A polygenic burden of rare disruptive mutations in schizophrenia

Article

关键词: DE-NOVO MUTATIONS;    MESSENGER-RNA;    POSTSYNAPTIC DENSITY-95;    INTELLECTUAL DISABILITY;    ASSOCIATION ANALYSIS;    PROTEIN;    VARIANT;    AUTISM;    RISK;    COMPLEX;   

DOI  :  10.1038/nature12975

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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