TY - JOUR
T1 - Microdeletions of 3q29 confer high risk for schizophrenia
AU - Mulle, Jennifer Gladys
AU - Dodd, Anne F.
AU - McGrath, John A.
AU - Wolyniec, Paula S.
AU - Mitchell, Adele A.
AU - Shetty, Amol C.
AU - Sobreira, Nara L.
AU - Valle, David
AU - Rudd, M. Katharine
AU - Satten, Glen
AU - Cutler, David J.
AU - Pulver, Ann E.
AU - Warren, Stephen T.
N1 - Funding Information:
Funding support for the genome-wide association of schizophrenia study was provided by the National Institute of Mental Health (NIMH), and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The data used for the analyses described in this manuscript were obtained from the database of Genotype and Phenotype (dbGaP; accession number phs000021.v). Samples and associated phenotype data for the genome-wide association of schizophrenia study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: P.V. Gejman, Evanston Northwestern Healthcare [ENH] and Northwestern University, Evanston, IL, USA). Funding for this study was provided by NIH grants NIMH MH080129 and MH083722 to S.T.W., a Ruth Kirschstein NRSA (5F32MH080583) to J.G.M., and a NARSAD Young Investigator Award to J.G.M. This work was also supported by a grant from the New York Crohn's Foundation to A.A.M. We wish to thank L. Ozelius (Mt. Sinai University) and M. Abreu (University of Miami) for contribution of Ashkenazi Jewish control samples; K. Keith, K.E. Hermetz, and I.S. Goldlust (Emory University) for help with CNV validation; and M.E. Zwick (Emory University) for helpful discussion. The authors wish to thank the individuals diagnosed with schizophrenia and their family members who participated in this research.
PY - 2010/8/13
Y1 - 2010/8/13
N2 - Schizophrenia (SZ) is a severe psychiatric illness that affects ∼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.
AB - Schizophrenia (SZ) is a severe psychiatric illness that affects ∼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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U2 - 10.1016/j.ajhg.2010.07.013
DO - 10.1016/j.ajhg.2010.07.013
M3 - Article
C2 - 20691406
AN - SCOPUS:77955568656
SN - 0002-9297
VL - 87
SP - 229
EP - 236
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -