Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci

Chani J Hodonsky; Adam W Turner; Mohammad Daud Khan; Nelson B Barrientos; Ruben Methorst; Lijiang Ma; Nicolas G Lopez; Jose Verdezoto Mosquera; Gaëlle Auguste; Emily Farber; Wei Feng Ma; Doris Wong; Suna Onengut-Gumuscu; Maryam Kavousi; Patricia A Peyser; Sander W van der Laan; Nicholas J Leeper; Jason C Kovacic; Johan L M Björkegren; Clint L Miller

doi:10.1016/j.xgen.2023.100465

Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci

Chani J Hodonsky, Adam W Turner, Mohammad Daud Khan, Nelson B Barrientos, Ruben Methorst, Lijiang Ma, Nicolas G Lopez, Jose Verdezoto Mosquera, Gaëlle Auguste, Emily Farber, Wei Feng Ma, Doris Wong, Suna Onengut-Gumuscu, Maryam Kavousi, Patricia A Peyser, Sander W van der Laan, Nicholas J Leeper, Jason C Kovacic, Johan L M Björkegren, Clint L Miller^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.

Original language	English
Article number	100465
Journal	Cell genomics
Volume	4
Issue number	1
Early online date	7 Dec 2023
DOIs	https://doi.org/10.1016/j.xgen.2023.100465
Publication status	Published - 10 Jan 2024

Keywords

coronary artery
eQTL
fine-mapping
gene regulation
genetic diversity
genome-wide association studies
RNA-seq

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1-s2.0-S2666979X23003099-mainFinal published version, 6.25 MBLicence: CC BY-NC-ND

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Hodonsky, C. J., Turner, A. W., Khan, M. D., Barrientos, N. B., Methorst, R., Ma, L., Lopez, N. G., Mosquera, J. V., Auguste, G., Farber, E., Ma, W. F., Wong, D., Onengut-Gumuscu, S., Kavousi, M., Peyser, P. A., van der Laan, S. W., Leeper, N. J., Kovacic, J. C., Björkegren, J. L. M., & Miller, C. L. (2024). Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci. Cell genomics, 4(1), Article 100465. https://doi.org/10.1016/j.xgen.2023.100465

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title = "Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci",

abstract = "Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.",

keywords = "coronary artery, eQTL, fine-mapping, gene regulation, genetic diversity, genome-wide association studies, RNA-seq",

author = "Hodonsky, {Chani J} and Turner, {Adam W} and Khan, {Mohammad Daud} and Barrientos, {Nelson B} and Ruben Methorst and Lijiang Ma and Lopez, {Nicolas G} and Mosquera, {Jose Verdezoto} and Ga{\"e}lle Auguste and Emily Farber and Ma, {Wei Feng} and Doris Wong and Suna Onengut-Gumuscu and Maryam Kavousi and Peyser, {Patricia A} and {van der Laan}, {Sander W} and Leeper, {Nicholas J} and Kovacic, {Jason C} and Bj{\"o}rkegren, {Johan L M} and Miller, {Clint L}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

month = jan,

day = "10",

doi = "10.1016/j.xgen.2023.100465",

language = "English",

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Hodonsky, CJ, Turner, AW, Khan, MD, Barrientos, NB, Methorst, R, Ma, L, Lopez, NG, Mosquera, JV, Auguste, G, Farber, E, Ma, WF, Wong, D, Onengut-Gumuscu, S, Kavousi, M, Peyser, PA, van der Laan, SW, Leeper, NJ, Kovacic, JC, Björkegren, JLM & Miller, CL 2024, 'Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci', Cell genomics, vol. 4, no. 1, 100465. https://doi.org/10.1016/j.xgen.2023.100465

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T1 - 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 - 2024/1/10

Y1 - 2024/1/10

N2 - Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.

AB - Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.

KW - coronary artery

KW - eQTL

KW - fine-mapping

KW - gene regulation

KW - genetic diversity

KW - genome-wide association studies

KW - RNA-seq

UR - http://www.scopus.com/inward/record.url?scp=85182172196&partnerID=8YFLogxK

U2 - 10.1016/j.xgen.2023.100465

DO - 10.1016/j.xgen.2023.100465

M3 - Article

C2 - 38190101

SN - 2666-979X

VL - 4

JO - Cell genomics

JF - Cell genomics

IS - 1

M1 - 100465

ER -

Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci

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Keywords

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