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 I. Goldstein, Aysu Okbay, Jonas Bybjerg-Grauholm, Thomas Werge, David M. Hougaard, Jacob Taylor, David Skuse, Bernie Devlin, Richard Anney, Stephan J. Sanders, Somer Bishop, Preben Bo Mortensen, Anders D. BørglumGeorge Davey Smith, Mark J. Daly, Elise B. Robinson, Marie Bækvad-Hansen, Ashley Dumont, Christine Hansen, Thomas F. Hansen, Daniel Howrigan, Manuel Mattheisen, Jennifer Moran, Ole Mors, Merete Nordentoft, Bent Nørgaard-Pedersen, Timothy Poterba, Jesper Poulsen, Christine Stevens, Verneri Anttila, Peter Holmans, Hailiang Huang, Lambertus Klei, Phil H. Lee, Sarah E. Medland, Benjamin Neale, Lauren A. Weiss, Lonnie Zwaigenbaum, Timothy W. Yu, Kerstin Wittemeyer, A. Jeremy Willsey, Ellen M. Wijsman, Suma Jacob, Psychiatric Genomics Consortium Autism Group, iPSYCH-Broad Autism Group

Research output: Contribution to journalArticlepeer-review

158 Scopus citations

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 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 (US)
Pages (from-to)978-985
Number of pages8
JournalNature Genetics
Volume49
Issue number7
DOIs
StatePublished - Jul 1 2017

Bibliographical note

Funding Information:
We thank S. Hyman and R. Hosking for their thoughtful comments. We also thank A. Pai for his help in the development of the pTDT analytic software. E.B.R. and D.J.W. were funded by National Institute of Mental Health grant 1K01MH099286-01A1 and Brain Behavior Research Foundation (NARSAD) Young Investigator grant 22379. E.M.W. was funded by the Stanley Center for Psychiatric Research at the Broad Institute. A.O. was funded by an ERC Consolidator Grant (647648 EdGe). We thank the families who took part in the Simons Simplex Collection study and the clinicians who collected data at each of the study sites. The iPSYCH project is funded by the Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH and PGC samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to M.J.D.), and the National Institute of Mental Health (5U01MH094432-02 to M.J.D.). This work was also supported by a grant from the Simons Foundation (SFARI 402281 to S.J.S.). The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found on the ExAC website (see URLs).

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

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