Contribution of Large Region Joint Associations to Complex Traits Genetics

摘要

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. Author Summary It is widely accepted that genetics influences a broad range of human traits and diseases, yet only a few genetic variants are known to determine these traits and their impact is modest. In this report, we made the hypothesis that combining information from a large number of genetic variants would help better explain how they together contribute to traits such as height. To do so, we first had to select a proper method to integrate large numbers of genetic variants in a single test, here named “large region joint association”. Next, we tested our method on height in 3,740 European participants from the Health and Retirement Study. We showed that the contribution of regional associations to variation in height was 17.2%, as compared to the 12.9% explained by known genetic determinants of height. In other words, the joint effect of multiple genetic variants integrated together contributed to a substantial fraction of the genetics of height. These results are significant because they can help identify new genes or genetic regions associated with human traits or diseases. Conversely, these results can be used to better understand genes that we already know are associated. Furthermore, our results provide insights on how traits are genetically determined.