Statistical independence of the colocalized association signals for type 1 diabetes and RPS26 gene expression on chromosome 12q13

Abstract

Following the recent success of genome-wide association studies in uncovering disease-associated genetic variants, the next challenge is to understand how these variants affect downstream pathways. The most proximal trait to a disease-associated variant, most commonly a single nucleotide polymorphism (SNP), is differential gene expression due to the cis effect of SNP alleles on transcription, translation, and/or splicing gene expression quantitative trait loci (eQTL). Several genome-wide SNP-gene expression association studies have already provided convincing evidence of widespread association of eQTLs. As a consequence, some eQTL associations are found in the same genomic region as a disease variant, either as a coincidence or a causal relationship. Cis-regulation of RPS26 gene expression and a type 1 diabetes (T1D) susceptibility locus have been colocalized to the 12q13 genomic region. A recent study has also suggested RPS26 as the most likely susceptibility gene for T1D in this genomic region. However, it is still not clear whether this colocalization is the result of chance alone or if RPS26 expression is directly correlated with T1D susceptibility, and therefore, potentially causal. Here, we derive and apply a statistical test of this hypothesis. We conclude that RPS26 expression is unlikely to be the molecular trait responsible for T1D susceptibility at this locus, at least not in a direct, linear connection.

Fig. 1.

Correlation between RPS26 expression and rs1131017 genotypes. RPS26 expression was measured using the Affymetrix HG-U133 Plus 2.0 gene expression chip.

Fig. 2.

Comparison of estimated regression coefficients in the T1D case–control and the eQTL RPS26 expression studies, analyzing 1 SNP at a time. Assuming a sole causal variant for both traits, the estimated regression coefficients should be proportional between both studies.

Fig. 3.

(A) Jointly estimated regression coefficients and confidence intervals for rs1131017 and rs705704 under the null hypothesis ₀ of a sole common variant and under the alternative ₁. Under the null hypothesis ₀, estimated regression coefficients have to be located on a line passing through the origin. (B) Rescaled version of (A) highlighting the fact that when compared on the same unit scale (i.e. regression estimates located on the unit circle), the variance of the estimated coefficients is higher for the T1D study. Therefore, regression estimates under the null are driven by the RPS26 expression data.