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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

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DOI

  • Daniel J Weiner, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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  • Emilie M Wigdor, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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  • Stephan Ripke, Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
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  • Raymond K Walters, 1] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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  • Jack A Kosmicki, Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
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  • Jakob Grove
  • Kaitlin E Samocha, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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  • Jacqueline I Goldstein, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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  • Aysu Okbay, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
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  • Jonas Bybjerg-Grauholm, Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
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  • Thomas Werge, University of Copenhagen
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  • David M Hougaard, Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
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  • Jacob Taylor, Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
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  • David Skuse, Behavioural Sciences Unit, Institute of Child Health, University College London, London, UK.
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  • Bernie Devlin, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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  • Richard Anney, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales, UK.
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  • Stephan J Sanders, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA.
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  • Somer Bishop, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA.
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  • Preben Bo Mortensen
  • Anders D Børglum
  • George Davey Smith, Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
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  • Mark J Daly, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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  • Elise B Robinson, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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  • iPSYCH-Broad Autism Group

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.

Original languageEnglish
JournalNature Genetics
Volume49
Issue7
Pages (from-to)978-985
ISSN1061-4036
DOIs
Publication statusPublished - 15 May 2017

    Research areas

  • Journal Article

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