Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression

Abstract

Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1654-x) contains supplementary material, which is available to authorized users.

A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus

“…Interestingly, whereas these show minimal evidence of acting as regulatory polymorphisms according to RegulomeDB (score 5 and 4, respectively), rs9603612 seems to influence the COG6 expression in monocytes, thus representing a better candidate to be the causal variant involved in the genetic predisposition to these three autoimmune conditions. Indeed, a very recent study focused on identifying functional variants for disease-associated loci , has confirmed this regulatory role of the rs9603612 polymorphism 32. Specifically, the minor allele (G) was found to increase the COG6 expression compared with the major allele, thus supporting that rs9603612 influences the development of SLE, RA and psoriasis by regulating the COG6 levels.…”

An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility

“…Further annotation of this DHS revealed that it overlapped with an erythroid enhancer chromatin signature as defined in primary human erythroid precursors (17) and with several GATA1-binding motifs, and harbored multiple erythroblast-specific eQTLs in strong LD that were associated with ATP2B4 expression and rbc phenotypes ( Figure 2D and Figure 3A). Supporting the regulatory potential of this DHS in erythroid cells, a recent analysis of ENCODE data found that it showed allele-specific transcription factor binding only in K562 cells (20).…”

Evaluating the impact of single nucleotide variants on transcription factor binding

“…For instance, the classification model may be under-fitted because the number of ASB events available for training was not sufficient. In the review stage of this manuscript, two studies compiled new ASB data sets in other cell lines to investigate GWAS loci or the variant impact on gene expression (17,57). In the future, we anticipate a rapidly growing body of ASB data will be critical in training more reliable models.…”