nature Genet. 42: 448-453, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418888</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20418888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1038/ng.573" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
|
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
|
</span>
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Cassandra L. Kniffin - updated : 4/23/2012
|
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</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
George E. Tiller - updated : 8/12/2010<br>Cassandra L. Kniffin - updated : 5/11/2010<br>Cassandra L. Kniffin - updated : 9/14/2009<br>Cassandra L. Kniffin - updated : 1/15/2009<br>Cassandra L. Kniffin - updated : 10/3/2008<br>George E. Tiller - updated : 6/16/2008<br>Ada Hamosh - updated : 5/16/2008<br>Cassandra L. Kniffin - updated : 4/11/2008<br>Victor A. McKusick - updated : 5/29/2007<br>Victor A. McKusick - updated : 9/26/2006<br>John Logan Black, III - updated : 4/6/2006<br>John Logan Black, III - updated : 8/9/2005<br>Victor A. McKusick - updated : 4/28/2005<br>Victor A. McKusick - updated : 4/13/2005<br>Victor A. McKusick - updated : 6/30/2004<br>Victor A. McKusick - updated : 3/11/1999
|
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</span>
|
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
|
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
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</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Victor A. McKusick : 9/21/1992
|
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</span>
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</div>
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</div>
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</div>
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<div>
|
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
carol : 06/04/2019
|
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</span>
|
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</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
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carol : 01/16/2019<br>carol : 07/30/2018<br>joanna : 08/04/2016<br>carol : 04/25/2012<br>ckniffin : 4/23/2012<br>wwang : 8/12/2010<br>alopez : 5/12/2010<br>ckniffin : 5/11/2010<br>wwang : 10/6/2009<br>ckniffin : 9/14/2009<br>wwang : 1/21/2009<br>ckniffin : 1/15/2009<br>wwang : 10/7/2008<br>ckniffin : 10/3/2008<br>wwang : 6/20/2008<br>terry : 6/16/2008<br>terry : 6/16/2008<br>alopez : 5/16/2008<br>wwang : 4/18/2008<br>ckniffin : 4/11/2008<br>alopez : 5/29/2007<br>alopez : 5/8/2007<br>terry : 9/26/2006<br>terry : 8/24/2006<br>carol : 4/7/2006<br>terry : 4/6/2006<br>carol : 8/9/2005<br>terry : 8/9/2005<br>tkritzer : 5/12/2005<br>terry : 4/28/2005<br>alopez : 4/14/2005<br>terry : 4/13/2005<br>alopez : 7/19/2004<br>alopez : 7/19/2004<br>terry : 6/30/2004<br>terry : 6/9/1999<br>carol : 3/16/1999<br>terry : 3/16/1999<br>terry : 3/11/1999<br>mimadm : 5/10/1995<br>davew : 7/18/1994<br>warfield : 4/21/1994<br>carol : 9/21/1992
|
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</span>
|
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</div>
|
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
|
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<h3>
|
|
<span class="mim-font">
|
|
<strong>#</strong> 188890
|
|
</span>
|
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</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
TOBACCO ADDICTION, SUSCEPTIBILITY TO
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
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</div>
|
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<div>
|
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<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
CIGARETTE HABITUATION, SUSCEPTIBILITY TO<br />
|
|
SMOKING HABIT, SUSCEPTIBILITY TO<br />
|
|
NICOTINE DEPENDENCE, SUSCEPTIBILITY TO<br />
|
|
NICOTINE ADDICTION, SUSCEPTIBILITY TO<br />
|
|
NICOTINE DEPENDENCE, PROTECTION AGAINST
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
5p15.33
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Nicotine dependence, protection against}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
188890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
SLC6A3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
126455
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
9q22.33
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Nicotine dependence, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
188890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
GABBR2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607340
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
9q22.33
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Nicotine dependence, protection against}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
188890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
