Genetic effects on liver chromatin accessibility identify disease regulatory variants

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...

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Bibliographic Details
Published in:American journal of human genetics 2021-07, Vol.108 (7), p.1169-1189
Main Authors: Currin, Kevin W., Erdos, Michael R., Narisu, Narisu, Rai, Vivek, Vadlamudi, Swarooparani, Perrin, Hannah J., Idol, Jacqueline R., Yan, Tingfen, Albanus, Ricardo D’Oliveira, Broadaway, K. Alaine, Etheridge, Amy S., Bonnycastle, Lori L., Orchard, Peter, Didion, John P., Chaudhry, Amarjit S., Barnabas, Beatrice B., Black, Sean, Bouffard, Gerard G., Brooks, Shelise Y., Coleman, Holly, Dekhtyar, Lyudmila, Han, Joel, Ho, Shi-ling, Kim, Juyun, Legaspi, Richelle, Maduro, Quino L., Masiello, Catherine A., McDowell, Jennifer C., Montemayor, Casandra, Mullikin, James C., Park, Morgan, Riebow, Nancy L., Schandler, Karen, Schmidt, Brian, Sison, Christina, Stantripop, Sirintorn, Thomas, James W., Thomas, Pamela J., Vemulapalli, Meghana, Young, Alice C., Innocenti, Federico, Schuetz, Erin G., Scott, Laura J., Parker, Stephen C.J., Collins, Francis S., Mohlke, Karen L.
Format: Article
Language:English
Subjects:
Amino Acid Motifs
ATAC-seq
Binding Sites
caQTL
cardiometabolic traits
Chromatin - metabolism
chromatin accessibility
Chromatin Assembly and Disassembly
Enhancer Elements, Genetic
eQTL
Genetic Variation
Genome-Wide Association Study
GWAS
Humans
Liver - metabolism
Promoter Regions, Genetic
Protein Binding
Quantitative Trait Loci
transcription factor motif
Transcription Factors - chemistry
Transcription Factors - metabolism
Transcriptome
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Summary: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.
ISSN:0002-9297
1537-6605
1537-6605
DOI:10.1016/j.ajhg.2021.05.001