Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

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dc.contributor.authorPardiñas, A.
dc.contributor.authorHolmans, P.
dc.contributor.authorPocklington, A.
dc.contributor.authorEscott-Price, V.
dc.contributor.authorRipke, S.
dc.contributor.authorCarrera, N.
dc.contributor.authorLegge, S.
dc.contributor.authorBishop, S.
dc.contributor.authorCameron, D.
dc.contributor.authorHamshere, M.
dc.contributor.authorHan, J.
dc.contributor.authorHubbard, L.
dc.contributor.authorLynham, A.
dc.contributor.authorMantripragada, K.
dc.contributor.authorRees, E.
dc.contributor.authorMacCabe, J.
dc.contributor.authorMcCarroll, S.
dc.contributor.authorBaune, B.
dc.contributor.authorBreen, G.
dc.contributor.authorByrne, E.
dc.contributor.authoret al.
dc.date.issued2018
dc.description.abstractSchizophrenia 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 insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new 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 persist in the population.
dc.description.statementofresponsibilityAntonio F. Pardiñas, Peter Holmans, Andrew J. Pocklington, Valentina Escott-Price, Stephan Ripke … Bernhard T Baune … et al.
dc.identifier.citationNature Genetics, 2018; 50(3):381-389
dc.identifier.doi10.1038/s41588-018-0059-2
dc.identifier.issn1061-4036
dc.identifier.issn1546-1718
dc.identifier.orcidBaune, B. [0000-0001-6548-426X]
dc.identifier.urihttp://hdl.handle.net/2440/111860
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1078901
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1053639
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/241944
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/339462
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/389875
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/389891
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/389892
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/389927
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/389938
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/442915
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/442981
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/496675
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/496739
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/552485
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/552498
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/613602
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/613608
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/613674
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/613667
dc.relation.granthttp://purl.org/au-research/grants/arc/FT0991360
dc.relation.granthttp://purl.org/au-research/grants/arc/FT0991022
dc.rights© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
dc.source.urihttps://doi.org/10.1038/s41588-018-0059-2
dc.subjectGERAD1 Consortium
dc.subjectCRESTAR Consortium
dc.subjectHumans
dc.subjectGenetic Predisposition to Disease
dc.subjectCase-Control Studies
dc.subjectSchizophrenia
dc.subjectGene Frequency
dc.subjectInheritance Patterns
dc.subjectPolymorphism, Single Nucleotide
dc.subjectAlleles
dc.subjectGenes, Lethal
dc.subjectGenome-Wide Association Study
dc.subjectSelection, Genetic
dc.subjectGenetic Loci
dc.titleCommon schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection
dc.typeJournal article
pubs.publication-statusPublished

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