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. Børglum; George 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; Thomas H. Wassink; Psychiatric Genomics Consortium Autism Group; iPSYCH-Broad Autism Group

doi:10.1038/ng.3863

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. Børglum

George 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, Thomas H. Wassink, Psychiatric Genomics Consortium Autism Group, iPSYCH-Broad Autism Group

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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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 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 language	English
Pages (from-to)	978-985
Number of pages	8
Journal	Nature Genetics
Volume	49
Issue number	7
Early online date	15 May 2017
DOIs	https://doi.org/10.1038/ng.3863
Publication status	Published - 1 Jul 2017

Funding

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).

Funders	Funder number
National Institute of Child Health and Human Development
Broad Institute
Lundbeckfonden
Stanley Foundation
Brain and Behavior Research Foundation
Exome Aggregation Consortium
Simons Foundation
National Institute of Mental Health	R00MH101367, R01MH094293, U01MH094432, K01MH099286, U01MH109539, U01MH109514
Eunice Kennedy Shriver National Institute of Child Health and Human Development	U54HD086984
Engineering Research Centers	647648 EdGe
National Alliance for Research on Schizophrenia and Depression	22379
Medical Research Council	MC_UU_12013/1, MR/L010305/1
Horizon 2020 Framework Programme	647648
National Institute of Environmental Health Sciences	P30ES013508
Simons Foundation Autism Research Initiative	402281, 311789, 5U01MH094432-02

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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disordersFinal published version, 789 KBLicence: Article 25fa Dutch Copyright Act

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Weiner, D. J., Wigdor, E. M., Ripke, S., Walters, R. K., Kosmicki, J. A., Grove, J., Samocha, K. E., Goldstein, J. I., Okbay, A., Bybjerg-Grauholm, J., Werge, T., Hougaard, D. M., Taylor, J., Skuse, D., Devlin, B., Anney, R., Sanders, S. J., Bishop, S., Mortensen, P. B., ... iPSYCH-Broad Autism Group (2017). Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nature Genetics, 49(7), 978-985. https://doi.org/10.1038/ng.3863

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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 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.",

author = "Weiner, \{Daniel J.\} and Wigdor, \{Emilie M.\} and Stephan Ripke and Walters, \{Raymond K.\} and Kosmicki, \{Jack A.\} and Jakob Grove and Samocha, \{Kaitlin E.\} and Goldstein, \{Jacqueline I.\} and Aysu Okbay and Jonas Bybjerg-Grauholm and Thomas Werge and Hougaard, \{David M.\} and Jacob Taylor and David Skuse and Bernie Devlin and Richard Anney and Sanders, \{Stephan J.\} and Somer Bishop and Mortensen, \{Preben Bo\} and B{\o}rglum, \{Anders D.\} and Smith, \{George Davey\} and Daly, \{Mark J.\} and Robinson, \{Elise B.\} and Marie B{\ae}kvad-Hansen and Ashley Dumont and Christine Hansen and Hansen, \{Thomas F.\} and Daniel Howrigan and Manuel Mattheisen and Jennifer Moran and Ole Mors and Merete Nordentoft and Bent N{\o}rgaard-Pedersen and Timothy Poterba and Jesper Poulsen and Christine Stevens and Verneri Anttila and Peter Holmans and Hailiang Huang and Lambertus Klei and Lee, \{Phil H.\} and Medland, \{Sarah E.\} and Benjamin Neale and Weiss, \{Lauren A.\} and Lonnie Zwaigenbaum and Yu, \{Timothy W.\} and Kerstin Wittemeyer and Willsey, \{A. Jeremy\} and Wijsman, \{Ellen M.\} and Wassink, \{Thomas H.\} and \{Psychiatric Genomics Consortium Autism Group\} and \{iPSYCH-Broad Autism Group\}",

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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, Børglum, AD, Smith, GD, Daly, MJ, Robinson, EB, Bækvad-Hansen, M, Dumont, A, Hansen, C, Hansen, TF, Howrigan, D, Mattheisen, M, Moran, J, Mors, O, Nordentoft, M, Nørgaard-Pedersen, B, Poterba, T, Poulsen, J, Stevens, C, Anttila, V, Holmans, P, Huang, H, Klei, L, Lee, PH, Medland, SE, Neale, B, Weiss, LA, Zwaigenbaum, L, Yu, TW, Wittemeyer, K, Willsey, AJ, Wijsman, EM, Wassink, TH, Psychiatric Genomics Consortium Autism Group & iPSYCH-Broad Autism Group 2017, 'Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders', Nature Genetics, vol. 49, no. 7, pp. 978-985. https://doi.org/10.1038/ng.3863

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AU - Weiner, Daniel J.

AU - Wigdor, Emilie M.

AU - Ripke, Stephan

AU - Walters, Raymond K.

AU - Kosmicki, Jack A.

AU - Grove, Jakob

AU - Samocha, Kaitlin E.

AU - Goldstein, Jacqueline I.

AU - Okbay, Aysu

AU - Bybjerg-Grauholm, Jonas

AU - Werge, Thomas

AU - Hougaard, David M.

AU - Taylor, Jacob

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AU - Mattheisen, Manuel

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AU - Mors, Ole

AU - Nordentoft, Merete

AU - Nørgaard-Pedersen, Bent

AU - Poterba, Timothy

AU - Poulsen, Jesper

AU - Stevens, Christine

AU - Anttila, Verneri

AU - Holmans, Peter

AU - Huang, Hailiang

AU - Klei, Lambertus

AU - Lee, Phil H.

AU - Medland, Sarah E.

AU - Neale, Benjamin

AU - Weiss, Lauren A.

AU - Zwaigenbaum, Lonnie

AU - Yu, Timothy W.

AU - Wittemeyer, Kerstin

AU - Willsey, A. Jeremy

AU - Wijsman, Ellen M.

AU - Wassink, Thomas H.

AU - Psychiatric Genomics Consortium Autism Group

AU - iPSYCH-Broad Autism Group

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AB - 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.

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SP - 978

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JO - Nature Genetics

JF - Nature Genetics

IS - 7

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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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