Polygenic Transmission Disequilibrium Confirms That Common and Rare Variation Act Additively to Create Risk for Autism Spectrum Disorders

Overview

Journal Nat Genet

Specialty Genetics

Date 2017 May 16

PMID 28504703

Citations 240

Authors

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 Borglum

George Davey Smith

Mark J Daly

Elise B Robinson

Affiliations

Soon will be listed here.

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.

Citing Articles

Generation and Characterization of a Knockout Mouse of an Enhancer of .

Hurtado E, Wotton J, Gulka A, Burke C, Ng J, Bah I bioRxiv. 2025; .

PMID: 39829799 PMC: 11741297. DOI: 10.1101/2025.01.09.631762.

Prematurity and Genetic Liability for Autism Spectrum Disorder.

Zhang Y, Yahia A, Sandin S, Aden U, Tammimies K medRxiv. 2024; .

PMID: 39606368 PMC: 11601743. DOI: 10.1101/2024.11.20.24317613.

Common genetic variants contribute more to rare diseases than previously thought.

Breen G Nature. 2024; 636(8042):304-305.

PMID: 39567806 DOI: 10.1038/d41586-024-03554-4.

Examining the role of common variants in rare neurodevelopmental conditions.

Huang Q, Wigdor E, Malawsky D, Campbell P, Samocha K, Chundru V Nature. 2024; 636(8042):404-411.

PMID: 39567701 PMC: 11634775. DOI: 10.1038/s41586-024-08217-y.

Resolving complex duplication variants in autism spectrum disorder using long-read genome sequencing.

Eisfeldt J, Higginbotham E, Lenner F, Howe J, Fernandez B, Lindstrand A Genome Res. 2024; 34(11):1763-1773.

PMID: 39472019 PMC: 11610597. DOI: 10.1101/gr.279263.124.

References

Hagenaars S, Harris S, Davies G, Hill W, Liewald D, Ritchie S . Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia. Mol Psychiatry. 2016; 21(11):1624-1632. PMC: 5078856. DOI: 10.1038/mp.2015.225. View

Kosmicki J, Samocha K, Howrigan D, Sanders S, Slowikowski K, Lek M . Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017; 49(4):504-510. PMC: 5496244. DOI: 10.1038/ng.3789. View

Lee S, Ripke S, Neale B, Faraone S, Purcell S, Perlis R . Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013; 45(9):984-94. PMC: 3800159. DOI: 10.1038/ng.2711. View

Chang C, Chow C, Tellier L, Vattikuti S, Purcell S, Lee J . Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015; 4:7. PMC: 4342193. DOI: 10.1186/s13742-015-0047-8. View

. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511(7510):421-7. PMC: 4112379. DOI: 10.1038/nature13595. View

Lek M, Karczewski K, Minikel E, Samocha K, Banks E, Fennell T . Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016; 536(7616):285-91. PMC: 5018207. DOI: 10.1038/nature19057. View

. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2014; 519(7542):223-8. PMC: 5955210. DOI: 10.1038/nature14135. View

Klei L, Sanders S, Murtha M, Hus V, Lowe J, Willsey A . Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism. 2012; 3(1):9. PMC: 3579743. DOI: 10.1186/2040-2392-3-9. View

Chaste P, Klei L, Sanders S, Hus V, Murtha M, Lowe J . A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?. Biol Psychiatry. 2014; 77(9):775-84. PMC: 4379124. DOI: 10.1016/j.biopsych.2014.09.017. View

10.

Munafo M, Tilling K, Taylor A, Evans D, Davey Smith G . Collider scope: when selection bias can substantially influence observed associations. Int J Epidemiol. 2017; 47(1):226-235. PMC: 5837306. DOI: 10.1093/ije/dyx206. View

11.

. WHO Motor Development Study: windows of achievement for six gross motor development milestones. Acta Paediatr Suppl. 2006; 450:86-95. DOI: 10.1111/j.1651-2227.2006.tb02379.x. View

12.

Wray N, Goddard M, Visscher P . Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res. 2007; 17(10):1520-8. PMC: 1987352. DOI: 10.1101/gr.6665407. View

13.

Locke A, Kahali B, Berndt S, Justice A, Pers T, Day F . Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015; 518(7538):197-206. PMC: 4382211. DOI: 10.1038/nature14177. View

14.

Robinson E, Samocha K, Kosmicki J, McGrath L, Neale B, Perlis R . Autism spectrum disorder severity reflects the average contribution of de novo and familial influences. Proc Natl Acad Sci U S A. 2014; 111(42):15161-5. PMC: 4210299. DOI: 10.1073/pnas.1409204111. View

15.

Gaugler T, Klei L, Sanders S, Bodea C, Goldberg A, Lee A . Most genetic risk for autism resides with common variation. Nat Genet. 2014; 46(8):881-5. PMC: 4137411. DOI: 10.1038/ng.3039. View

16.

Clarke T, Lupton M, Fernandez-Pujals A, Starr J, Davies G, Cox S . Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population. Mol Psychiatry. 2015; 21(3):419-25. PMC: 4759203. DOI: 10.1038/mp.2015.12. View

17.

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

18.

Fischbach G, Lord C . The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron. 2010; 68(2):192-5. DOI: 10.1016/j.neuron.2010.10.006. View

19.

Samocha K, Robinson E, Sanders S, Stevens C, Sabo A, McGrath L . A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014; 46(9):944-50. PMC: 4222185. DOI: 10.1038/ng.3050. View

20.

Spielman R, McGinnis R, Ewens W . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993; 52(3):506-16. PMC: 1682161. View