Sep 21, 2015

Haplotype synthesis analysis in public reference data reveals functional variants underlying known genome-wide associated susceptibility loci

BioRxiv : the Preprint Server for Biology
André Lacour, Tim Becker


The functional mechanisms underlying disease association identified by Genome-wide Association Studies remain unknown for susceptibility loci located outside gene coding regions. In addition to the regulation of gene expression, synthesis of effects from multiple surrounding functional variants has been suggested as an explanation of hard-to-interpret associations. Here, we define filter criteria based on linkage disequilibrium measures and allele frequencies which reflect expected properties of synthesizing variant sets. For eligible candidate sets we search for those haplotypes that are highly correlated with the risk alleles of a genome-wide associated variant. We applied our methods to 1,000 Genomes reference data and confirmed Crohn's Disease and Type 2 Diabetes susceptibility loci. Of these, a proportion of 32% allowed explanation by three-variant-haplotypes carrying at least two functional variants, as compared to a proportion of 16% for random variants (P=2.9 x t10^-6). More importantly, we detected examples of known loci whose association can fully be explained by surrounding missense variants: three missense variants from MUC19 synthesize rs11564258 (LOC105369736/MUC19, intron; Crohn's Disease). Next, rs2797685 (PER3,...Continue Reading

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Mentioned in this Paper

Genome-Wide Association Study
Diabetes Mellitus, Non-Insulin-Dependent
Regulation of Biological Process
PER3 protein, human

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