Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program

Abstract

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 , IL-6 , 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.

Measuring lipoprotein(a) for cardiovascular disease prevention – in whom and when?

“…This was corroborated by evidence from the from the Emerging Risk Factors Collaboration [8], and in a large study on genetic variation in the LPA gene [7]. Following this, an association of high lipoprotein(a) with aortic valve stenosis was also identified [11,14], though whether high lipoprotein(a) levels contribute to aortic valve stenosis progression is less clear [15 & ]. High plasma lipoprotein(a) is also associated with risk of ischemic stroke, peripheral arterial disease, heart failure, cardiovascular mortality, and all-cause mortality [3…”

Lipoprotein(a) and calcific aortic valve disease: current evidence and future directions

“…After the inception of calcification, the decreased compliance of the cusps leads to further mechanical stress, inducing a cycle whereby “calcium begets calcium” [14 ▪▪ ]. Permissive risk factors for CAVD include age, male sex, hypertension, smoking, obesity, congenital bicuspid morphology, genetic variants, LDL-cholesterol, Lp(a) and other apoB-containing lipoproteins [13,15 ▪▪ ,16 ▪▪ ,17 ▪ ].…”

“…Recent studies of association between Lp(a) and CAVD/AS are shown in Table 1[15 ▪▪ ,16 ▪▪ ,29 ▪▪ ,30 ▪▪ –36 ▪▪ ]. Many prior studies have reported Lp(a) concentration in mg/dl.…”

“…Moreover, two single nucleotide polymorphisms (SNPs), rs10455872 and rs3798220, are associated with Lp(a) levels [43]. Recent genetic studies support a causal role of Lp(a) in the development of CAVD/AS [15 ▪▪ ,16 ▪▪ ,36 ▪▪ ].…”

The 10 essential questions regarding lipoprotein(a)

“…A multiancestry genome-wide association study in the million veteran programs recently showed that Lp(a) and LDL were both associated with calcific aortic stenosis, but the association of LDL was attenuated when adjusting for Lp(a) [51].…”