ImportanceObservational studies suggest that major psychiatric disorders and substance use behaviors reduce longevity, making it difficult to disentangle their relationships with aging-related outcomes.ObjectiveTo evaluate the associations between the genetic liabilities for major psychiatric disorders, substance use behaviors (smoking and alcohol consumption), and longevity.Design, Settings, and ParticipantsThis 2-sample mendelian randomization (MR) study assessed associations between psychiatric disorders, substance use behaviors, and longevity using single-variable and multivariable models. Multiomics analyses were performed elucidating transcriptomic underpinnings of the MR associations and identifying potential proteomic therapeutic targets. This study sourced summary-level genome-wide association study (GWAS) data, gene expression, and proteomic data from cohorts of European ancestry. Analyses were performed from May 2022 to November 2023.ExposuresGenetic susceptibility for major depression (n = 500 199), bipolar disorder (n = 413 466), schizophrenia (n = 127 906), problematic alcohol use (n = 435 563), weekly alcohol consumption (n = 666 978), and lifetime smoking index (n = 462 690).Main Outcomes and MeasuresThe main outcome encompassed aspects of health span, lifespan, and exceptional longevity. Additional outcomes were epigenetic age acceleration (EAA) clocks.ResultsFindings from multivariable MR models simultaneously assessing psychiatric disorders and substance use behaviorsm suggest a negative association between smoking and longevity in cohorts of European ancestry (n = 709 709; 431 503 [60.8%] female; β, −0.33; 95% CI, −0.38 to −0.28; P = 4.59 × 10−34) and with increased EAA (n = 34 449; 18 017 [52.3%] female; eg, PhenoAge: β, 1.76; 95% CI, 0.72 to 2.79; P = 8.83 × 10−4). Transcriptomic imputation and colocalization identified 249 genes associated with smoking, including 36 novel genes not captured by the original smoking GWAS. Enriched pathways included chromatin remodeling and telomere assembly and maintenance. The transcriptome-wide signature of smoking was inversely associated with longevity, and estimates of individual smoking-associated genes, eg, XRCC3 and PRMT6, aligned with the smoking-longevity MR analyses, suggesting underlying transcriptomic mediators. Cis-instrument MR prioritized brain proteins associated with smoking behavior, including LY6H (β, 0.02; 95% CI, 0.01 to 0.03; P = 2.37 × 10−6) and RIT2 (β, 0.02; 95% CI, 0.01 to 0.03; P = 1.05 × 10−5), which had favorable adverse-effect profiles across 367 traits evaluated in phenome-wide MR.ConclusionsThe findings suggest that the genetic liability of smoking, but not of psychiatric disorders, is associated with longevity. Transcriptomic associations offer insights into smoking-related pathways, and identified proteomic targets may inform therapeutic development for smoking cessation strategies.

中文翻译：

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主要精神疾病、药物使用行为和长寿


重要性观察性研究表明，主要精神疾病和物质使用行为会缩短寿命，因此很难理清它们与衰老相关结果的关系。目的评估主要精神疾病的遗传倾向、物质使用行为（吸烟和饮酒）、设计、设置和参与者这项 2 样本孟德尔随机化 (MR) 研究使用单变量和多变量模型评估了精神疾病、物质使用行为和寿命之间的关联。进行多组学分析，阐明 MR 关联的转录组基础并确定潜在的蛋白质组治疗靶点。这项研究来源于欧洲血统群体的汇总级全基因组关联研究 (GWAS) 数据、基因表达和蛋白质组数据。分析于 2022 年 5 月至 2023 年 11 月进行。暴露重度抑郁症 (n = 500 199)、双向情感障碍 (n = 413 466)、精神分裂症 (n = 127 906)、有问题的饮酒 (n = 435 563) 的遗传易感性，每周饮酒量（n = 666 978）和终生吸烟指数（n = 462 690）。主要结果和措施主要结果包括健康寿命、寿命和超长寿命等方面。其他结果是表观遗传年龄加速 (EAA) 时钟。 结果同时评估精神疾病和物质使用行为的多变量 MR 模型的结果表明，欧洲血统队列中吸烟与长寿之间存在负相关（n = 709 709；431 503 [60.8%] 女性） ；β，-0.33；95% CI，-0.38 至 -0.28；P = 4.59 × 10−34）且 EAA 增加（n = 34 449；18 017 [52.3%] 女性；例如，PhenoAge：β，1.76； 95% CI，0.72 至 2。79； P = 8.83 × 10−4)。转录组插补和共定位确定了 249 个与吸烟相关的基因，其中包括 36 个原始吸烟 GWAS 未捕获的新基因。丰富的途径包括染色质重塑以及端粒组装和维护。吸烟的全转录组特征与寿命呈负相关，并且个体吸烟相关基因（例如 XRCC3 和 PRMT6）的估计与吸烟-寿命 MR 分析一致，表明潜在的转录组介质。顺式仪器 MR 优先考虑与吸烟行为相关的大脑蛋白，包括 LY6H（β，0.02；95% CI，0.01 至 0.03；P = 2.37 × 10−6）和 RIT2（β，0.02；95% CI，0.01 至 0.03；P = 2.37 × 10−6）。 P = 1.05 × 10−5)，在全表型 MR 评估的 367 个特征中具有有利的不良影响。结论研究结果表明，吸烟的遗传倾向与长寿相关，但精神疾病的遗传倾向则不然。转录组学关联提供了对吸烟相关途径的深入了解，并且确定的蛋白质组靶标可能为戒烟策略的治疗开发提供信息。