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Common alleles contribute to schizophrenia in CNV carriers

Tansey, Katherine E., Rees, Elliott, Linden, David Edmund Johannes, Ripke, S., Chambert, D., Moran, J. L., McCarroll, S. A., Holmans, Peter Alan, Kirov, George, Walters, James Tynan Rhys, Owen, Michael John and O'Donovan, Michael Conlon 2016. Common alleles contribute to schizophrenia in CNV carriers. Molecular Psychiatry 21 (8) , pp. 1085-1089. 10.1038/mp.2015.143

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Abstract

The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10−17) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: Nature Publishing Group
ISSN: 1359-4184
Funders: MRC
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 5 August 2015
Last Modified: 23 Feb 2018 10:05
URI: http://orca.cf.ac.uk/id/eprint/78598

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