Scientific Publications

A polygenic burden of rare disruptive mutations in schizophrenia.

Publication TypeJournal Article
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 PK, Banks E., Shakir K., Garimella K., Fennell T., DePristo M., Grant SG, Haggarty SJ, Gabriel S., Scolnick EM, Lander E. S., Hultman CM, Sullivan PF, McCarroll SA, and Sklar P.
AbstractSchizophrenia 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.
Year of Publication2014
JournalNature
Volume506
Issue7487
Pages185-90
Date Published (YYYY/MM/DD)2014/02/13
ISSN Number0028-0836
DOI10.1038/nature12975
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/24463508?dopt=Abstract