Contribution of large region joint associations to complex traits genetics

PLoS Genet. 2015 Apr 9;11(4):e1005103. doi: 10.1371/journal.pgen.1005103. eCollection 2015 Apr.

Abstract

A polygenic model of inheritance, whereby hundreds or thousands of weakly associated variants contribute to a trait's heritability, has been proposed to underlie the genetic architecture of complex traits. However, relatively few genetic variants have been positively identified so far and they collectively explain only a small fraction of the predicted heritability. We hypothesized that joint association of multiple weakly associated variants over large chromosomal regions contributes to complex traits variance. Confirmation of such regional associations can help identify new loci and lead to a better understanding of known ones. To test this hypothesis, we first characterized the ability of commonly used genetic association models to identify large region joint associations. Through theoretical derivation and simulation, we showed that multivariate linear models where multiple SNPs are included as independent predictors have the most favorable association profile. Based on these results, we tested for large region association with height in 3,740 European participants from the Health and Retirement Study (HRS) study. Adjusting for SNPs with known association with height, we demonstrated clustering of weak associations (p = 2x10-4) in regions extending up to 433.0 Kb from known height loci. The contribution of regional associations to phenotypic variance was estimated at 0.172 (95% CI 0.063-0.279; p < 0.001), which compared favorably to 0.129 explained by known height variants. Conversely, we showed that suggestively associated regions are enriched for known height loci. To extend our findings to other traits, we also tested BMI, HDLc and CRP for large region associations, with consistent results for CRP. Our results demonstrate the presence of large region joint associations and suggest these can be used to pinpoint weakly associated SNPs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Mass Index
  • C-Reactive Protein / genetics
  • Cholesterol, LDL / genetics
  • Chromosomes, Human / genetics
  • Female
  • Humans
  • Male
  • Models, Genetic
  • Phenotype*
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait Loci*

Substances

  • Cholesterol, LDL
  • C-Reactive Protein

Grant support

This work was supported by the Canada Research Chair Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.