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

Psychiatric Genomics Consortium Autism Group, iPSYCH-Broad Autism Group

Research output: Contribution to journalArticle

94 Citations (Scopus)

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

Fingerprint

Autism Spectrum Disorder
Schizophrenia
Phenotype

ASJC Scopus subject areas

  • Genetics

Cite this

Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. / Psychiatric Genomics Consortium Autism Group; iPSYCH-Broad Autism Group.

In: Nature Genetics, Vol. 49, No. 7, 01.07.2017, p. 978-985.

Research output: Contribution to journalArticle

Psychiatric Genomics Consortium Autism Group ; iPSYCH-Broad Autism Group. / Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. In: Nature Genetics. 2017 ; Vol. 49, No. 7. pp. 978-985.
@article{30016d7e86984676ab8bb889f39ca6df,
title = "Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders",
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 = "{Psychiatric Genomics Consortium Autism Group} and {iPSYCH-Broad Autism Group} and 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 John Nurnberger",
year = "2017",
month = "7",
day = "1",
doi = "10.1038/ng.3863",
language = "English (US)",
volume = "49",
pages = "978--985",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

AU - Psychiatric Genomics Consortium Autism Group

AU - iPSYCH-Broad Autism Group

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

AU - Skuse, David

AU - Devlin, Bernie

AU - Anney, Richard

AU - Sanders, Stephan J.

AU - Bishop, Somer

AU - Mortensen, Preben Bo

AU - Børglum, Anders D.

AU - Smith, George Davey

AU - Daly, Mark J.

AU - Robinson, Elise B.

AU - Bækvad-Hansen, Marie

AU - Dumont, Ashley

AU - Hansen, Christine

AU - Hansen, Thomas F.

AU - Howrigan, Daniel

AU - Mattheisen, Manuel

AU - Moran, Jennifer

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 - Nurnberger, John

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85021757773&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021757773&partnerID=8YFLogxK

U2 - 10.1038/ng.3863

DO - 10.1038/ng.3863

M3 - Article

C2 - 28504703

AN - SCOPUS:85021757773

VL - 49

SP - 978

EP - 985

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 7

ER -