Genome-wide association analysis of imputed rare variants: application to seven common complex diseases.
Bottom Line: Genome-wide association studies have been successful in identifying loci contributing effects to a range of complex human traits.However, genome-wide association study genotyping chips have been designed primarily to capture common variation, and thus are underpowered to detect the effects of rare variants.The results of our analyses highlight that genome-wide association studies have the potential to offer an exciting opportunity for gene discovery through association with rare variants, conceivably leading to substantial advancements in our understanding of the genetic architecture underlying complex human traits.
Affiliation: Estonian Genome Centre, University of Tartu, Tartu, Estonia.Show MeSH
Related in: MedlinePlus
Mentions: We observed genome-wide significant evidence of association of coronary artery disease with rare variants in the gene PRDM10 (P = 4.9 × 10–8). The gene contained 122 well-imputed rare variants with mean MAF of 0.23%. Accumulations of minor alleles across these variants were associated with decreased risk of disease: odds ratio 0.828 (0.774–0.886) per minor allele. We also observed 10 genes with genome-wide significant evidence of rare variant association with type 1 diabetes, all located within the major histocompatibility complex (MHC) (Table 1 and Figure 4). The strongest signal of association was observed for HLA-DRA (P = 2.0 × 10−13), which has been previously implicated in susceptibility to type 1 diabetes [Nejentsev et al., 2007. Accumulations of minor alleles at rare variants in nine of the MHC genes were associated with reduced risk of type 1 diabetes (Table 1). The only gene demonstrating evidence of association of accumulations of minor alleles with increased risk of type 1 diabetes was TNXA, with odds ratio 2.346 (1.772–3.107) per minor allele.
Affiliation: Estonian Genome Centre, University of Tartu, Tartu, Estonia.