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Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="qlRpwGIrioeILToeT2GoCdLwb4v71GRJH8Bu9wbNSZ1cFku4wljq6lhaJ8djUhp3">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="qlRpwGIrioeILToeT2GoCdLwb4v71GRJH8Bu9wbNSZ1cFku4wljq6lhaJ8djUhp3">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="qlRpwGIrioeILToeT2GoCdLwb4v71GRJH8Bu9wbNSZ1cFku4wljq6lhaJ8djUhp3">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="qlRpwGIrioeILToeT2GoCdLwb4v71GRJH8Bu9wbNSZ1cFku4wljq6lhaJ8djUhp3">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="qlRpwGIrioeILToeT2GoCdLwb4v71GRJH8Bu9wbNSZ1cFku4wljq6lhaJ8djUhp3">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="36244801">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(22)01448-2"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3048&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=36244801&amp;db=pubmed&amp;nlmid=0213264"
title="See full text options at Elsevier Science"
data-ga-category="full_text"
data-ga-action="Elsevier Science"
data-ga-label="36244801"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif" alt="Elsevier Science full text link"><span class="text">
Elsevier Science
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/36244801/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=36244801&amp;db=pubmed&amp;nlmid=0213264"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="36244801"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/36244801/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/36244801/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="36244801" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F36244801%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="qlRpwGIrioeILToeT2GoCdLwb4v71GRJH8Bu9wbNSZ1cFku4wljq6lhaJ8djUhp3"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
Choose a collection:
</label><select id="collections-action-dialog-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
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data-ga-label="Frank R Wendt">Frank R Wendt</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut; VA CT Healthcare System, West Haven, Connecticut; Department of Anthropology, University of Toronto, Mississauga, Ontario, Canada; Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. Electronic address: frank.wendt@utoronto.ca." href="#short-view-affiliation-1" ref="linksrc=author_aff">
1
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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2
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Kritika Singh">Kritika Singh</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee." href="#short-view-affiliation-3" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Murray B Stein">Murray B Stein</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Psychiatry Service, VA San Diego Healthcare System, San Diego, California; Department of Psychiatry, University of California, San Diego, San Diego, California; Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, San Diego, California." href="#short-view-affiliation-4" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Karestan C Koenen">Karestan C Koenen</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Stanley Center for Psychiatry Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Psychiatry and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts." href="#short-view-affiliation-5" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Lea K Davis">Lea K Davis</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee." href="#short-view-affiliation-3" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Renato Polimanti">Renato Polimanti</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut; VA CT Healthcare System, West Haven, Connecticut. Electronic address: renato.polimanti@yale.edu." href="#short-view-affiliation-8" ref="linksrc=author_aff">
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Affiliations
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<li data-affiliation-id="short-view-affiliation-1"
id="short-view-affiliation-1"
><sup class="key">1</sup> Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut; VA CT Healthcare System, West Haven, Connecticut; Department of Anthropology, University of Toronto, Mississauga, Ontario, Canada; Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. Electronic address: frank.wendt@utoronto.ca.</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut; VA CT Healthcare System, West Haven, Connecticut.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> Psychiatry Service, VA San Diego Healthcare System, San Diego, California; Department of Psychiatry, University of California, San Diego, San Diego, California; Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, San Diego, California.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Stanley Center for Psychiatry Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Psychiatry and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut.</li>
<li data-affiliation-id="short-view-affiliation-7"
id="short-view-affiliation-7"
><sup class="key">7</sup> Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut; Department of Neuroscience, Yale School of Medicine, New Haven, Connecticut; VA CT Healthcare System, West Haven, Connecticut.</li>
<li data-affiliation-id="short-view-affiliation-8"
id="short-view-affiliation-8"
><sup class="key">8</sup> Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut; VA CT Healthcare System, West Haven, Connecticut. Electronic address: renato.polimanti@yale.edu.</li>
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Abstract
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<p>
<strong class="sub-title">
Background:
</strong>
The presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric disorders displaying prominent sex differences. We performed genome-wide association studies of neuroticism separately in males and females to identify sex-specific genetic and transcriptomic profiles.
</p>
<p>
<strong class="sub-title">
Methods:
</strong>
Neuroticism scores were derived from the Eysenck Personality Inventory Neuroticism scale. Genome-wide association studies were performed in 145,669 females and 129,229 males from the UK Biobank considering autosomal and X chromosomal variation. Two-sided z tests were used to test for sex-specific effects of discovered loci, genetic correlates (n = 673 traits), tissue and gene transcriptomic profiles, and polygenic associations across health outcomes in the Vanderbilt University Biobank (39,692 females and 31,268 males).
