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

Contribution of large region joint associations to complex traits genetics.

Author information

1
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Population Genomics Program, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada; Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada; Thrombosis and Atherosclerosis Research Institute, Hamilton, Canada.
2
Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada.
3
Department of Statistical Sciences, University of Toronto, Toronto, Canada.

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.

PMID:
25856144
PMCID:
PMC4391841
DOI:
10.1371/journal.pgen.1005103
[Indexed for MEDLINE]
Free PMC Article

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