TY - UNPB
T1 - Integrative multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci
AU - Hodonsky, Chani J
AU - Turner, Adam W
AU - Khan, Mohammad Daud
AU - Barrientos, Nelson B
AU - Methorst, Ruben
AU - Ma, Lijiang
AU - Lopez, Nicolas G
AU - Mosquera, Jose Verdezoto
AU - Auguste, Gaëlle
AU - Farber, Emily
AU - Ma, Wei Feng
AU - Wong, Doris
AU - Onengut-Gumuscu, Suna
AU - Kavousi, Maryam
AU - Peyser, Patricia A
AU - van der Laan, Sander W
AU - Leeper, Nicholas J
AU - Kovacic, Jason C
AU - Björkegren, Johan L M
AU - Miller, Clint L
PY - 2023/2/14
Y1 - 2023/2/14
N2 - Genome-wide association studies (GWAS) have identified hundreds of genetic risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWAS and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotype information to identify quantitative trait loci (QTL) for gene expression and splicing in coronary arteries obtained from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary arteries and 19% exhibited cell-type-specific expression. Colocalization analysis with GWAS identified subgroups of eGenes unique to CAD and blood pressure. Fine-mapping highlighted additional eGenes of interest, including
TBX20 and
IL5 . Splicing (s)QTLs for 1,690 genes were also identified, among which
TOR1AIP1 and
ULK3 sQTLs demonstrated the importance of evaluating splicing events to accurately identify disease-relevant gene expression. Our work provides the first human coronary artery eQTL resource from a patient sample and exemplifies the necessity of diverse study populations and multi-omic approaches to characterize gene regulation in critical disease processes.
AB - Genome-wide association studies (GWAS) have identified hundreds of genetic risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWAS and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotype information to identify quantitative trait loci (QTL) for gene expression and splicing in coronary arteries obtained from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary arteries and 19% exhibited cell-type-specific expression. Colocalization analysis with GWAS identified subgroups of eGenes unique to CAD and blood pressure. Fine-mapping highlighted additional eGenes of interest, including
TBX20 and
IL5 . Splicing (s)QTLs for 1,690 genes were also identified, among which
TOR1AIP1 and
ULK3 sQTLs demonstrated the importance of evaluating splicing events to accurately identify disease-relevant gene expression. Our work provides the first human coronary artery eQTL resource from a patient sample and exemplifies the necessity of diverse study populations and multi-omic approaches to characterize gene regulation in critical disease processes.
U2 - 10.1101/2023.02.09.23285622
DO - 10.1101/2023.02.09.23285622
M3 - Preprint
C2 - 36824883
BT - Integrative multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci
PB - medRxiv
ER -