GABBR2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607340
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
19q13.2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Nicotine addiction, protection from}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
188890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
CYP2A6
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
122720
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
20q13.33
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Nicotine addiction, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
188890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
CHRNA4
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
118504
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because polymorphisms in several genes are believed to predispose to nicotine dependence and smoking behavior, including the gene encoding G protein-coupled receptor-51 (GPR51; 607340) on chromosome 9q22.</p><p>Li et al. (2006) found evidence of significant linkage of chromosome 10q22-q25 to smoking quantity (SQTL1; 611003). Saccone et al. (2007) found evidence of linkage of chromosome 22q12 to a heavy smoking phenotype (SQTL2; 611004). See also SQTL3 (612052), which is associated with polymorphisms in the nicotinic acetylcholine receptor gene cluster on chromosome 15q25.1. </p><p>Li (2008) provided a review of susceptibility loci for nicotine dependence identified to date. Thirteen regions, located on chromosomes 3 through 7, 9 through 11, 17, 20, and 22 are suggestive or significant in at least 2 independent samples. </p>
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<strong>Inheritance</strong>
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<p>Evidence for moderate genetic influences on lifetime smoking practices was found by Carmelli et al. (1992) in an analysis of male twins in the National Academy of Sciences--National Research Twin Registry. The registry included male twins who were born in the United States between 1917 and 1927 and who were members of the Armed Forces during World World II. Information on smoking history was available for 4,775 pairs of twins who were first surveyed when they were in their forties and then resurveyed when they were aged 56 to 66. Eighty percent of the subjects had smoked at some time, 60% were still smokers in their forties, and 39% were smoking at the time of the resurvey. Monozygotic twins showed a higher concordance rate than dizygotic twins for having never smoked, for continuing to smoke, for quitting smoking, and for cigar or pipe smoking. For moderate smokers, there was no evidence of either familial or genetic influences; genetic factors seemed to contribute only in light smokers and heavy smokers. A metaanalysis of the data from 5 studies, each involving more than 1,000 twin pairs, showed an estimated heritability of 60% for the propensity to smoke (Heath and Madden, 1995). Twin studies also showed that the genetic factors involved in the initiation and cessation of smoking are partially overlapping but mostly independent (Heath and Martin, 1993). </p>
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<strong>Mapping</strong>
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<p>Gelernter et al. (2004) completed a genomewide scan to map loci increasing the risk for cigarette smoking in a set of families originally identified because they segregated panic disorder. They studied 142 genotyped individuals in a total of 12 families. Of these, 69 individuals were affected with habitual cigarette smoking. The 3 highest multipoint Zlr scores (3.43, 3.04, and 3.01; p = 0.0003, 0.0012, and 0.0013, respectively) reflected suggestive evidence for linkage and were observed in multipoint linkage analyses on chromosomes 11p and 9. Gelernter et al. (2004) noted that the chromosome 11 region has previously been linked to alcohol dependence and illegal drug abuse (e.g., Long et al., 1998), while the chromosome 9 region has previously been identified as significantly linked to panic disorder in Icelandic pedigrees (see 607853). </p><p>In a genomewide scan of 505 individuals consisting mostly of dizygotic twin pairs from 153 Finnish families ascertained for nicotine dependence, Loukola et al. (2008) found suggestive evidence for linkage to chromosomes 7q31 and 11p15 (maximum lod scores of 2.50 at D7S486 and 2.25 at D11S4181, respectively). Both regions also showed evidence for linkage to the comorbid phenotype of smoking and alcohol use. A male-specific locus for isolated smoking and for the comorbid phenotype was also found at chromosome 7q35 (maximum 2-point lod scores of 2.90 and 2.74 at D7S661, respectively). Loukola et al. (2008) suggested that these findings may represent shared genetic etiology for these traits. </p><p>The Tobacco and Genetics Consortium (2010) reported the findings of genomewide association studies for number of cigarettes smoked per day among 73,853 