|Title:||Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness|
|Journal:||Am J Med Genet B Neuropsychiatr Genet|
|Alternate Journal:||American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics|
|Keywords:||Bipolar Disorder/genetics Case-Control Studies Depressive Disorder, Major/genetics Family *Genetic Predisposition to Disease *Genome-Wide Association Study Humans Inheritance Patterns/genetics Models, Genetic Multifactorial Inheritance/*genetics Polymorphism, Single Nucleotide/genetics Schizophrenia/*genetics Gwas family history polygenic schizophrenia|
|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.|
|Notes:||1552-485x Bigdeli, Tim B Ripke, Stephan Bacanu, Silviu-Alin Lee, Sang Hong Wray, Naomi R Gejman, Pablo V Rietschel, Marcella Cichon, Sven St Clair, David Corvin, Aiden Kirov, George McQuillin, Andrew Gurling, Hugh Rujescu, Dan Andreassen, Ole A Werge, Thomas Blackwood, Douglas H R Pato, Carlos N Pato, Michele T Malhotra, Anil K O'Donovan, Michael C Kendler, Kenneth S Fanous, Ayman H Schizophrenia Working Group of the Psychiatric Genomics Consortium G1000708/Medical Research Council/United Kingdom Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. United States Am J Med Genet B Neuropsychiatr Genet. 2016 Mar;171B(2):276-89. doi: 10.1002/ajmg.b.32402. Epub 2015 Dec 11.|
|Authors Address:||Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. 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. University of Aberdeen, Institute of Medical Sciences, Aberdeen, Scotland, United Kingdom. Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Ireland. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, United Kingdom. Department of Psychiatry, University of Halle, Halle, Germany. Department of Psychiatry, University of Munich, Munich, Germany. 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. 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. Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom. 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. 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. National Centre for Mental Health, Cardiff University, Cardiff, Wales. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia. Mental Health Service Line, Washington VA Medical Center, Washington, District of Columbia. Department of Psychiatry, Georgetown University School of Medicine, Washington, District of Columbia.|
|Appears in Collections:||2016|
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