Identifying Loci Affecting Trait Variability and Detecting Interactions in Genome-Wide Association Studies

Nat Genet. 2018 Nov;50(11):1608-1614. doi: 10.1038/s41588-018-0225-6. Epub 2018 Oct 15.

Abstract

Identification of genetic variants with effects on trait variability can provide insights into the biological mechanisms that control variation and can identify potential interactions. We propose a two-degree-of-freedom test for jointly testing mean and variance effects to identify such variants. We implement the test in a linear mixed model, for which we provide an efficient algorithm and software. To focus on biologically interesting settings, we develop a test for dispersion effects, that is, variance effects not driven solely by mean effects when the trait distribution is non-normal. We apply our approach to body mass index in the subsample of the UK Biobank population with British ancestry (n ~408,000) and show that our approach can increase the power to detect associated loci. We identify and replicate novel associations with significant variance effects that cannot be explained by the non-normality of body mass index, and we provide suggestive evidence for a connection between leptin levels and body mass index variability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Specimen Banks
  • Body Composition / genetics
  • Body Mass Index
  • Body Weights and Measures / statistics & numerical data
  • Epistasis, Genetic* / physiology
  • Female
  • Gene-Environment Interaction*
  • Genetic Loci / physiology*
  • Genetic Variation
  • Genome-Wide Association Study / methods*
  • Humans
  • Male
  • Models, Genetic
  • Observer Variation
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*
  • Software
  • United Kingdom