European individuals from multiple different cohorts, including those of Liu et al. (2010) and Thorgeirsson et al. (2010). An association was also found for the G allele of rs3733829 in the EGLN2 gene (606424) on chromosome 19q13 (p = 1.04 x 10(-8)). </p><p>One part of this cohort was reported independently and simultaneously by Thorgeirsson et al. (2010), who conducted genomewide association metaanalyses for the number of cigarettes smoked per day among 31,266 individuals. Significant associations were found with the C allele of rs4105144 on 19q13 (p = 1.2 x 10(-9)). When combined with the studies of The Tobacco and Genetics Consortium (2010) and Liu et al. (2010) (n = 83,317), the p value for rs4105144 became 2.2 x 10(-12). Thorgeirsson et al. (2010) also found an association with the T allele of rs6474412 on chromosome 8p11 (p = 1.4 x 10(-8)) when combining the 3 studies. These 2 loci include genes involved in nicotine metabolism, such as CYP2A6 (122720) and CYP2B6 (123930) on 19q13, and nicotinic acetylcholine receptor subunits on 8p11 (CHRNB3; 118508) and CHRNA6 (606888). No associations were found when considering smoking initiation. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Glutamate Transporters</em></strong></p><p>
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In a group of 23 individuals, including 5 nonalcoholic nonsmokers, 5 alcoholic nonsmokers, 7 nonalcoholic smokers, and 6 alcoholic smokers, Flatscher-Bader et al. (2008) found that expression levels of the glutamate transporters SLC1A2 (600300), SLC17A6 (607563), and SLC17A7 (605208) were robustly induced by smoking, an effect that was reduced by alcohol coexposure. Bonferroni post hoc analyses identified a relative increase in SLC1A2 mRNA levels by real-time PCR analysis in chronic smokers with and without alcohol abuse compared with nonsmoking alcoholics (3.99 times, p = 6 x 10(-3); 2.94 times, p = 6 x 10(-3), respectively), although this was not significant at the protein level. There was a striking induction of higher SLC17A6 relative expression in nonalcoholic smokers compared with controls (27.91 times, p = 2 x 10(-7)), as well as smoking chronic alcoholics (3.08 times, p = 3 x 10(-2)) and nonsmoking chronic alcoholics (13.27 times, p = 3 x 10(-6)). Additionally, relative SLC17A6 expression was significantly elevated in smoking chronic alcoholics compared with controls (9.06 times, p = 10(-4)) and nonsmoking alcohol abusers (4.31 times, p = 3 x 10(-3)). Relative SLC17A7 transcription was highly induced in heavy smokers compared with controls (18.64 times, p = 5 x 10(-3)), nonsmoking alcoholics, (15.16 times, p = 2 x 10(-3)), and smoking chronic alcoholics (9.97 times, p = 6 x 10(-4)). Glutamatergic transmission is vital for the control of the VTA and may also be critical to the weighting of novelty and importance of a stimulus, an essential output of this brain region. Flatscher-Bader et al. (2008) concluded that plasticity within the VTA may be a major molecular mechanism for the maintenance of smoking addiction and that alcohol, nicotine, and coabuse have distinct impacts on neuronal plasticity and glutamatergic transmission. </p><p><strong><em>Dopamine Transporter/Receptors</em></strong></p><p>
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Sabol et al. (1999) and Lerman et al. (1999) found a significant association between a particular polymorphism of the dopamine transporter gene SLC6A3 (126455) and smoking status. Individuals with the SLC6A3*9 allele were significantly less likely to be smokers, especially if they also had the DRD2*A2 genotype at the dopamine receptor D2 locus (DRD2; 126450). </p><p>The search for susceptibility loci for smoking-related behavior was discussed by Li et al. (2004). The review included a metaanalysis of 12 reported studies showing a significantly higher prevalence of the DRD2 TaqI A1 allele in smokers than in nonsmokers. For other candidate genes, insufficient published studies were available to allow a metaanalysis to be performed, or metaanalysis showed no significant difference between smokers and nonsmokers. </p><p>Huang et al. (2008) found a significant association between nicotine dependence and a SNP (rs686) in the DRD1 gene (126449) among 1,366 African Americans. In a pooled sample of 1,366 African Americans and 671 European Americans, rs686 and rs4532 were both significantly associated with nicotine dependence. Several haplotypes related to these SNPs also suggested an association. In vitro functional expression studies indicated that rs686, which is located in the 3-prime untranslated region, is functionally involved in the regulation of DRD1 expression. </p><p><strong><em>DOPA Decarboxylase</em></strong></p><p>