</p>
<p>
<strong class="sub-title">
Results:
</strong>
The single nucleotide polymorphism heritability of neuroticism was not statistically different between males (h<sup>2</sup> = 10.6%) and females (h<sup>2</sup> = 11.85%). Four female-specific (rs10736549-CNTN5, rs6507056-ASXL3, rs2087182-MMS22L, and rs72995548-HSPB2) and 2 male-specific (rs10507274-MED13L and rs7984597) neuroticism risk loci reached genome-wide significance. Male- and female-specific neuroticism polygenic scores were most significantly associated with mood disorders (males: odds ratio = 1.11, p = 1.40 × 10<sup>-9</sup>; females: odds ratio = 1.14, p = 6.05 × 10<sup>-22</sup>). They also associated with sex-specific laboratory measurements related to erythrocyte count, distribution, and hemoglobin concentration. Gene expression variation in the pituitary was enriched for neuroticism loci in males (male: b = 0.026, p = .002), and genetically regulated transcriptomic changes highlighted the effect of SHISHA9, TEX26, and NCOA6.
</p>
<p>
<strong class="sub-title">
Conclusions:
</strong>
Through a comprehensive assessment of genetic risk for neuroticism and the associated biological processes, this study identified several molecular pathways that can partially explain the known sex differences in neurotic symptoms and their psychiatric comorbidities.
</p>
</div>
<p>
<strong class="sub-title">
Keywords:
</strong>
Biomarkers; GWAS; Neuroticism; Pituitary gland; Sex effects; TWAS.
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Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Conflict of interest statement
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">DISCLOSURES</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Drs. Gelernter is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. Dr. Stein is paid for his editorial work on the journals Biological Psychiatry and Depression and Anxiety, and the health professional reference Up-To-Date; he has also in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Eisai, Clexio, EmpowerPharm, Engrail Therapeutics, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech. Drs. Polimanti and Gelernter are paid for their editorial work on the journal Complex Psychiatry. The other authors have no competing interests to report.</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Dr. Krystals financial disclosures are as follows:</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Consultant (Note: The Individual Consultant Agreements listed below are less than $5,000 per year)</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Aptinyx, Inc., Atai Life Sciences, Biogen, Idec, MA, Bionomics, Limited (Australia), Boehringer Ingelheim International, Cadent Therapeutics, Inc., Clexio Bioscience, Ltd., COMPASS Pathways, Limited, United Kingdom, Concert Pharmaceuticals, Inc., Epiodyne, Inc. , EpiVario, Inc., Greenwich Biosciences, Inc., Heptares Therapeutics, Limited (UK), Janssen Research &amp; Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc. , Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, Taisho Pharmaceutical Co., Ltd</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Board of Directors</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Freedom Biosciences, Inc.</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Scientific Advisory Board</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), Cadent Therapeutics, Inc. (Clinical Advisory Board), Cerevel Therapeutics, LLC, Delix Therapeutics, Inc., EpiVario, Inc., Eisai, Inc., Jazz Pharmaceuticals, Inc., Neurocrine Biosciences, Inc., Novartis Pharmaceuticals Corporation, PsychoGenics, Inc., Neumora Therapeutics, Inc. , Tempero Bio, Inc., Terran Biosciences, Inc.</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Stock</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Biohaven Pharmaceuticals , Sage Pharmaceuticals, Spring Care, Inc.</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Stock Options</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Biohaven Pharmaceuticals Medical Sciences , EpiVario, Inc., Neumora Therapeutics, Inc. , Terran Biosciences, Inc., Tempero Bio, Inc.</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Income Greater than $10,000</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Editorial Board</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Editor - Biological Psychiatry</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Patents and Inventions</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">1. Seibyl JP, Krystal JH, Charney DS. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. US Patent #:5,447,948.September 5, 1995</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">2. Vladimir, Coric, Krystal, John H, Sanacora, Gerard Glutamate Modulating Agents in the Treatment of Mental Disorders. US Patent No. 8,778,979 B2 Patent Issue Date: July 15, 2014. US Patent Application No. 15/695,164:</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Filing Date: 09/05/2017</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">3. Charney D, Krystal JH, Manji H, Matthew S, Zarate C., - Intranasal Administration of Ketamine to Treat Depression United States Patent Number: 9592207, Issue date: 3/14/2017. Licensed to Janssen Research &amp; Development</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">4. Zarate, C, Charney, DS, Manji, HK, Mathew, Sanjay J, Krystal, JH, Yale University “Methods for Treating Suicidal Ideation”, Patent Application No. 15/379,013 filed on December 14, 2016 by Yale University Office of Cooperative Research</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">5. Arias A, Petrakis I, Krystal JH. Composition and methods to treat addiction.</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Provisional Use Patent Application no.61/973/961. April 2, 2014. Filed by Yale University Office of Cooperative Research.</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">6. Chekroud, A., Gueorguieva, R., &amp; Krystal, JH. “Treatment Selection for Major Depressive Disorder” [filing date 3<sup>rd</sup> June 2016, USPTO docket number Y0087.70116US00]. Provisional patent submission by Yale University</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">7. Gihyun, Yoon, Petrakis I, Krystal JH Compounds, Compositions and Methods for Treating or Preventing Depression and Other Diseases. U. S. Provisional Patent Application No. 62/444,552, filed on</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">January10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">8. Abdallah, C, Krystal, JH, Duman, R, Sanacora, G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 62/719,935 filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">9. John Krystal, Godfrey Pearlson, Stephanie OMalley, Marc Potenza, Fabrizio Gasparini, Baltazar Gomez-Mancilla, Vincent Malaterre. Mavoglurant in treating gambling and gaming disorders. U.S. Provisional Patent Application No. 63/125,181filed on December 14, 2020 by Yale University Office of Cooperative Research OCR 8065 US00</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">NON Federal Research Support</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">AstraZeneca Pharmaceuticals provides the drug, Saracatinib, for research related to NIAAA grant “Center for Translational Neuroscience of Alcoholism [CTNA-4]</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Novartis provides the drug, Mavoglurant, for research related to NIAAA grant “Center for Translational Neuroscience of Alcoholism [CTNA-4]</p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Cerevel provides the drug PF-06412562 for A Translational and Neurocomputational Evaluation of a D1R Partial Agonist for Schizophrenia (1 U01 MH121766-01)</p>
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<p> Fig 1.. Sex-stratified GWAS and locus differences. </p>
</strong>
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<p> Fig 1.. Sex-stratified GWAS and locus differences. </p>
</strong>
<div class="figure-caption-contents"><p> Manhattan plots for neuroticism in males (top) and… </p></div>
</div>
<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig 1.. Sex-stratified GWAS and locus differences.
