Importance Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD.

Objective To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD.

Design, Setting, Participants This study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P < 5 × 10⁻⁸) were obtained from published genome-wide association studies. Summary-level statistics for these instruments were obtained for advanced AMD from the International AMD Genomics Consortium 2016 data set, which consisted of 16 144 individuals with AMD and 17 832 control individuals. Data were analyzed from July 2020 to September 2021.

Exposures Smoking initiation, smoking cessation, lifetime smoking, age at smoking initiation, alcoholic drinks per week, body mass index, systolic and diastolic blood pressure, type 2 diabetes, glycated hemoglobin, fasting glucose, and fasting insulin.

Main Outcomes and Measures Advanced AMD and its subtypes, geographic atrophy (GA), and neovascular AMD.

Results A 1-SD increase in logodds of genetically predicted smoking initiation was associated with higher risk of advanced AMD (odds ratio [OR], 1.26; 95% CI, 1.13-1.40; P < .001), while a 1-SD increase in logodds of genetically predicted smoking cessation (former vs current smoking) was associated with lower risk of advanced AMD (OR, 0.66; 95% CI, 0.50-0.87; P = .003). Genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (OR per 1-SD increase in lifetime smoking behavior, 1.32; 95% CI, 1.09-1.59; P = .004). Genetically predicted alcohol consumption was associated with higher risk of GA (OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; 95% CI, 1.48-4.94; P = .001). There was insufficient evidence to suggest that genetically predicted blood pressure, body mass index, and glycemic traits were associated with advanced AMD.

Conclusions and Relevance This study provides genetic evidence that increased alcohol intake may be a causal risk factor for GA. As there are currently no known treatments for GA, this finding has important public health implications. These results also support previous observational studies associating smoking behavior with risk of advanced AMD, thus reinforcing existing public health messages regarding the risk of blindness associated with smoking.

重要性 晚期年龄相关性黄斑变性 (AMD) 是西方国家失明的主要原因。需要确定因果性、可改变的风险因素，以制定针对晚期 AMD 的预防措施。

目的 评估吸烟、饮酒、血压、体重指数和血糖特征是否与晚期 AMD 风险增加相关。

设计、设置、参与者 本研究采用 2 样本孟德尔随机化。由与全基因组显着性风险因素相关的变体组成的遗传工具（P  < 5 × 10 ^-8）是从已发表的全基因组关联研究中获得的。这些仪器的概要级统计数据是从国际 AMD 基因组联盟 2016 数据集中获得的高级 AMD 数据，该数据集包括 16 144 名 AMD 患者和 17 832 名对照个体。数据分析时间为 2020 年 7 月至 2021 年 9 月。

暴露 开始吸烟、戒烟、终生吸烟、开始吸烟的年龄、每周饮酒量、体重指数、收缩压和舒张压、2 型糖尿病、糖化血红蛋白、空腹血糖和空腹胰岛素。

主要结果和措施 晚期 AMD 及其亚型、地图样萎缩 (GA) 和新生血管性 AMD。

结果 基因预测吸烟开始概率增加 1-SD 与晚期 AMD 风险较高相关（比值比 [OR]，1.26；95% CI，1.13-1.40；P  < .001），而 1-SD 增加基因预测戒烟次数（以前吸烟与当前吸烟）与晚期 AMD 风险较低相关（OR，0.66；95% CI，0.50-0.87；P  = .003）。基因预测终生吸烟量增加与晚期 AMD 风险增加相关（终生吸烟行为每增加 1-SD，OR 为 1.32；95% CI，1.09-1.59；P  = .004）。基因预测的饮酒量与较高的 GA 风险相关（每周对数转换酒精饮料每增加 1-SD，OR 为 2.70；95% CI，1.48-4.94；P  = 0.001）。没有足够的证据表明基因预测的血压、体重指数和血糖特征与晚期 AMD 相关。

结论和相关性 这项研究提供了遗传证据，表明酒精摄入量增加可能是 GA 的一个致病危险因素。由于目前尚无已知的 GA 治疗方法，这一发现具有重要的公共卫生意义。这些结果也支持之前将吸烟行为与晚期 AMD 风险联系起来的观察性研究，从而强化了有关吸烟导致失明风险的现有公共卫生信息。