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DOPA decarboxylase (DDC; 107930) is involved in the synthesis of dopamine, norepinephrine, and serotonin, and is located on chromosome 7p11, which showed a 'suggestive linkage' to nicotine dependence (ND) in a genomewide scan in the Framingham Heart Study population. Ma et al. (2005) tested 8 SNPs within DDC for association with ND, which was assessed by smoking quantity (SQ), heaviness of smoking index (HSI), and the Fagerstrom test for ND (FTND) score, in a total of 2,037 smokers and nonsmokers from 602 nuclear families of African American or European American ancestry. Association analysis for individual SNPs indicated that rs921451 was significantly associated with 2 of the 3 adjusted ND measures in European Americans. Haplotype-based association analysis revealed a protective T-G-T-G haplotype for rs921451-rs3735273-rs1451371-rs2060762 in African Americans, which was significantly associated with all 3 adjusted ND measures after correction for multiple testing. In contrast, the authors found a high-risk T-G-T-G haplotype for a different SNP combination in European Americans, rs921451-rs3735273-rs1451371-rs3757472, which showed a significant association with the SQ and FTND score. </p><p><strong><em>Cholinergic Receptors</em></strong></p><p>
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Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine were logical candidates for vulnerability to nicotine addiction. Feng et al. (2004) studied 6 SNPs in the CHRNA4 gene (118504) on chromosome 20q13.2-q13.3 and 4 SNPs in the CHRNB2 gene (118507) on chromosome 1q21 in relation to nicotine dependence in a collection of 901 subjects (815 sibs and 86 parents) from 222 nuclear families with multiple nicotine-addicted sibs. Because only 5.8% of female offspring were smokers, only male subjects were included in the final analyses. Univariate (single-marker) family-based association tests (FBATs) demonstrated that variant alleles of 2 SNPs in exon 5 of the CHRNA4 gene (118504.0005, 118504.0006) were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype. Furthermore, the haplotype-specific FBAT showed a common (22.5%) CHRNA4 haplotype that was significantly associated with a protective effect against nicotine addiction. </p><p>The determination of gene-by-gene and gene-by-environment interactions represents one of the greatest challenges in genetics. Combinatorial approaches, such as the multifactor dimensionality reduction (MDR) method of Ritchie et al. (2001), are useful but have limitations such as not allowing for covariates that restrict their practical use. Lou et al. (2007) reported a generalized MDR (GMDR) method that permitted adjustment for discrete and quantitative covariates and was applicable to both dichotomous and continuous phenotypes in population-based studies of various designs. Computer simulations indicated that the GMDR method had superior performance in its ability to identify epistatic loci, compared with current methods in the literature. Lou et al. (2007) applied the method to a genetic study of 4 genes that were reported to be associated with nicotine dependence: CHRNA2 (118502), CHRNB4 (118509), BDNF (113503), and NTRK2 (600456). They found significant joint action between CHRNB4 and NTRK2. Lou et al. (2007) commented that ubiquity of joint actions appears to be a natural property of complex inherited traits and that the term 'epistasis,' coined for a specific type of gene-by-gene interaction, has evolved to have different meanings in biologic and statistical genetics. </p><p>Thorgeirsson et al. (2008) identified a common variant, rs1051730, in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, nicotine dependence, and the risk of 2 smoking-related diseases (lung cancer and peripheral artery disease) in populations of European descent. The SNP rs1051730, which resides in the CHRNA3 gene (118503.0001), was strongly associated with smoking quantity (P = 5 x 10(-16)). The same variant was associated with nicotine dependence in a previous genomewide association study that used low-quantity smokers as controls (Saccone et al., 2007; Bierut et al., 2007). With a similar approach, Thorgeirsson et al. (2008) observed a highly significant association with nicotine dependence. The authors also demonstrated an association with lung cancer in a gene-environment interaction; see 612052. </p><p>Keskitalo et al. (2009) measured the number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level (a nicotine metabolite) in 516 daily smokers (aged 30-75 years; 303 males and 213 females) from an adult Finnish population. Association of 21 SNPs from a 100-kb region of chromosome 15q25.1 with cotinine and CPD were examined. The SNP rs1051730 showed the strongest association to both measures; however, this SNP accounted for nearly a 5-fold larger proportion of variance in cotinine levels than in CPD (R(2) 4.3% vs 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. Keskitalo et al. (2009) concluded that variation at the CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers. </p><p>Hong et al. (2010) found a significant association (p = 0.020) between the CHRNA5 