Abstract
A causative role for single nucleotide polymorphisms (SNPs) in many genetic disorders has become evident through numerous genome-wide association studies. However, identification of these common causal variants and the molecular mechanisms underlying these associations remains a major challenge. Differential transcription factor binding at a SNP resulting in altered gene expression is one possible mechanism. Here we apply PWAS (âproteome-wide analysis of SNPsâ), a methodology based on quantitative mass spectrometry that enables rapid screening of SNPs for differential transcription factor binding, to 12 SNPs that are highly associated with type 1 diabetes at the IL2RA locus, encoding the interleukin-2 receptor CD25. We report differential, allele-specific binding of the transcription factors RUNX1, LEF1, CREB, and TFAP4 to IL2RA SNPs rs12722508*A, rs12722522*C, rs41295061*A, and rs2104286*A and demonstrate the functional influence of RUNX1 at rs12722508 by reporter gene assay. Thus, PWAS may be able to contribute to our understanding of the molecular consequences of human genetic variability underpinning susceptibility to multi-factorial disease.
Highlights
Genome-wide association studies (GWAS) of common diseases typically result in the identification of genomic susceptibility loci, in which several single nucleotide polymorphisms (SNPs) showing strong inter-marker linkage disequilibrium (LD) are associated with disease predisposition
To demonstrate proteome-wide analysis of SNPsââ (PWAS) in a disease relevant context, we report differential transcription factor binding to type 1 diabetes- (T1D-) associated SNPs at the IL2RA or CD25 locus
We develop a method termed ââproteome-wide analysis of SNPsââ (PWAS) that identifies differentially binding transcription factors (TFs) and thereby helps to unravel the molecular mechanisms by which the SNPs may exert their effect on gene regulation
Summary
Genome-wide association studies (GWAS) of common diseases typically result in the identification of genomic susceptibility loci, in which several single nucleotide polymorphisms (SNPs) showing strong inter-marker linkage disequilibrium (LD) are associated with disease predisposition. The SNPs that are most associated with the disease are commonly located in non-coding regions where they have no obvious function. Such SNPs presumably alter expression of a nearby gene via differential transcription factor (TF) binding or by influencing gene splicing. Analysis of differential interactions due to single nucleotide changes is challenging because SNP-related differences in binding affinity are typically low. We describe PWAS, a technique to study differential transcription factor binding to nucleotide sequences in a streamlined manner. To demonstrate PWAS in a disease relevant context, we report differential transcription factor binding to type 1 diabetes- (T1D-) associated SNPs at the IL2RA or CD25 locus
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