Atrial fibrillation variant-to-gene prioritization through cross-ancestry eQTL and single-nucleus multiomic analyses
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 <i>GNB4</i> and rs242557 at <i>MAPT</i>. Finally, we showed that the repression of the strongest AF-associated eQTL gene, <i>LINC01629</i>, 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.
Authors
- Kai Kang (ORCID: https://orcid.org/0000-0002-9802-2309)
- Svetlana Reilly (ORCID: https://orcid.org/0000-0003-1231-1239)
- Zhenwei Pan (ORCID: https://orcid.org/0000-0002-1011-0954)
- Stanley Nattel (ORCID: https://orcid.org/0000-0002-5565-3311)
- Chang Jie Mick Lee (ORCID: https://orcid.org/0000-0001-6673-9391)
- Juan Xu (ORCID: https://orcid.org/0000-0003-4623-9343)
- Guillaume Lettre (ORCID: https://orcid.org/0000-0002-7740-3399)
- Lina Xuan (ORCID: https://orcid.org/0000-0003-2127-592X)
- Roger Foo (ORCID: https://orcid.org/0000-0002-8079-4618)
- Xuexin Jin
- Baofeng Yang (ORCID: https://orcid.org/0000-0002-0125-1608)
- Francis Leblanc (ORCID: https://orcid.org/0000-0001-7619-3097)
- Neelam Mehta
- Marouane Benzaki
- Hicham Belhaj
- Wenbo Ma (ORCID: https://orcid.org/0000-0002-4767-7209)
- Chukwuemeka George Anene-Nzelu
Institutions
- Harbin Medical University (CN)
- National University of Singapore (SG)
- Montreal Heart Institute (CA)
- John Radcliffe Hospital (GB)
- University of Oxford (GB)
- Electrophysiology and Heart Modeling Institute (FR)
- First Affiliated Hospital of Harbin Medical University (CN)
- West German Heart and Vascular Center Essen (DE)
- McGill University (CA)
- Université de Montréal (CA)
Publication Details
- Journal
- iScience
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1016/j.isci.2024.110660
- Citations
- 7
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 3.85
Funders
- Wellcome Trust
- Compute Canada
- National Institute for Health and Care Research
- British Heart Foundation
- National Natural Science Foundation of China
- Fondation Institut de Cardiologie de Montréal
- Institut de Cardiologie de Montréal
- National Research Council Canada
- Fonds de Recherche du Québec - Santé
- John Fell Fund, University of Oxford