title: 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.
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Cavalli
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Gang
authors.initials: G
authors.lastname: Pan
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Nord
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.|Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Wallerman
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.|Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institute, Novum, Huddinge, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Wallén Arzt
authors.affiliation: Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Berggren
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Elvers
authors.affiliation: Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Maija-Leena
authors.initials: ML
authors.lastname: Eloranta
authors.affiliation: Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad Toh
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. claes.wadelius@igp.uu.se.
authors.forename: Claes
authors.initials: C
authors.lastname: Wadelius
mesh_terms: D000483:Alleles; D015415:Biomarkers; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020014:K562 Cells; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D015415:Biomarkers; D014157:Transcription Factors