A Polygenic Burden of Rare Disruptive Mutations in Schizophrenia

Overview

Journal Nature

Specialty Science

Date 2014 Jan 28

PMID 24463508

Citations 787

Authors

Shaun M Purcell

Jennifer L Moran

Menachem Fromer

Douglas Ruderfer

Nadia Solovieff

Panos Roussos

Colm ODushlaine

Kimberly Chambert

Sarah E Bergen

Anna Kahler

Laramie Duncan

Eli Stahl

Giulio Genovese

Esperanza Fernandez

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

Stacey Gabriel

Edward M Scolnick

Eric S Lander

Christina M Hultman

Patrick F Sullivan

Steven A McCarroll

Pamela Sklar

Affiliations

Soon will be listed here.

Abstract

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.

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