title: Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness.
abstract: Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Tim B
authors.initials: TB
authors.lastname: Bigdeli
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Silviu-Alin
authors.initials: SA
authors.lastname: Bacanu
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Sang Hong
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois.|Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois.
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Gejman
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.|Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: University of Aberdeen, Institute of Medical Sciences, Aberdeen, Scotland, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Ireland.
authors.forename: Aiden
authors.initials: A
authors.lastname: Corvin
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.affiliation: Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: McQuillin
authors.affiliation: Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, United Kingdom.
authors.forename: Hugh
authors.initials: H
authors.lastname: Gurling
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.|Department of Psychiatry, University of Munich, Munich, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Denmark.|Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Douglas H R
authors.initials: DH
authors.lastname: Blackwood
authors.affiliation: Department of Psychiatry, Keck School of Medicine at University of Southern California, Los Angeles, California.|Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, California.
authors.forename: Carlos N
authors.initials: CN
authors.lastname: Pato
authors.affiliation: Department of Psychiatry, Keck School of Medicine at University of Southern California, Los Angeles, California.|Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, California.
authors.forename: Michele T
authors.initials: MT
authors.lastname: Pato
authors.affiliation: The Zucker Hillside Hospital, Glen Oaks, New York.|The Feinstein Institute for Medical Research, Manhasset, New York.|The Hofstra NS-LIJ School of Medicine, Hempstead, New York.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Malhotra
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.|National Centre for Mental Health, Cardiff University, Cardiff, Wales.
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.|Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Keck School of Medicine at University of Southern California, Los Angeles, California.|Mental Health Service Line, Washington VA Medical Center, Washington, District of Columbia.|Department of Psychiatry, Georgetown University School of Medicine, Washington, District of Columbia.
authors.forename: Ayman H
authors.initials: AH
authors.lastname: Fanous
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics; D005190:Family; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008957:Models, Genetic; D020412:Multifactorial Inheritance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
keywords: GWAS; family history; polygenic; schizophrenia