Journal Article

Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations

Bourque, Guillaume, Dunham, Ian, Berndt, Sonja I., van Dongen, Jenny, Stamatoyannopoulos, John, Reynolds, Alex, Beck, Stephan, Lan, Qing, Franceschini, Nora, Breeze, Charles E., Haugen, Eric, Teschendorff, Andrew, Rothman, Nathaniel

2022

Overview

Background Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk. Results To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 ( https://forge2.altiusinstitute.org/ ), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology. Conclusion In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Animal Genetics and Genomics / Bioinformatics / Biomedical and Life Sciences / Chromatin / Consortia / Deoxyribonuclease / deoxyribonucleases / Disease / Enhancers / epigenome / etiology / Evolutionary Biology / Gene expression / Gene loci / Genome-wide association studies / genome-wide association study / Genomes / heart / Histones / Human Genetics / Life Sciences / Markov chain / Markov chains / Microbial Genetics and Genomics / Plant Genetics and Genomics / Regulatory elements / Regulatory sequences / risk / Single-nucleotide polymorphism / Transcription / world wide web