A polygenic burden of rare disruptive mutations in schizophrenia.
Purcell, Shaun M. 1,2,3,4,5; Moran, Jennifer L. 1,15; Fromer, Menachem 1,2,3,4,15; Ruderfer, Douglas 2,3,15; Solovieff, Nadia 4; Roussos, Panos 2,3; O'Dushlaine, Colm 1; Chambert, Kimberly 1; Bergen, Sarah E. 1,6; Kahler, Anna 6; Duncan, Laramie 1,4,5; Stahl, Eli 2,3; Genovese, Giulio 1; Fernandez, Esperanza 7,8; Collins, Mark O. 9; Komiyama, Noboru H. 9; Choudhary, Jyoti S. 9; Magnusson, Patrik K. E. 6; Banks, Eric 5; Shakir, Khalid 5; Garimella, Kiran 5; Fennell, Tim 5; DePristo, Mark 5; Grant, Seth G. N. 10; Haggarty, Stephen J. 1,4,11; Gabriel, Stacey 5; Scolnick, Edward M. 1; Lander, Eric S. 5; Hultman, Christina M. 6; Sullivan, Patrick F. 12; McCarroll, Steven A. 1,5,13; Sklar, Pamela 2,3,14
[Article]
Nature.
506(7487):185-190, February 13, 2014.
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: Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.
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