A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity? Academic Article uri icon

Overview

MeSH

  • Family
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Male
  • Polymorphism, Single Nucleotide

MeSH Major

  • Autism Spectrum Disorder
  • Autistic Disorder
  • Phenotype

abstract

  • 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. 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. 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. 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. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

publication date

  • May 1, 2015

has subject area

  • Autism Spectrum Disorder
  • Autistic Disorder
  • Family
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4379124

Digital Object Identifier (DOI)

  • 10.1016/j.biopsych.2014.09.017

PubMed ID

  • 25534755

Additional Document Info

start page

  • 775

end page

  • 784

volume

  • 77

number

  • 9