A genome-wide association study of autism using the Simons simplex collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Pauline Chaste, Lambertus Klei, Stephan J. Sanders, Vanessa Hus, Michael T. Murtha, Jennifer K. Lowe, A. Jeremy Willsey, Daniel Moreno-De-Luca, Timothy W. Yu, Eric Fombonne, Daniel Geschwind, Dorothy E. Grice, David H. Ledbetter, Shrikant M. Mane, Donna M. Martin, Eric M. Morrow, Christopher A. Walsh, James S. Sutcliffe, Christa Lese Martin, Arthur L. BeaudetCatherine Lord, Matthew W. State, Edwin H. Cook, Bernie Devlin

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)775-784
Number of pages10
JournalBiological Psychiatry
Volume77
Issue number9
DOIs
StatePublished - May 1 2015

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Genome-Wide Association Study
Autistic Disorder
Alleles
Genome
Aptitude
Single Nucleotide Polymorphism
Odds Ratio
Phenotype
Population
Autism Spectrum Disorder
Power (Psychology)

Keywords

  • Autism
  • Genetics
  • GWAS
  • Heterogeneity
  • Phenotype
  • Power

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

A genome-wide association study of autism using the Simons simplex collection : Does reducing phenotypic heterogeneity in autism increase genetic homogeneity? / Chaste, Pauline; Klei, Lambertus; Sanders, Stephan J.; Hus, Vanessa; Murtha, Michael T.; Lowe, Jennifer K.; Willsey, A. Jeremy; Moreno-De-Luca, Daniel; 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.; Lese Martin, Christa; Beaudet, Arthur L.; Lord, Catherine; State, Matthew W.; Cook, Edwin H.; Devlin, Bernie.

In: Biological Psychiatry, Vol. 77, No. 9, 01.05.2015, p. 775-784.

Research output: Contribution to journalArticle

Chaste, P, Klei, L, Sanders, SJ, Hus, V, Murtha, MT, Lowe, JK, Willsey, AJ, Moreno-De-Luca, D, Yu, TW, Fombonne, E, Geschwind, D, Grice, DE, Ledbetter, DH, Mane, SM, Martin, DM, Morrow, EM, Walsh, CA, Sutcliffe, JS, Lese Martin, C, Beaudet, AL, Lord, C, State, MW, Cook, EH & Devlin, B 2015, 'A genome-wide association study of autism using the Simons simplex collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?', Biological Psychiatry, vol. 77, no. 9, pp. 775-784. https://doi.org/10.1016/j.biopsych.2014.09.017
Chaste, Pauline ; Klei, Lambertus ; Sanders, Stephan J. ; Hus, Vanessa ; Murtha, Michael T. ; Lowe, Jennifer K. ; Willsey, A. Jeremy ; Moreno-De-Luca, Daniel ; 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. ; Lese Martin, Christa ; Beaudet, Arthur L. ; Lord, Catherine ; State, Matthew W. ; Cook, Edwin H. ; Devlin, Bernie. / A genome-wide association study of autism using the Simons simplex collection : Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?. In: Biological Psychiatry. 2015 ; Vol. 77, No. 9. pp. 775-784.
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abstract = "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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AU - Hus, Vanessa

AU - Murtha, Michael T.

AU - Lowe, Jennifer K.

AU - Willsey, A. Jeremy

AU - Moreno-De-Luca, Daniel

AU - Yu, Timothy W.

AU - Fombonne, Eric

AU - Geschwind, Daniel

AU - Grice, Dorothy E.

AU - Ledbetter, David H.

AU - Mane, Shrikant M.

AU - Martin, Donna M.

AU - Morrow, Eric M.

AU - Walsh, Christopher A.

AU - Sutcliffe, James S.

AU - Lese Martin, Christa

AU - Beaudet, Arthur L.

AU - Lord, Catherine

AU - State, Matthew W.

AU - Cook, Edwin H.

AU - Devlin, Bernie

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N2 - 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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KW - GWAS

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