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Nature DOI:10.1038/nature12975

A polygenic burden of rare disruptive mutations in schizophrenia.

Publication TypeJournal Article
Year of Publication2014
AuthorsPurcell, 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
Date Published2014 Feb 13
KeywordsAutistic 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

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.


Alternate JournalNature
PubMed ID24463508
PubMed Central IDPMC4136494
Grant ListR01 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