No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

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  • Emma C Johnson, Department of Psychology and Neuroscience, University of Colorado at Boulder, United States of America.
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  • Douglas W Bjelland, Institute for Behavioral Genetics, University of Colorado at Boulder, United States of America.
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  • Daniel P Howrigan, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
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  • Abdel Abdellaoui, Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
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  • Gerome Breen, IDepartment of Social Genetic and Developmental Psychiatry, King's College London, London, United Kingdom.
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  • Anders Borglum
  • Sven Cichon, The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
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  • Franziska Degenhardt, The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
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  • Andreas J Forstner, The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
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  • Josef Frank, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
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  • Giulio Genovese, Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
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  • Stefanie Heilmann-Heimbach, The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
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  • Stefan Herms, The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
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  • Per Hoffman, The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
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  • Wolfgang Maier, Department of Psychiatry, University of Bonn, Germany.
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  • Manuel Mattheisen
  • Derek Morris, Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, St. James's Hospital, Ireland.
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  • Bryan Mowry, Queensland Centre for Schizophrenia Mental Health Research, The Park, Centre for Mental Health, Wacol, Australia.
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  • Betram Müller-Mhysok, Max Planck Institute of Psychiatry, Munich, Germany.
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  • Benjamin Neale, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
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  • Igor Nenadic, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
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  • Markus M Nöthen, The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
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  • Colm O'Dushlaine, Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Ireland.
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  • Marcella Rietschel, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
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  • Douglas M Ruderfer, Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
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  • Dan Rujescu, Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstrasse 7, 80336 Munich, Germany.
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  • Thomas G Schulze, Institute for Psychiatric Phenomics and Genomics (IPPG), Ludwig-Maximilians-University, Munich, Germany.
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  • Matthew A Simonson, Mayo Clinic, Department of Health Sciences, Division of Biomedical Statistics and Informatics, Rochester, Minnesota, United States of America.
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  • Eli Stahl, Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
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  • Jana Strohmaier, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
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  • Stephanie H Witt, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
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  • Patrick F Sullivan, Department of Community Medicine, University of Tromsø-the Arctic University of Norway, Tromsø, Norway; Department of Research, Cancer Registry of Norway, Oslo, Norway; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Samfundet Folkhälsan, Helsinki, Finland;
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  • Matthew C Keller, Department of Psychology and Neuroscience, University of Colorado at Boulder, United States of America.
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  • Schizophrenia Working Group of the Psychiatric Genomics Consortium

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest.

Original languageEnglish
JournalP L o S Genetics
Volume12
Issue10
Pages (from-to)e1006343
ISSN1553-7390
DOIs
Publication statusPublished - Oct 2016

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