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.


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