D398N variant (118505.0001) and smoking among 149 smokers and 148 nonsmokers (odds ratio of 1.84, p = 0.03 for 1 allele; odds ratio of 3.59, p = 0.032 for 2 alleles). The sample included individuals with psychiatric illnesses, which are associated with smoking; however, the D398N variant was not associated with psychiatric illness. Among 93 smokers and 79 nonsmokers who completed a functional MRI scan, smokers had significantly decreased functional connectivity between the dorsal anterior cingulate (dACC)-ventral striatum compared to nonsmokers, and the decrease was associated with the N389 risk allele. In addition, reduced connectivity of this circuit correlated with greater severity of nicotine addiction. Nonsmoker carriers of the N389 risk allele also showed reduced connectivity of this circuit, confirming a genetic effect independent of smoking status. Hong et al. (2010) postulated that variation in the nAChR alpha-4/beta-2/alpha-5 receptor may modulate dopamine release, which may regulate the reinforcing effects and addictive properties of nicotine. </p><p><strong><em>G Protein-Coupled Receptor-51</em></strong></p><p>
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Beuten et al. (2005) concluded from findings in association studies that variants in the GABABR2 gene (607340), which encodes subunit 2 of the gamma-aminobutyric acid type B receptor, play an important role in the etiology of nicotine dependence. </p><p><strong><em>Serotonin Transporter</em></strong></p><p>
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Gerra et al. (2005) examined the association of the serotonin transporter promoter polymorphism (SLC6A4; 182138.0001) with smoking behavior among adolescents. They genotyped 210 Caucasian high school students, including 103 nonsmokers and 107 tobacco smokers, aged 14 to 19 years. They also assessed aggressiveness levels, temperamental traits, and school performance. Short-short (SS) genotype frequency was higher among smokers compared to nonsmokers (p = 0.023). The odds ratio for the SS genotype versus the long-long (LL) genotype frequency was 1.17 (95% CI, 0.30-2.05) when smokers were compared with nonsmokers. The SS genotype frequency was higher among heavy smokers with early onset compared with moderate smokers with late onset (p = 0.042). Irritability scores and school failure frequency were significantly higher in the smokers than in the nonsmokers. Multivariate model-fitting analyses evidenced a significantly greater relationship of genotype with irritability levels (0.34, p less than 0.001) and temperament traits (0.36, p less than 0.001) than with school performance (rate of school underachievement, 0.18, p less than 0.05) and nicotine smoking (0.24, p less than 0.01). Gerra et al. (2005) suggested that decreased expression of the SLC6A4 gene caused by the S allele may be associated with smoking behavior among adolescents and with increased risk for developing nicotine dependence, possibly in relationship to personality traits, temperamental characteristics, and school underachievement. </p><p>Kremer et al. (2005) studied 330 families and 244 individuals who had ever smoked (54 past smokers, 190 current smokers) along with various personality measures by genotyping them for the serotonin transporter gene promoter polymorphism. In contrast to the findings of Gerra et al. (2005), they found a significant excess of the long allele of the SLC6A4 promoter polymorphism in current smokers, past smokers, and ever smokers compared to participants who had never smoked. </p><p><strong><em>Taste Receptor Polymorphisms</em></strong></p><p>
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Mangold et al. (2008) presented evidence suggesting that the 3 SNPs in the TAS2R38 gene (607751.0001-607751.0003) identified by Kim et al. (2003) may play a role in the development of nicotine dependence among African Americans. The taster haplotype PAV was inversely associated (p = 0.0165), and the nontaster haplotype AVI was positively associated (p = 0.0120), with smoking quantity in a study of 1,053 African American smokers. The nontaster haplotype was positively associated with all measures of nicotine dependence in female African American smokers (p = 0.01-0.003). No significant associations were observed in a sample of 515 European smokers. Mangold et al. (2008) postulated that heightened oral sensitivity confers protection against nicotine dependence. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<p class="mim-text-font">
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Beuten, J., Ma, J. Z., Payne, T. J., Dupont, R. T., Crews, K. M., Somes, G., Williams, N. J., Elston, R. C., Li, M. D.
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<strong>Single- and multilocus allelic variants with the GABA(B) receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence.</strong>
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Am. J. Hum. Genet. 76: 859-864, 2005.
