Genetic effects on liver chromatin accessibility identify disease regulatory variants

Kevin W Currin, Michael R Erdos, Narisu Narisu, Vivek Rai, Swarooparani Vadlamudi, Hannah J Perrin, Jacqueline R Idol, Tingfen Yan, Ricardo D'Oliveira Albanus, K Alaine Broadaway, Amy S Etheridge, Lori L Bonnycastle, Peter Orchard, John P Didion, Amarjit S Chaudhry, NISC Comparative Sequencing Program; Federico Innocenti, Erin G Schuetz, Laura J Scott, Stephen C J Parker, Francis S Collins, Karen L Mohlke.
Am J Hum Genet.. 2021-05-20;S0002-9297(21):00185-3.
Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging. Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues. Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs. The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver. We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs. Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene. At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity. These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci.
Consortium data used in this publication
Summary statistics for caQTL data are available at https://mohlke. Raw and processed genotype, ATAC-seq, and RNA-seq data are available in the Gene Expression Omnibus (GEO). The accession number for the data reported in this paper is GEO: GSE164942. ATAC-seq on liver tissue from 20 individuals GSE164870. RNA-seq on liver tissue from 20 individuals GSE164876.