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

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DOI

  • Tim B Bigdeli, Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
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  • Stephan Ripke, Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin, Germany.
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  • Silviu-Alin Bacanu, Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
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  • Sang Hong Lee
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  • Naomi R Wray, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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  • Pablo V Gejman, Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois.
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  • Marcella Rietschel, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Sven Cichon
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  • David St Clair, University of Aberdeen, Institute of Medical Sciences, Aberdeen, Scotland, United Kingdom.
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  • Aiden Corvin, Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Ireland.
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  • George Kirov, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, United Kingdom.
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  • Andrew McQuillin, Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, United Kingdom.
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  • Hugh Gurling, Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, United Kingdom.
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  • Dan Rujescu, The Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
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  • Ole A Andreassen, K. G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway ; Department of Psychology, University of Oslo, Oslo, Norway.
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  • Thomas Werge, Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Denmark.
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  • Douglas H R Blackwood, Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
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  • Carlos N Pato, Department of Psychiatry, Keck School of Medicine at University of Southern California, Los Angeles, California.
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  • Michele T Pato, Department of Psychiatry, Keck School of Medicine at University of Southern California, Los Angeles, California.
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  • Anil K Malhotra, The Zucker Hillside Hospital, Glen Oaks, New York.
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  • Michael C O'Donovan, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, United Kingdom.
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  • Kenneth S Kendler, Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
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  • Ayman H Fanous, Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
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  • Schizophrenia Working Group of the Psychiatric Genomics Consortium

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.

Original languageEnglish
JournalAmerican journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
Volume171B
Issue2
Pages (from-to)276-89
Number of pages14
ISSN1552-4841
DOIs
Publication statusPublished - Mar 2016
Externally publishedYes

    Research areas

  • Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.

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