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[PubMed: 15759211]
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[Full Text: https://doi.org/10.1086/429839]
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Bierut, L. J., Madden, P. A., Breslau, N., Johnson, E. O., Hatsukami, D., Pomerleau, O. F., Swan, G. E., Rutter, J., Bertelsen, S., Fox, L., Fugman, D., Goate, A. M., and 10 others.
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<strong>Novel genes identified in a high-density genome wide association study for nicotine dependence.</strong>
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Hum. Molec. Genet. 16: 24-35, 2007.
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[PubMed: 17158188]
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Carmelli, D., Swan, G. E., Robinette, D., Fabsitz, R.
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<strong>Genetic influence on smoking--a study of male twins.</strong>
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New Eng. J. Med. 327: 829-833, 1992.
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[Full Text: https://doi.org/10.1056/NEJM199209173271201]
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Feng, Y., Niu, T., Xing, H., Xu, X., Chen, C., Peng, S., Wang, L., Laird, N., Xu, X.
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<strong>A common haplotype of the nicotine acetylcholine receptor alpha-4 subunit gene is associated with vulnerability to nicotine addiction in men.</strong>
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Am. J. Hum. Genet. 75: 112-121, 2004.
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[PubMed: 15154117]
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[Full Text: https://doi.org/10.1086/422194]
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</p>
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<p class="mim-text-font">
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Flatscher-Bader, T., Zuvela, N., Landis, N., Wilce, P. A.
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<strong>Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area.</strong>
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Hum. Molec. Genet. 17: 38-51, 2008.
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[PubMed: 17928304]
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[Full Text: https://doi.org/10.1093/hmg/ddm283]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gelernter, J., Liu, X., Hesselbrock, V., Page, G. P., Goddard, A., Zhang, H.
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<strong>Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking.</strong>
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Am. J. Med. Genet. Neuropsychiat. Genet. 128B: 94-101, 2004.
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[PubMed: 15211640]
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<li>
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<p class="mim-text-font">
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Gerra, G., Garofano, L., Zaimovic, A., Moi, G., Branchi, B., Bussandri, M., Brambilla, F., Donnini, C.
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<strong>Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents.</strong>
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Am. J. Med. Genet. Neuropsychiat. Genet. 135B: 73-78, 2005.
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[PubMed: 15806583]
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[Full Text: https://doi.org/10.1002/ajmg.b.30173]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Heath, A. C., Madden, P. G.
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<strong>Behavior genetic approaches in behavioral medicine. In: Turner, J. R.; Cardon, L. R.; Hewitt, J. K. (eds.): Behavior Genetic Influences on Smoking Behavior.</strong>
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New York: Plenum 1995. Pp. 37-48.
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</p>
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<p class="mim-text-font">
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Heath, A. C., Martin, N. G.
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<strong>Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence.</strong>
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Addictive Behav. 18: 19-34, 1993.
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</li>
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<li>
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Hong, L. E., Hodgkinson, C. A., Yang, Y., Sampath, H., Ross, T. J., Buchholz, B., Salmeron, B. J., Srivastava, V., Thaker, G. K., Goldman, D., Stein, E. A.
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<strong>A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction.</strong>
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Proc. Nat. Acad. Sci. 107: 13509-13514, 2010.
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[PubMed: 20643934]
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</li>
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<li>
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<p class="mim-text-font">
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Huang, W., Ma, J. Z., Payne, T. J., Beuten, J., Dupont, R. T., Li, M. D.
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<strong>Significant association of DRD1 with nicotine dependence.</strong>
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Hum. Genet. 123: 133-140, 2008.
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[PubMed: 18092181]
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[Full Text: https://doi.org/10.1007/s00439-007-0453-9]
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</li>
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<li>
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<p class="mim-text-font">
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Keskitalo, K., Broms, U., Heliovaara, M., Ripatti, S., Surakka, I., Perola, M., Pitkaniemi, J., Peltonen, L., Aromaa, A., Kaprio, J.
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<strong>Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15.</strong>
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Hum. Molec. Genet. 18: 4007-4012, 2009.
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[PubMed: 19628476]
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[Full Text: https://doi.org/10.1093/hmg/ddp322]
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<p>
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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