ABSTRACT: Importance:Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective:To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants:This genome-wide association study used a case-control design to evaluate 44?703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256?926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures:Genetic variants (615?643 variants) and polyunsaturated fatty acids (?-6 and ?-3) measured in blood samples. Main Outcomes and Measures:Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results:The mean (SD) age of the 44?703 GERA participants was 69.7 (8.4) years, and 22?019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P?=?3.0?×?10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312?118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P?=?2.5?×?10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P?=?.03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P?=?6.6?×?10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P?=?7.4?×?10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P?=?.04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P?=?4.1?×?10-4]). Conclusions and Relevance:Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ?-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.
