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

Nat Genet. 2017 Jul;49(7):978-985. doi: 10.1038/ng.3863. Epub 2017 May 15.

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.

MeSH terms

  • Adult
  • Autism Spectrum Disorder / epidemiology
  • Autism Spectrum Disorder / genetics*
  • Child
  • Cohort Studies
  • Educational Status
  • Ethnic Groups / genetics
  • Family Health
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genetics, Behavioral
  • Humans
  • Intellectual Disability / genetics
  • Intelligence / genetics
  • Male
  • Multifactorial Inheritance*
  • Phenotype
  • Risk Factors
  • Schizophrenia / genetics
  • Sequence Deletion