Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Background: Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS. Methods: We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study. Results: We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the FTO locus. However, the FTO locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis. Conclusions: We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Circulation |
| Vol/bind | 147 |
| Udgave nummer | 12 |
| Sider (fra-til) | 942-955 |
| Antal sider | 14 |
| ISSN | 0009-7322 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Vanderbilt University Medical Center’s BioVU projects are supported by numerous sources by means of institutional funding, private agencies, and federal grants. These include National Institutes of Health–funded shared instrumentation grants S10OD017985, S10RR025141, and S10OD025092 and Clinical and Translational Science Awards Program grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects, including U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711. Dr Damrauer is supported by IK2-CX001780. Dr Natarajan is supported by grants from the National Institutes of Health (R01HL142711, 148050, R01HL151283, R01HL127564, U01HG011719, and R01HL151152). Dr Peloso is supported by grants from the National Institutes of Health (R01HL142711 and R01HL127564). Dr Wang was supported by National Institutes of Health grant 1R01HL139731 and American Heart Association grant 18SFRN34110082. Drs Wilson and Cho are supported by the Veterans Affairs Merit Award BX004821. This research is based on data from the Million Veteran Program, Office of Research and Development, and Veterans Health Administration, and was supported by award BX004821. This publication does not represent the views of the Department of Veterans Affairs or the US government.
Funding Information:
Vanderbilt University Medical Center's BioVU projects are supported by numerous sources by means of institutional funding, private agencies, and federal grants. These include National Institutes of Health-funded shared instrumentation grants S10OD017985, S10RR025141, and S10OD025092 and Clinical and Translational Science Awards Program grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects, including U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711. Dr Damrauer is supported by IK2-CX001780. Dr Natarajan is supported by grants from the National Institutes of Health (R01HL142711, 148050, R01HL151283, R01HL127564, U01HG011719, and R01HL151152). Dr Peloso is supported by grants from the National Institutes of Health (R01HL142711 and R01HL127564). Dr Wang was supported by National Institutes of Health grant 1R01HL139731 and American Heart Association grant 18SFRN34110082. Drs Wilson and Cho are supported by the Veterans Affairs Merit Award BX004821. This research is based on data from the Million Veteran Program, Office of Research and Development, and Veterans Health Administration, and was supported by award BX004821. This publication does not represent the views of the Department of Veterans Affairs or the US government.
Publisher Copyright:
© 2023 American Heart Association, Inc.
ID: 340695000