Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
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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.
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Most of the autistic population is idiopathic with causes unknown, likely due to complex polygenic and environmental interactions.
“Most of the autistic population is considered “idiopathic” with causes unknown, likely the result of complex polygenic and environmental interactions [1,2,3,4].”
From The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders (2020) · cites this paper as [1]
The polygenic TDT test had previously demonstrated overtransmission of PSASD, PSSZ and PSEA to cases, establishing proof of concept for including these scores in this study.
“For this reason, these polygenic scores were selected for the first family-based study that applied a polygenic TDT test (also used in this study) to demonstrate an overtransmission of PSASD, PSSZ and PSEA to cases17. This established for us the proof of concept for their inclusion in this study.”
From A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex (2022) · cites this paper as [17]
Many types of ASD-associated de novo variants are observed more frequently in female cases.
“Many types of ASD-associated de novo variants are observed more frequently in female cases.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [4]
Genetic studies of de novo variants have consistently supported a female protective effect against ASD.
“The possibility of a “female protective effect” (FPE) against ASD has been described extensively and has received consistent support from the results of genetic studies of de novo variants.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [4]
Inconsistent observations of elevated polygenic risk in female cases could be a function of statistical power, as the ASD PRS currently explains limited case-control variance on the liability scale (<3%) and under 4,000 female cases are present in published ASD GWAS meta-analyses.
“Inconsistent observations could be a function of statistical power, as the polygenic risk score (PRS) for ASD currently explains limited case-control variance on the liability scale (<3%), and under 4,000 female cases are present in published ASD genome-wide association study (GWAS) meta-analyses.4,15”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [4]
Elevated polygenic risk for ASD in female cases has not been consistently observed.
“Given the findings above, we may expect elevated polygenic risk for ASD in female cases; however, that has not been consistently observed.4,15,16”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [4]
Children with ASD, on average, substantially over-inherit their parents' polygenic risk for ASD, as well as for schizophrenia and increased educational attainment.
“We have previously shown that children with ASD, on average, substantially over-inherit their parents’ polygenic risk for ASD, as well as for schizophrenia and increased educational attainment.4”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [4]
Polygenic risk for ASD is, in the general population, associated with many positive traits.
“We also note that polygenic risk for ASD is, in the general population, associated with many positive traits.4,15,30”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [4]
Across individuals with ASD, de novo variant count is associated with variant impact: as de novo variant count increases, so does their average effect size contribution to ASD.
“Across individuals with ASD, de novo variant count is associated with variant impact: as de novo variant count increases, so does their average effect size contribution to ASD.4”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [4]
Common variant-related polygenic risk and rare inherited variants in the genetic background also impact the phenotypic expression of rare, large-effect pathogenic variants in NDDs.
“Common variant-related polygenic risk and rare inherited variants in the genetic background also impact the phenotypic expression of rare, large-effect pathogenic variants in NDDs”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [55]
Common variant-associated risk may load on cognitive and behavioral dimensions that are distinct from those affected by rare variants and may be more specific to ASD.
“In contrast to the situation with large-effect rare variants, genetic model fitting in twins53 and the consistent positive correlation of ASD with polygenic scores for IQ and educational attainment54, 55, 56, 57 suggest that common variant-associated risk may load on cognitive and behavioral dimensions that are distinct from those affected by rare variants and may be more specific to ASD.”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [55]
Some pleiotropy of copy number variants may be due to modification by genetic risk scores, because even in individuals with autism spectrum disorder or schizophrenia carrying large-effect de novo mutations there appears to be an additive effect of common variation on phenotypic expression.
“Emerging evidence suggests that among other factors, some of this pleiotropy may be due to modification GRS because even in those with ASD or SCZ carrying large effect de novo mutations, there appears to be an additive effect of common variation on phenotypic expression (Tansey et al., 2016; Weiner et al., 2017).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Weiner et al., 2017
Individuals with ASD carrying de novo mutations have significantly increased ASD PRS compared to typically developing controls.
“A recent study reported that individuals with ASD that carry de novo mutations have significantly increased PRS for ASD compared to typically developing controls (Weiner et al., 2017).”
From Getting to the cores of autism (2019) · cites this paper as Weiner et al., 2017
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Hoang, N., Buchanan, J. A., & Scherer, S. W. (2018) · npj Genomic Medicine · doi:10.1038/s41525-018-0066-3 · Cited by 26 · see citing works
- Authors
- iPSYCH-Broad Autism Group, Weiner, D. J., Psychiatric Genomics Consortium Autism Group, 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., Børglum, A. D., Smith, G. D., Daly, M. J., & Robinson, E. B.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- Lundbeck Foundation (DK)
- Statens Serum Institut (DK)
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- Aarhus University (DK)
- Corresponding author
- Robinson, Elise B
- ORCID
- Weiner, Daniel J
- Wigdor, Emilie M
- Ripke, Stephan
- Walters, Raymond K
- Kosmicki, Jack A
- Grove, Jakob
- Samocha, Kaitlin E
- Goldstein, Jacqueline I
- Okbay, Aysu
- Werge, Thomas
- Hougaard, David M
- Taylor, Jacob
- Skuse, David
- Devlin, Bernie
- Anney, Richard
- Sanders, Stephan J
- Mortensen, Preben Bo
- Børglum, Anders D
- Smith, George Davey
- Daly, Mark J
- Robinson, Elise B
- Venue
- Nature Genetics
- Published
- 2017-05-15
- Volume
- 49
- Issue
- 7
- Pages
- 978-985
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5552240
- OpenAlex
- W2616744713
- Cited by
- 516
- References
- 36
- Citations by year
- 2026: 31 · 2025: 36 · 2024: 48 · 2023: 41 · 2022: 52 · 2021: 63 · 2020: 56 · 2019: 77 · 2018: 90 · 2017: 22
- FWCI
- 38.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- VU Research Portal (publishedVersion, other-oa)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Explore Bristol Research (acceptedVersion, other-oa)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- HAL (submittedVersion, other-oa)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, other-oa)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Brain and Behavior Research Foundation
- Brain Research Foundation
- Simons Foundation (311789, 307705, SFARI 311789)
- National Alliance for Research on Schizophrenia and Depression
- Broad Institute (402281)
- Simons Foundation Autism Research Initiative (402281)
- Lundbeckfonden (R155-2014-1724)
- H. Lundbeck A/S
- National Institutes of Health (5k01mh099286-02, 5u01mh094432-04)
- Stanley Center for Psychiatric Research, Broad Institute
- Medical Research Council (MR/L010305/1)
- National Institute of Mental Health (U01MH109539, U01MH109514, U01 MH094432, R01MH094293, 402281, R00MH101367, R01MH100027, K01 MH099286, 1K01MH099286-01A1, 5U01MH094432‐02)
- National Institute of Environmental Health Sciences (P30ES013508)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD086984)
- H2020 European Research Council (647648)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, polygenic risk, de novo mutations, family-based association, schizophrenia, educational attainment
- MeSH terms
- Autism Spectrum Disorder, Adult, Child, Educational Status, Ethnicity, Family Health, Female, Genetics, Behavioral, Humans, Intelligence, Male, Intellectual Disability, Phenotype, Risk Factors, Schizophrenia, Genetic Variation, Cohort Studies, Sequence Deletion, Genetic Predisposition to Disease, Multifactorial Inheritance, Genetic Association Studies
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