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. 2010 Aug 13;87(2):229-36.
doi: 10.1016/j.ajhg.2010.07.013.

Microdeletions of 3q29 confer high risk for schizophrenia

Jennifer Gladys Mulle  1 , Anne F Dodd, John A McGrath, Paula S Wolyniec, Adele A Mitchell, Amol C Shetty, Nara L Sobreira, David Valle, M Katharine Rudd, Glen Satten, David J Cutler, Ann E Pulver, Stephen T Warren
Affiliations

Microdeletions of 3q29 confer high risk for schizophrenia

Jennifer Gladys Mulle et al. Am J Hum Genet. .

Abstract

Schizophrenia (SZ) is a severe psychiatric illness that affects approximately 1% of the population and has a strong genetic underpinning. Recently, genome-wide analysis of copy-number variation (CNV) has implicated rare and de novo events as important in SZ. Here, we report a genome-wide analysis of 245 SZ cases and 490 controls, all of Ashkenazi Jewish descent. Because many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases, with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3-1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, because increasing evidence suggests an overlap of specific rare copy-number variants (CNVs) between autism and SZ. By combining our data with prior CNV studies of SZ and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with SZ (p = 0.02) and an odds ratio estimate of 17 (95% confidence interval: 1.36-1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior SZ family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for SZ susceptibility.

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Figures

Figure 1
Figure 1
Raw Data, Validation, and Fine Mapping of the Chromosome 3q29 Variant (A) Raw log ratio data from the Affymetrix Human Genome-Wide SNP Array 6.0 is shown for chromosome 3, 190 Mb–3qtel, for the SZ proband and both parents. The 3q29 de novo deletion is denoted with an arrow. (B) TaqMan validation data for the 3q29 variant for the SZ proband and both parents (the father was assayed in replicate). Results of ABI CopyCaller software are shown; predicted copy number is indicated on the y axis. (C) Raw log ratio data for the SZ proband from a custom Agilent array with 27,661 probes in the terminal 6.2 Mb of chromsome 3q. Position on chromosome 3 is plotted on the x axis (194.3–200.1 Mb shown), log ratio data on the y axis. The deletion region is indicated with an arrow.
Figure 2
Figure 2
Chromosome 3, Coordinates 196.5–199 Mb Shown The deletion detected in the current study is shown, along with other 3q29 deletions reported or detected in SZ cohorts (top track: ISC, International Schizophrenia Consortium; GAIN, Genetic Analysis Information Network cohort; Walsh, reference ; Quintero, reference 24). The 378 kb region tested by deCode is indicated, along with the positions of 49 SNPs used by deCode to determine deletion status of 1438 SZ cases and 33,246 controls (tracks 2 and 3). Locations of reported linkage peaks in prior studies are shown (track 4: study indicated by first author of publication). Refseq genes and segmental duplications, which likely mediate nonhomologous recombination events, are also shown (tracks 5 and 6).
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