Figure 14. Model of allelic architecture for functional variations in common disease risk loci.
(A) A working model of the architecture of the variations within common disease risk loci. Disease associated tagging SNPs associate an LD block with a disease phenotype. Within this LD block, multiple variations are in tight LD, including nonfunctional, functional, and causal variants. Causal variants potentiate the disease phenotype by modulating endophenotypes. In this model, causal variants impact two adjacent genes, one of which is not located within the LD block, both of which contribute endophenotypes towards disease. Haplotype and MJ analysis using functional variants in tight LD with original tagging SNP define haplotypes that contain all of the causal variants. The peak risk haplotype defines a disease allele with increased disease association in comparison to the original GWAS tagging SNP. (B) A plot of all of the odds ratios attributable to the GWAS tagging SNP (blue bars) versus the peak risk haplotype (additional red bar) for each of the sixteen risk loci analyzed in detail. A consistent gain in odds ratio for SLE was obtained with regulatory haplotypes that averaged 17% in the present study. (C) Frequency of STAT4, IRF5-TNPO3, ITGAM-ITGAX, UBE2L3 and HLA-D SLE risk haplotypes among our own study and 26 ethnic populations characterized in the 1000 Genomes project. The x-axis of the graph shows population groups and y axis show frequency of haplotypes.