Bayesian refinement of association signals for 14 loci in 3 common diseases

Abstract

To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves’ disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves’ disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.

Genome‐wide association studies of multiple sclerosis

“…Fine‐mapping approaches, therefore, aim to assign posterior probabilities of causality for each variant based on some criteria. One such approach is to assess the posterior probability of causality using genotype and minor allele frequency information and then select the smallest group of variants in each locus that are likely to include the causal one at some threshold 52. When applied to 6356 MS cases and 9617 controls from the United Kingdom, this approach only meaningfully resolved a small subset of associations, with 8/68 loci we analysed resolving to fewer than five candidate variants, and from these, we have been able to identify a relevant candidate gene in three 45.…”

Characterization of the transcriptional machinery bound across the widely presumed type 2 diabetes causal variant, rs7903146, within TCF7L2

“…The situation is somewhat more advanced for the T2D locus, TCF7L2, where rs7903146 is widely regarded as the causal variant through a logical process of elimination leveraging multiple ethnicities and novel statistical approaches. [16][17][18] Indeed, when we first reported the association of TCF7L2 with T2D, we noted that rs12255372 and rs7903146 both captured the association well, 6 but subsequent studies in other ethnicities observed rs12255372 was a less optimal tag-SNP and revealed rs7903146 to be clearly the best SNP to test across multiple populations. 16,17 As such, rs12255372 served as good control in this current study.…”

“…15 Resolving the underlying functional mechanism to a given genetic association in the post-GWAS era has proven extremely challenging. However, the discovery of the TCF7L2 locus in the context of T2D presents a specific opportunity for translational analyses, as studies in multiple ethnicities 16,17 and with Bayesian modeling 18 have now strongly implicated the intron 3 SNP rs7903146 (NG_012631.1:g.53341C4T) as the causal variant within this gene.…”

Redundant enhancers and causal variants in the TCF7L2 gene

“…[8][9][10] The present letter discussed published data from European and nonEuropean populations and postulated that an independent secondary signal tagged by the rs12255372 SNP is also present in the TCF7L2 gene. The author also discussed recent results that show the presence of multiple enhancers in the TCF7L2 gene, 6,7 and advanced the hypothesis that these enhancers are redundant and there is person-to-person variability in their use.…”

“…[8][9][10] However, a critical assessment of published results does not rule out the presence of an independent secondary signal. Helgason et al 8 carried out haplotype analysis of SNPs, rs7903146 and rs12255372, and the microsatellite DG10S478 (ie, the three markers that were initially found with the strongest association with T2D 11 ) in Danish and Icelandic populations, and concluded that rs7903146 is the most likely causal variant.…”