title: Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis.
abstract: Heritability analyses of genome-wide association study (GWAS) cohorts have yielded important insights into complex disease architecture, and increasing sample sizes hold the promise of further discoveries. Here we analyze the genetic architectures of schizophrenia in 49,806 samples from the PGC and nine complex diseases in 54,734 samples from the GERA cohort. For schizophrenia, we infer an overwhelmingly polygenic disease architecture in which ≥71% of 1-Mb genomic regions harbor ≥1 variant influencing schizophrenia risk. We also observe significant enrichment of heritability in GC-rich regions and in higher-frequency SNPs for both schizophrenia and GERA diseases. In bivariate analyses, we observe significant genetic correlations (ranging from 0.18 to 0.85) for several pairs of GERA diseases; genetic correlations were on average 1.3 tunes stronger than the correlations of overall disease liabilities. To accomplish these analyses, we developed a fast algorithm for multicomponent, multi-trait variance-components analysis that overcomes prior computational barriers that made such analyses intractable at this scale.
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Po-Ru
authors.initials: PR
authors.lastname: Loh
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhatia
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gusev
authors.affiliation: Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Hilary K
authors.initials: HK
authors.lastname: Finucane
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Brendan K
authors.initials: BK
authors.lastname: Bulik-Sullivan
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Samuela J
authors.initials: SJ
authors.lastname: Pollack
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado, USA.
authors.forename: Teresa R
authors.initials: TR
authors.lastname: de Candia
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.|School of Environmental and Rural Science, University of New England, Armidale, New South Wales, Australia.
authors.forename: Sang Hong
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Naomi R
authors.identifier: http://orcid.org/0000-0001-7421-3357
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Department of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: Michael C
authors.identifier: http://orcid.org/0000-0001-7073-2379
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Benjamin M
authors.identifier: http://orcid.org/0000-0003-1513-6077
authors.initials: BM
authors.lastname: Neale
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
mesh_terms: D000375:Aging / Q000235:genetics; D000465:Algorithms; D000704:Analysis of Variance; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020412:Multifactorial Inheritance / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000145:classification* / Q000453:epidemiology / Q000235:genetics*