|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Purcell, SM, Moran, JL, Fromer, M, Ruderfer, D, Solovieff, N, Roussos, P, O'Dushlaine, C, Chambert, K, Bergen, SE, Kähler, A, Duncan, L, Stahl, E, Genovese, G, Fernández, E, Collins, MO, Komiyama, NH, Choudhary, JS, Magnusson, PK, Banks, E, Shakir, K, Garimella, K, Fennell, T, DePristo, M, Grant, SG, Haggarty, SJ, Gabriel, S, Scolnick, EM, Lander, ES, Hultman, CM, Sullivan, PF, McCarroll, SA, Sklar, P|
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.