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Mol Psychiatry DOI:10.1038/mp.2014.40

Copy number variation in schizophrenia in Sweden.

Publication TypeJournal Article
Year of Publication2014
AuthorsSzatkiewicz, JP, O'Dushlaine, C, Chen, G, Chambert, K, Moran, JL, Neale, BM, Fromer, M, Ruderfer, D, Akterin, S, Bergen, SE, Kähler, A, Magnusson, PKE, Kim, Y, Crowley, JJ, Rees, E, Kirov, G, O'Donovan, MC, Owen, MJ, Walters, J, Scolnick, E, Sklar, P, Purcell, S, Hultman, CM, McCarroll, SA, Sullivan, PF
JournalMol Psychiatry
Date Published2014 Jul
KeywordsAdult, Case-Control Studies, DNA Copy Number Variations, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Schizophrenia, Sweden

Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare copy number variations (CNVs) in SCZ cases and identified multiple rare recurrent CNVs that increase risk of SCZ although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for SCZ CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with SCZ using a Swedish national sample (4719 cases and 5917 controls). High-confidence CNV calls were generated using genotyping array intensity data, and their effect on risk of SCZ was measured. Our data confirm increased burden of large, rare CNVs in SCZ cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not SCZ. Intriguingly, gene set association analyses implicate biological pathways previously associated with SCZ through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500 kb) in genes present in the postsynaptic density, in genomic regions implicated via SCZ genome-wide association studies and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry--genome-wide screens for CNVs, common variation and exonic variation--are converging on similar sets of pathways and/or genes.


Alternate JournalMol. Psychiatry
PubMed ID24776740
PubMed Central IDPMC4271733
Grant ListR01 MH095034 / MH / NIMH NIH HHS / United States
R01 MH077139 / MH / NIMH NIH HHS / United States
G0601635 / / Medical Research Council / United Kingdom
G0800509 / / Medical Research Council / United Kingdom
U01 MH094421 / MH / NIMH NIH HHS / United States
G0801418 / / Medical Research Council / United Kingdom
MR/L010305/1 / / Medical Research Council / United Kingdom
K01 MH093517 / MH / NIMH NIH HHS / United States