Atrial fibrillation variant-to-gene prioritization through cross-ancestry eQTL and single-nucleus multiomic analyses

Francis J A Leblanc; Xuexin Jin; Kai Kang; Chang Jie Mick Lee; Juan Xu; Lina Xuan; Wenbo Ma; Hicham Belhaj; Marouane Benzaki; Neelam Mehta; Roger Sik Yin Foo; Svetlana Reilly; Chukwuemeka George Anene-Nzelu; Zhenwei Pan; Stanley Nattel; Baofeng Yang; Guillaume Lettre

doi:10.1016/j.isci.2024.110660

Atrial fibrillation variant-to-gene prioritization through cross-ancestry eQTL and single-nucleus multiomic analyses

iScience. 2024 Aug 5;27(9):110660. doi: 10.1016/j.isci.2024.110660. eCollection 2024 Sep 20.

Authors

Francis J A Leblanc^{1

2}, Xuexin Jin^{3

4}, Kai Kang⁵, Chang Jie Mick Lee⁶, Juan Xu⁷, Lina Xuan³, Wenbo Ma³, Hicham Belhaj¹, Marouane Benzaki^{1

2}, Neelam Mehta⁸, Roger Sik Yin Foo⁶, Svetlana Reilly⁸, Chukwuemeka George Anene-Nzelu^{1

2

6}, Zhenwei Pan³, Stanley Nattel^{1

2

9

10

11}, Baofeng Yang³, Guillaume Lettre^{1

2}

Affiliations

¹ Montreal Heart Institute, Montreal, QC, Canada.
² Department of Medicine, Université de Montréal, Montréal, QC, Canada.
³ Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Disease, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
⁴ Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
⁵ Department of Cardiovascular Surgery, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
⁶ Cardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁷ College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
⁸ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
⁹ Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
¹⁰ IHU Liryc and Fondation Bordeaux Université, Bordeaux, France.
¹¹ Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.

Abstract

Atrial fibrillation (AF) is the most common arrhythmia in the world. Human genetics can provide strong AF therapeutic candidates, but the identification of the causal genes and their functions remains challenging. Here, we applied an AF fine-mapping strategy that leverages results from a previously published cross-ancestry genome-wide association study (GWAS), expression quantitative trait loci (eQTLs) from left atrial appendages (LAAs) obtained from two cohorts with distinct ancestry, and a paired RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) LAA single-nucleus assay (sn-multiome). At nine AF loci, our co-localization and fine-mapping analyses implicated 14 genes. Data integration identified several candidate causal AF variants, including rs7612445 at GNB4 and rs242557 at MAPT. Finally, we showed that the repression of the strongest AF-associated eQTL gene, LINC01629, in human embryonic stem cell-derived cardiomyocytes using CRISPR inhibition results in the dysregulation of pathways linked to genes involved in the development of atrial tissue and the cardiac conduction system.

Keywords: Techniques in genetics; Transcriptomics; association analysis; expression study; genomic analysis; quantitative genetics.