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

Lookup NU author(s): Professor Jeremy Parr, Professor Ann Le Couteur

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Abstract

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. 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.


Publication metadata

Author(s): Weiner DJ, Wigdor EM, Ripke S, Walters RK, Kosmicki JA, Grove J, Samocha KE, Goldstein JI, Okbay A, Bybjerg-Grauholm J, Werge T, Hougaard DM, Taylor J, Skuse D, Devlin B, Anney R, Sanders SJ, Bishop S, Mortensen PB, Borglum AD, Smith GD, Daly MJ, Robinson EB, Parr JR, Le Couteur AS, iPSYCH-Broad Autism Group, Psychiatric Genomics Consortium Autism Group

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2017

Volume: 49

Issue: 7

Pages: 978-985

Print publication date: 01/07/2017

Online publication date: 15/05/2017

Acceptance date: 13/04/2017

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/ng.3863

DOI: 10.1038/ng.3863


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