Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection

Pardinas, Antonio, Holmans, Peter, Pocklington, Andrew, Escott-Price, Valentina, Ripke, Stephan, Carrera, Noa, Legge, Sophie E., Bishop, Sophie, Cameron, Darren, Hamshere, Marian L., Han, Jun, Hubbard, Leon, Lynham, Amy, Mantripragada, Kiran, Rees, Elliott, MacCabe, James H., McCarroll, Stephen A., Baune, Bernhard T., Breen, Gerome, Byrne, Enda M., Dannlowski, Udo, Eley, Thalia C., Hayward, Caroline, Martin, Nicholas G., McIntosh, Andrew M., Plomin, Robert, Porteous, David J., Wray, Naomi R., Consortium, ,the GERADI, Collier, David A., Rujescu, Dan, Kirov, George, Owen, Michael, O'Donovan, Michael and Walters, James 2016. Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection. bioRxiv 10.1101/068593

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (1MB) | Preview

Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide such insight. We report the largest single cohort genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) and through meta-analysis with existing data we identify 50 novel GWAS loci. Using gene-wide association statistics we implicate an additional set of 22 novel associations that map onto a single gene. We show for the first time that the common variant association signal is highly enriched among genes that are intolerant to loss of function mutations and that variants in these genes persist in the population despite the low fecundity associated with the disorder through the process of background selection. Associations point to novel areas of biology (e.g. metabotropic GABA-B signalling and acetyl cholinesterase), reinforce those implicated in earlier GWAS studies (e.g. calcium channel function), converge with earlier rare variants studies (e.g. NRXN1, GABAergic signalling), identify novel overlaps with autism (e.g. RBFOX1, FOXP1, FOXG1), and support early controversial candidate gene hypotheses (e.g. ERBB4 implicating neuregulin signalling). We also demonstrate the involvement of six independent central nervous system functional gene sets in schizophrenia pathophysiology. These findings provide novel insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation intolerant genes and suggest a mechanism by which common risk variants are maintained in the population.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Publisher: Cold Spring Harbor Laboratory
Date of First Compliant Deposit: 14 November 2016
Date of Acceptance: 9 August 2016
Last Modified: 13 Apr 2019 03:04
URI: http://orca.cf.ac.uk/id/eprint/96134

Citation Data

Cited 7 times in Google Scholar. View in Google Scholar

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics