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Observational studies have consistently proposed cardiovascular benefits associated with light alcohol consumption, while recent genetic analyses (ie, mendelian randomization studies) have suggested a possible causal link between alcohol intake and increased risk of cardiovascular disease. However, traditional approaches to genetic epidemiology assume a linear association and thus have not fully evaluated dose-response estimates of risk across different levels of alcohol intake.To assess the association of habitual alcohol intake with cardiovascular disease risk and to evaluate the direction and relative magnitude of cardiovascular risk associated with different amounts of alcohol consumption.This cohort study used the UK Biobank (2006-2010, follow-up until 2016) to examine confounding in epidemiologic associations between alcohol intake and cardiovascular diseases. Using both traditional (ie, linear) and nonlinear mendelian randomization, potential associations between alcohol consumption and cardiovascular diseases (eg, hypertension and coronary artery disease) as well as corresponding association shapes were assessed. Data analysis was conducted from July 2019 to January 2022.Genetic predisposition to alcohol intake.The association between alcohol consumption and cardiovascular diseases, including hypertension, coronary artery disease, myocardial infarction, stroke, heart failure, and atrial fibrillation.This study included 371 463 participants (mean [SD] age, 57.0 [7.9] years; 172 400 [46%] men), who consumed a mean (SD) 9.2 (10.6) standard drinks per week. Overall, 121 708 participants (33%) had hypertension. Light to moderate alcohol consumption was associated with healthier lifestyle factors, adjustment for which attenuated the cardioprotective epidemiologic associations with modest intake. In linear mendelian randomization analyses, a 1-SD increase in genetically predicted alcohol consumption was associated with 1.3-fold (95% CI, 1.2-1.4) higher risk of hypertension (P .001) and 1.4-fold (95% CI, 1.1-1.8) higher risk of coronary artery disease (P = .006). Nonlinear mendelian randomization analyses suggested nonlinear associations between alcohol consumption and both hypertension and coronary artery disease: light alcohol intake was associated with minimal increases in cardiovascular risk, whereas heavier consumption was associated with exponential increases in risk of both clinical and subclinical cardiovascular disease.In this cohort study, coincident, favorable lifestyle factors attenuated the observational benefits of modest alcohol intake. Genetic epidemiology suggested that alcohol consumption of all amounts was associated with increased cardiovascular risk, but marked risk differences exist across levels of intake, including those accepted by current national guidelines.

IMPORTANCE: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis. OBJECTIVE: To assess the contributions of rare and common genetic variation to risk of HCM in the general population. DESIGN, SETTING, AND PARTICIPANTS: This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022. EXPOSURES: Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors. MAIN OUTCOMES AND MEASURES: Risk of HCM. RESULTS: The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87). CONCLUSIONS AND RELEVANCE: Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.

Genetic analyses have suggested a causal association between alcohol intake and cardiovascular diseases, questioning the purported cardioprotective effects of modest intake. Though traditional approaches to genetic epidemiology are limited in ability to assess association shapes, we hypothesized that any alcohol may increase risk of cardiovascular disease. In 371,463 participants from the UK Biobank, we first examined for confounding in epidemiological associations between alcohol intake and cardiovascular diseases. Next, using traditional and non-linear genetic approaches (Mendelian randomization), we assessed for causal links of alcohol consumption with several cardiovascular diseases and evaluated the shapes of all causal associations identified. Study participants consumed 9.2 (SD, 10.6) standard drinks per week on average; 121,708 (32.8%) and 27,667 (7.5%) subjects had hypertension and CAD, respectively. Modest consumers of alcohol demonstrated healthier lifestyles - such as lower BMI and greater physical activity - than abstainers, and adjustment for lifestyle factors attenuated the observed benefits of light alcohol intake. Traditional and non-linear Mendelian randomization demonstrated consistently risk-increasing and quadratic associations between alcohol consumption and both clinical and subclinical cardiovascular disease, with exponential increases in risk across levels of drinking; relative to abstainers, consumption of 7, 14, 21, and 28 drinks per week conferred 1.2, 1.7, 3.4, and 8.9-fold odds of hypertension and 1.2, 2.3, 6.2, and 25.9-fold odds of CAD, respectively (both models p