title: Genome-wide autozygosity is associated with lower general cognitive ability.
abstract: Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Stanley Center for Psychiatric Genetics, Broad Institute of Harvard and MIT, Cambridge Center, Cambridge, MA, USA.
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authors.affiliation: Division of Data Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
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authors.initials: MA
authors.lastname: Simonson
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: G
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authors.lastname: Davies
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK.|The Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, UK.
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authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
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authors.initials: JM
authors.lastname: Starr
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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authors.affiliation: Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.|Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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authors.affiliation: Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.
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authors.affiliation: Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.
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authors.affiliation: Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.
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authors.affiliation: Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.
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authors.affiliation: Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK.
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authors.affiliation: Centre for Clinical and Cognitive Neurosciences, Institute of Brain Behaviour and Mental Health, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK.
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authors.affiliation: Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK.
authors.forename: W E
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authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.|Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
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authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.|Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.|EMGO+ Institute for Health and Care Research, Amsterdam, The Netherlands.
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authors.affiliation: Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA.|Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.|Hofstra North Shore - LIJ School of Medicine, Departments of Psychiatry and Molecular Medicine, Hempstead, NY, USA.
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authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
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authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
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authors.affiliation: NORMENT, KG Jebsen Centre, Oslo, Norway.|Oslo University Hospital, Oslo, Norway.
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authors.affiliation: NORMENT, KG Jebsen Centre, Oslo, Norway.|Oslo University Hospital, Oslo, Norway.|University of Oslo, Oslo, Norway.
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authors.affiliation: NORMENT, KG Jebsen Centre, Oslo, Norway.|Oslo University Hospital, Oslo, Norway.|University of Oslo, Oslo, Norway.
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authors.initials: OA
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authors.affiliation: K.G. Jebsen Centre for Psychosis Research, Dr. Einar Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
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authors.affiliation: K.G. Jebsen Centre for Psychosis Research, Dr. Einar Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: V M
authors.initials: VM
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authors.affiliation: K.G. Jebsen Centre for Psychosis Research, Dr. Einar Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
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authors.affiliation: NORMENT, KG Jebsen Centre, Oslo, Norway.|Department of Psychology, University of Oslo, Oslo, Norway.
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authors.affiliation: Department of Psychology, University of Oslo, Oslo, Norway.
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authors.affiliation: Department of Psychology, University of Oslo, Oslo, Norway.|Norwegian Center for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
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authors.affiliation: K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.|Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.|Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital, Bergen, Norway.
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authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
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authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
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authors.affiliation: Department of Psychology, University of Crete, Rethymno, Crete, Greece.
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authors.affiliation: Department of Psychiatry, Friedman Brain Institute, Department of Genetics and Genomic Sciences, and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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authors.affiliation: Department of Psychiatry, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece.|Computational Medicine Laboratory, Institute of Computer Science at FORTH, Heraklion, Greece.
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authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.|Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.|University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia.
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authors.affiliation: Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA.|Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.|Hofstra North Shore - LIJ School of Medicine, Departments of Psychiatry and Molecular Medicine, Hempstead, NY, USA.
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authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Stanley Center for Psychiatric Genetics, Broad Institute of Harvard and MIT, Cambridge Center, Cambridge, MA, USA.
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authors.affiliation: Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA.|Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.|Hofstra North Shore - LIJ School of Medicine, Departments of Psychiatry and Molecular Medicine, Hempstead, NY, USA.
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authors.affiliation: Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA.|Department of Psychology, University of Colorado at Boulder, Boulder, CO, USA.
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mesh_terms: D000328:Adult; D000483:Alleles; D002874:Chromosome Mapping / Q000379:methods; D003071:Cognition / Q000502:physiology*; D005260:Female; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D000071422:Inbreeding Depression / Q000235:genetics* / Q000502:physiology; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics