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, PKE, Banks, E, Shakir, K, Garimella, K, Fennell, T, DePristo, M, Grant, SGN, Haggarty, SJ, Gabriel, S, Scolnick, EM, Lander, ES, Hultman, CM, Sullivan, PF, McCarroll, SA, Sklar, P |
Journal | Nature |
Volume | 506 |
Issue | 7487 |
Pages | 185-90 |
Date Published | 2014 Feb 13 |
ISSN | 1476-4687 |
Keywords | Autistic Disorder, Calcium Channels, Cytoskeletal Proteins, DNA Copy Number Variations, Female, Fragile X Mental Retardation Protein, Genome-Wide Association Study, Humans, Intellectual Disability, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Multifactorial Inheritance, Mutation, Nerve Tissue Proteins, Receptors, N-Methyl-D-Aspartate, Schizophrenia |
Abstract | 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. |
URL | http://dx.doi.org/10.1038/nature12975 |
DOI | 10.1038/nature12975 |
Pubmed | |
Alternate Journal | Nature |
PubMed ID | 24463508 |
PubMed Central ID | PMC4136494 |
Grant List | R01 MH095034 / MH / NIMH NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States RC2 MH089905 / MH / NIMH NIH HHS / United States R01 MH077139 / MH / NIMH NIH HHS / United States R01 MH091115 / MH / NIMH NIH HHS / United States TT32MH017119 / MH / NIMH NIH HHS / United States / / Medical Research Council / United Kingdom U54HG003067 / HG / NHGRI NIH HHS / United States R01 MH099126 / MH / NIMH NIH HHS / United States I01 BX002395 / BX / BLRD VA / United States RC2MH089905 / MH / NIMH NIH HHS / United States G0802238 / / Medical Research Council / United Kingdom T32 MH017119 / MH / NIMH NIH HHS / United States R01 HG005827 / HG / NHGRI NIH HHS / United States / / Wellcome Trust / United Kingdom R01 MH095088 / MH / NIMH NIH HHS / United States |
Nature DOI:10.1038/nature12975
A polygenic burden of rare disruptive mutations in schizophrenia.
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