A polygenic burden of rare disruptive mutations in schizophrenia : Nature : Nature Publishing Group

A polygenic burden of rare disruptive mutations in schizophrenia : Nature : Nature Publishing Group

A polygenic burden of rare disruptive mutations in schizophrenia

• Shaun M. Purcell,
• Jennifer L. Moran,
• Menachem Fromer,
• Douglas Ruderfer,
• Nadia Solovieff,
• Panos Roussos,
• Colm O’Dushlaine,
• Kimberly Chambert,
• Sarah E. Bergen,
• Anna Kähler,
• Laramie Duncan,
• Eli Stahl,
• Giulio Genovese,
• Esperanza Fernández,
• Mark O. Collins,
• Noboru H. Komiyama,
• Jyoti S. Choudhary,
• Patrik K. E. Magnusson,
• Eric Banks,
• Khalid Shakir,
• Kiran Garimella,
• Tim Fennell,
• Mark DePristo,
• Seth G. N. Grant,
• Stephen J. Haggarty
• et al.

• Affiliations
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Nature

 

(2014)

 

doi:10.1038/nature12975

Received

 

25 June 2013 

Accepted

 

24 December 2013 

Published online

 

22 January 2014

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Abstract

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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.