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

Daniel J Weiner, Emilie M Wigdor, Stephan Ripke, Raymond K Walters, Jack A Kosmicki, Jakob Grove, Kaitlin E Samocha, Jacqueline Goldstein, Aysu Okbay, Jonas Bybjerg-Grauholm, Thomas Werge, David M Hougaard, Jacob Taylor, iPSYCH-Broad Autism Group, Genomics Consortium Autism Group, David Skuse, Bernie Devlin, Richard Anney, Stephan J Sanders, Somer BishopPreben Bo Mortensen, Anders D Borglum, George Davey Smith, Mark J Daly, Elise B Robinson

Research output: Contribution to journalArticle (Academic Journal)peer-review

167 Citations (Scopus)
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Abstract

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASDs and to identify subgroups of ASD cases, including those with strong 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 ASDs, schizophrenia, and greater educational attainment is over transmitted to children with ASDs. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strong 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 ASDs’ genetic influences are additive and suggest they create risk through at least partially distinct etiologic pathways.
Original languageEnglish
Pages (from-to)978-985
Number of pages8
JournalNature Genetics
Volume49
Issue number7
Early online date15 May 2017
DOIs
Publication statusPublished - Jul 2017

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