A polygenic burden of rare disruptive mutations in schizophrenia
Author(s)Lander, Eric S.
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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.
DepartmentMassachusetts Institute of Technology. Department of Biology
Nature Publishing Group
Purcell, Shaun M., Jennifer L. Moran, Menachem Fromer, Douglas Ruderfer, Nadia Solovieff, Panos Roussos, Colm O’Dushlaine, et al. “A Polygenic Burden of Rare Disruptive Mutations in Schizophrenia.” Nature 506, no. 7487 (January 22, 2014): 185–190.
Author's final manuscript