</strong>
<div class="figure-caption-contents">Manhattan plots for neuroticism in males (top) and females (bottom) with GWAS quality statistics embedded in each. Sex specificity of identified risk loci are shown in Table 1.</div>
</figcaption>
</figure>
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aria-describedby="figure-caption-1"
role="button"
data-image-width="1050"
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data-pmc-id="PMC10508260"
data-figure-id="F2">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-1"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1923/10508260/a2fa3f0cecc8/nihms-1927364-f0002.gif"
alt="Fig 2." />
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<strong class="figure-label">
<p> Fig 2.. PheWAS and LabWAS results. </p>
</strong>
<div class="figure-caption-contents"><p> Manhattan… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig 2.. PheWAS and LabWAS results. </p>
</strong>
<div class="figure-caption-contents"><p> Manhattan plots of sex-stratified phenome-wide (PheWAS in panel A)… </p></div>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig 2.. PheWAS and LabWAS results.
</strong>
<div class="figure-caption-contents">Manhattan plots of sex-stratified phenome-wide (PheWAS in panel A) and laboratory-wide association studies (LabWAS in panel B) of neuroticism polygenic scores in the Vanderbilt University Biobank (BioVU). Each data point represents a single phecode (PheWAS) or laboratory measurement (LabWAS) with sample sizes per data point provided in Tables S6 and S7. Abbreviations: RDW=red blood cell distribution width; Trigs: triglyceride concentration; URBC=urinary red blood cell count.</div>
</figcaption>
</figure>
<figure class="figure-item "
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itemprop="associatedMedia"
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data-label-slug="fig-3">
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itemprop="contentUrl"
aria-describedby="figure-caption-2"
role="button"
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data-pmc-id="PMC10508260"
data-figure-id="F3">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1923/10508260/8df930d59d66/nihms-1927364-f0003.gif"
alt="Fig 3." />
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<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="1050">
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<strong class="figure-label">
<p> Fig 3.. TWAS comparison. </p>
</strong>
<div class="figure-caption-contents"><p> (A) Relationship between… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig 3.. TWAS comparison. </p>
</strong>
<div class="figure-caption-contents"><p> (A) Relationship between male and female frontal cortex TWAS Z-scores for… </p></div>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig 3.. TWAS comparison.
</strong>
<div class="figure-caption-contents">(A) Relationship between male and female frontal cortex TWAS Z-scores for all significant associations after multiple testing correction in either sex (<i>P</i> &lt; 9.23x10<sup>6</sup>). Each data point is a single gene associated with neuroticism in either males or females. Purple lines indicate z-score of 0 (no association). The dashed grey line denotes the 1-to-1 relationship between males and females and the blue line shows the linear regression between sexes. Labeled genes (in red) are significantly associated with neuroticism in one sex but do not meet nominal significance in the other. (B) Relationship between male and female pituitary TWAS Z-scores for all significant associations after multiple testing correction in either sex (<i>P</i> &lt; 8.10x10<sup>6</sup>).</div>
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Widiger TA, Oltmanns JR (2017): Neuroticism is a fundamental domain of personality with enormous public health implications. World Psychiatry. 16:144145.
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Schmitt DP, Realo A, Voracek M, Allik J (2008): Why cant a man be more like a woman? Sex differences in Big Five personality traits across 55 cultures. J Pers Soc Psychol. 94:168182.
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South SC, Jarnecke AM, Vize CE (2018): Sex differences in the Big Five model personality traits: A behavior genetics exploration. Journal of Research in Personality. 74:158165.
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Weisberg YJ, Deyoung CG, Hirsh JB (2011): Gender Differences in Personality across the Ten Aspects of the Big Five. Front Psychol. 2:178.
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Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, Stohl M, et al. (2018): Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry. 75:336346.
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