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

Cavalli M, Pan G, Nord H, Wallerman O, Wallén Arzt E, Berggren O, Elvers I, Eloranta ML, Rönnblom L, Lindblad Toh K, Wadelius C - Hum. Genet. (2016)

Bottom Line: 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.Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types.

View Article: PubMed Central - PubMed

Affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

Allelic effects of rare variants. Allele-specific effect (see “Materials and methods”) at heterozygous SNPs with a significant difference between the ChIP-seq reads of alleles G1 and G2 in four different cell lines
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Fig1: Allelic effects of rare variants. Allele-specific effect (see “Materials and methods”) at heterozygous SNPs with a significant difference between the ChIP-seq reads of alleles G1 and G2 in four different cell lines

Mentions: Most AS-SNPs are common in the population, but notably 16 % (13–19 %) of all AS-SNPs (1563 AS-SNPs) had an AF <1 %. Out of all heterozygous SNPs in a cell, 14 % have AF <1 % so an equal fraction shows allele-specific TF binding. To estimate the AS effect, we calculated the ratio between the allele with higher read number count over the total read count observed at common or rare heterozygous SNPs (see “Materials and methods”). We found a strikingly higher ratio with rare AS-SNPs in all cells except H1-hESC (Fig. 1), indicating that rare variants may have a larger effect on regulatory elements than common variants. With the exception of H1-hESC, there was no difference in the ratio for AF 1–10 % or 1–5 % compared to common alleles (Fig S5 in Supplementary material 1). Our data suggest that rare variants frequently affect the function of regulatory sequences and their effect may be larger than common alleles (Lappalainen et al. 2013) and that they therefore may contribute to common diseases to a higher degree than rare variants in coding sequences.Fig. 1


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

Cavalli M, Pan G, Nord H, Wallerman O, Wallén Arzt E, Berggren O, Elvers I, Eloranta ML, Rönnblom L, Lindblad Toh K, Wadelius C - Hum. Genet. (2016)

Allelic effects of rare variants. Allele-specific effect (see “Materials and methods”) at heterozygous SNPs with a significant difference between the ChIP-seq reads of alleles G1 and G2 in four different cell lines
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835527&req=5

Fig1: Allelic effects of rare variants. Allele-specific effect (see “Materials and methods”) at heterozygous SNPs with a significant difference between the ChIP-seq reads of alleles G1 and G2 in four different cell lines
Mentions: Most AS-SNPs are common in the population, but notably 16 % (13–19 %) of all AS-SNPs (1563 AS-SNPs) had an AF <1 %. Out of all heterozygous SNPs in a cell, 14 % have AF <1 % so an equal fraction shows allele-specific TF binding. To estimate the AS effect, we calculated the ratio between the allele with higher read number count over the total read count observed at common or rare heterozygous SNPs (see “Materials and methods”). We found a strikingly higher ratio with rare AS-SNPs in all cells except H1-hESC (Fig. 1), indicating that rare variants may have a larger effect on regulatory elements than common variants. With the exception of H1-hESC, there was no difference in the ratio for AF 1–10 % or 1–5 % compared to common alleles (Fig S5 in Supplementary material 1). Our data suggest that rare variants frequently affect the function of regulatory sequences and their effect may be larger than common alleles (Lappalainen et al. 2013) and that they therefore may contribute to common diseases to a higher degree than rare variants in coding sequences.Fig. 1

Bottom Line: 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.Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types.

View Article: PubMed Central - PubMed

Affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus