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A polygenic burden of rare disruptive mutations in schizophrenia.

Purcell, Shaun M; Moran, Jennifer L; Fromer, Menachem; Ruderfer, Douglas; Solovieff, Nadia; Roussos, Panos; O'Dushlaine, Colm; Chambert, Kimberly; Bergen, Sarah E; Kähler, Anna; Duncan, Laramie; Stahl, Eli; Genovese, Giulio; Fernández, Esperanza; Collins, Mark O; Komiyama, Noboru H; Choudhary, Jyoti S; Magnusson, Patrik K E; Banks, Eric; Shakir, Khalid; Garimella, Kiran; Fennell, Tim; DePristo, Mark; Grant, Seth G N; Haggarty, Stephen J; Gabriel, Stacey; Scolnick, Edward M; Lander, Eric S; Hultman, Christina M; Sullivan, Patrick F; McCarroll, Steven A; Sklar, Pamela.
Nature; 506(7487): 185-90, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24463508
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.
Selo DaSilva