title: Exome arrays capture polygenic rare variant contributions to schizophrenia.
abstract: Schizophrenia is a highly heritable disorder. Genome-wide association studies based largely on common alleles have identified over 100 schizophrenia risk loci, but it is also evident from studies of copy number variants (CNVs) and from exome-sequencing studies that rare alleles are also involved. Full characterization of the contribution of rare alleles to the disorder awaits the deployment of sequencing technology in very large sample sizes, meanwhile, as an interim measure, exome arrays allow rare non-synonymous variants to be sampled at a fraction of the cost. In an analysis of exome array data from 13 688 individuals (5585 cases and 8103 controls) from the UK, we found that rare (minor allele frequency < 0.1%) variant association signal was enriched among genes that map to autosomal loci that are genome-wide significant (GWS) in common variant studies of schizophrenia genome-wide association study (PGWAS = 0.01) as well as gene sets known to be enriched for rare variants in sequencing studies (PRARE = 0.026). We also identified the gene-wise equivalent of GWS support for WDR88 (WD repeat-containing protein 88), a gene of unknown function (P = 6.5 × 10(-7)). Rare alleles represented on exome chip arrays contribute to the genetic architecture of schizophrenia, but as is the case for GWAS, very large studies are required to reveal additional susceptibility alleles for the disorder.
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Richards
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
authors.forename: G
authors.initials: G
authors.lastname: Leonenko
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
authors.forename: J T
authors.initials: JT
authors.lastname: Walters
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave, New York, NY 10029, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Kavanagh
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
authors.forename: E G
authors.initials: EG
authors.lastname: Rees
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
authors.forename: A
authors.initials: A
authors.lastname: Evans
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA and.
authors.forename: K D
authors.initials: KD
authors.lastname: Chambert
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA and.
authors.forename: J L
authors.initials: JL
authors.lastname: Moran
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA and.
authors.forename: J
authors.initials: J
authors.lastname: Goldstein
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA and Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA and.
authors.forename: S A
authors.initials: SA
authors.lastname: McCarroll
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Pocklington
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: Holmans
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Cardiff CF24 4HQ, UK, odonovanmc@cardiff.ac.uk.
authors.forename: M C
authors.initials: MC
authors.lastname: O'Donovan
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D018401:Sample Size; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; D011506:Proteins; C000612075:WDR88 protein, human