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Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness.

  • Bigdeli TB Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
  • Ripke S Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
  • Bacanu SA Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
  • Lee SH Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
  • Wray NR Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
  • Gejman PV Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois.
  • Rietschel M Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
  • Cichon S Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • St Clair D University of Aberdeen, Institute of Medical Sciences, Aberdeen, Scotland, United Kingdom.
  • Corvin A Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Ireland.
  • Kirov G MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
  • McQuillin A Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, United Kingdom.
  • Gurling H Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, United Kingdom.
  • Rujescu D Department of Psychiatry, University of Halle, Halle, Germany.
  • Andreassen OA NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • Werge T Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Denmark.
  • Blackwood DH Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
  • Pato CN Department of Psychiatry, Keck School of Medicine at University of Southern California, Los Angeles, California.
  • Pato MT Department of Psychiatry, Keck School of Medicine at University of Southern California, Los Angeles, California.
  • Malhotra AK The Zucker Hillside Hospital, Glen Oaks, New York.
  • O'Donovan MC MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
  • Kendler KS Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
  • Fanous AH Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
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  • 2015-12-15
Published in:
  • American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. - 2016
GWAS
family history
polygenic
schizophrenia
Bipolar Disorder
Case-Control Studies
Depressive Disorder, Major
Family
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Inheritance Patterns
Models, Genetic
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Schizophrenia
English 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.
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  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/231928
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