A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?
Open accessAbstract
Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD.Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup.Results Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups.Conclusions In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.
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Grouping by ASD diagnostic category, IQ, ASD severity, insistence on sameness, and symptom profiles did not significantly increase genetic homogeneity as defined by SNPs and did not yield more discoveries for common variation.
“However, in one recent study, grouping by ASD diagnostic category, IQ, ASD severity, insistence on sameness and symptom profiles did not significantly increase genetic homogeneity, at least as defined by SNPs nor does it yield more discoveries for common variation (104,105).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [104]
rs1409313 has previously been implicated as a paternally inherited risk marker for ASD within the Simons Simplex Collection data.
“This marker has previously been implicated as a paternally inherited risk marker for ASD within the Simons Simplex Collection (SSC) data [25].”
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- Authors
- Chaste, P., Klei, L., Sanders, S. J., Hus, V., Murtha, M. T., Lowe, J. K., Willsey, A. J., Moreno-De-Luca, D., Yu, T. W., Fombonne, E., Geschwind, D., Grice, D. E., Ledbetter, D. H., Mane, S. M., Martin, D. M., Morrow, E. M., Walsh, C. A., Sutcliffe, J. S., Lese Martin, C., Beaudet, A. L., Lord, C., State, M. W., Cook, E. H., & Devlin, B.
- Affiliations
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- Yale University (US)
- University of California, Los Angeles (US)
- Boston Children's Hospital (US)
- Oregon Health & Science University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Autism & Developmental Medicine Institute (US)
- University of Michigan (US)
- Brown University (US)
- Vanderbilt University (US)
- Baylor College of Medicine (US)
- Weill Cornell Medicine (US)
- University of Illinois Chicago (US)
- Corresponding author
- Chaste, Pauline
- ORCID
- Chaste, Pauline
- Klei, Lambertus
- Sanders, Stephan J.
- Lowe, Jennifer K.
- Willsey, A. Jeremy
- Yu, Timothy W.
- Fombonne, Eric
- Geschwind, Daniel
- Grice, Dorothy E.
- Ledbetter, David H.
- Mane, Shrikant M.
- Martin, Donna M.
- Morrow, Eric M.
- Walsh, Christopher A.
- Sutcliffe, James S.
- Beaudet, Arthur L.
- Lord, Catherine
- State, Matthew W.
- Cook, Edwin H.
- Devlin, Bernie
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 77
- Issue
- 9
- Pages
- 775-784
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4379124
- OpenAlex
- W1987925623
- Cited by
- 144
- References
- 76
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 10 · 2021: 16 · 2020: 16 · 2019: 19 · 2018: 15 · 2017: 27 · 2016: 17 · 2015: 18
- FWCI
- 11.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institutes of Health (NIH) (R01HD065272, R01MH089390, R37 MH057881)
- National Institute of Mental Health (5R25MH071584-07, T32 MH19961-14)
- 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, phenotypic heterogeneity, subphenotyping, genetic homogeneity, genetic risk variants, Simons Simplex Collection, family-based association study, heritability, single nucleotide polymorphisms, genetic susceptibility
- MeSH terms
- Autism Spectrum Disorder, Autistic Disorder, Family, Female, Humans, Male, Phenotype, Genetic Variation, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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