title: No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study.
abstract: 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.
authors: Department of Psychology and Neuroscience, University of Colorado at Boulder, United States of America.|Institute for Behavioral Genetics, University of Colorado at Boulder, United States of America.
authors: Emma C
authors: http://orcid.org/0000-0003-0394-777X
authors: EC
authors: Johnson
authors: Institute for Behavioral Genetics, University of Colorado at Boulder, United States of America.
authors: Douglas W
authors: DW
authors: Bjelland
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.|Broad Institute, Cambridge, Massachusetts, United States of America.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, United States of America.
authors: Daniel P
authors: DP
authors: Howrigan
authors: Department of Biological Psychology, VU University Amsterdam, Amsterdam, Netherlands.
authors: Abdel
authors: A
authors: Abdellaoui
authors: IDepartment of Social Genetic and Developmental Psychiatry, King's College London, London, United Kingdom.
authors: Gerome
authors: G
authors: Breen
authors: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.|Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Department P, Aarhus University Hospital, Risskov, Denmark.
authors: Anders
authors: A
authors: Borglum
authors: Department of Genomics, Life and Brain Center, University of Bonn, Germany.|Division of Medical Genetics, Department of Biomedicine, University Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Juelich, Juelich, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: Sven
authors: S
authors: Cichon
authors: Department of Genomics, Life and Brain Center, University of Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: Franziska
authors: F
authors: Degenhardt
authors: Department of Genomics, Life and Brain Center, University of Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: Andreas J
authors: AJ
authors: Forstner
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, Mannheim, Germany.
authors: Josef
authors: http://orcid.org/0000-0003-3578-7053
authors: J
authors: Frank
authors: Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Giulio
authors: G
authors: Genovese
authors: Department of Genomics, Life and Brain Center, University of Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: Stefanie
authors: S
authors: Heilmann-Heimbach
authors: Department of Genomics, Life and Brain Center, University of Bonn, Germany.|Division of Medical Genetics, Department of Biomedicine, University Basel, Basel, Switzerland.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: Stefan
authors: http://orcid.org/0000-0002-2786-8200
authors: S
authors: Herms
authors: Department of Genomics, Life and Brain Center, University of Bonn, Germany.|Division of Medical Genetics, Department of Biomedicine, University Basel, Basel, Switzerland.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: Per
authors: P
authors: Hoffman
authors: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors: Wolfgang
authors: W
authors: Maier
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: Manuel
authors: M
authors: Mattheisen
authors: Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, St. James's Hospital, Ireland.
authors: Derek
authors: D
authors: Morris
authors: Queensland Centre for Schizophrenia Mental Health Research, The Park, Centre for Mental Health, Wacol, Australia.|Department of Psychiatry, University of Queensland, Brisbane, Australia.
authors: Bryan
authors: B
authors: Mowry
authors: Max Planck Institute of Psychiatry, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|University of Liverpool, Institute of Translational Medicine, Liverpool, United Kingdom.
authors: Betram
authors: B
authors: Müller-Mhysok
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.|Broad Institute, Cambridge, Massachusetts, United States of America.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, United States of America.
authors: Benjamin
authors: B
authors: Neale
authors: Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
authors: Igor
authors: I
authors: Nenadic
authors: Department of Genomics, Life and Brain Center, University of Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: Markus M
authors: MM
authors: Nöthen
authors: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Ireland.
authors: Colm
authors: C
authors: O'Dushlaine
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, Mannheim, Germany.
authors: Marcella
authors: M
authors: Rietschel
authors: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors: Douglas M
authors: DM
authors: Ruderfer
authors: Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany.|Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
authors: Dan
authors: D
authors: Rujescu
authors: Institute for Psychiatric Phenomics and Genomics (IPPG), Ludwig-Maximilians-University, Munich, Germany.
authors: Thomas G
authors: TG
authors: Schulze
authors: Mayo Clinic, Department of Health Sciences, Division of Biomedical Statistics and Informatics, Rochester, Minnesota, United States of America.
authors: Matthew A
authors: MA
authors: Simonson
authors: Broad Institute, Cambridge, Massachusetts, United States of America.|Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors: Eli
authors: E
authors: Stahl
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, Mannheim, Germany.
authors: Jana
authors: J
authors: Strohmaier
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, Mannheim, Germany.
authors: Stephanie H
authors: http://orcid.org/0000-0002-1571-1468
authors: SH
authors: Witt
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.|Department of Genetics, University of North Carolina, Chapel Hill, NC, United States of America.|Department of Psychiatry, University of North Carolina, Chapel Hill, NC, United States of America.
authors: Patrick F
authors: PF
authors: Sullivan
authors: Department of Psychology and Neuroscience, University of Colorado at Boulder, United States of America.|Institute for Behavioral Genetics, University of Colorado at Boulder, United States of America.
authors: Matthew C
authors: MC
authors: Keller
mesh_terms: D003241:Consanguinity; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D023281:Genomics; D006720:Homozygote; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology