Importance  Major depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive.

Objective  To examine whether AD and MDD overlap genetically, using a polygenic score approach.

Design, Settings, and Participants  Association analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta-analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P < .05 to P ≤ .99 in each AD GWAS data set.

Main Outcomes and Measures  Association between MDD PRS and AD.

Results  Participants analyzed included 788 cases (548 [69.5%] men; mean [SD] age, 38.2 [10.8] years) and 522 controls (151 [28.9.%] men; age [SD], 43.9 [11.6] years) from COGA; 631 cases (333 [52.8%] men; age [SD], 35.0 [7.7] years) and 756 controls (260 [34.4%] male; age [SD] 36.1 [7.7] years) from SAGE; 2135 cases (1375 [64.4%] men; age [SD], 39.4 [11.5] years) and 350 controls (126 [36.0%] men; age [SD], 43.5 [13.9] years) from Yale-Penn; and 317 cases (295 [93.1%] men; age [SD], 59.1 [13.1] years) and 1719 controls (1545 [89.9%] men; age [SD], 64.5 [13.3] years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P = 1.7 × 10⁻⁶, R² = 0.026; SAGE: best P = .001, R² = 0.01; Yale-Penn: best P = .035, R² = 0.0018; and NHRVS: best P = .004, R² = 0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P = 3.3 × 10⁻⁹). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P = 7.6 × 10⁻⁶, R² = 0.023; Yale-Penn: best P = .08, R² = 0.0013; and NHRVS: best P = .006, R² = 0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P = .007).

Conclusions and Relevance  These results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD.

重要性重度抑郁症 (MDD) 和酒精依赖 (AD) 是具有重大公共健康负担的遗传性疾病，而且它们经常同时发病。人们在家庭、双胞胎和收养研究中寻找影响 MDD 和 AD 同时发生的常见遗传因素，迄今为止的结果是有希望的，但尚无定论。

目的使用多基因评分方法检查 AD 和 MDD 是否在基因上重叠。

设计、设置和参与者对来自 4 个独立全基因组关联研究 (GWAS) 数据集的欧洲血统样本的 MDD 多基因风险评分 (PRS) 和 AD 病例对照状态进行关联分析：酒精中毒遗传学合作研究（COGA）；成瘾、遗传学和环境研究（SAGE）；耶鲁-宾夕法尼亚大学物质依赖遗传学研究；以及国家退伍军人健康与复原力研究 (NHRVS)。来自精神病基因组学联盟的 MDD 荟萃分析结果（9240 名 MDD 患者和 9519 名对照者）用于计算每个 AD GWAS 数据集中 P < .05 至 P ≤ .99 阈值的 PRS。

MDD PRS 和 AD 之间的主要成果和措施关联。

结果分析的参与者包括 788 名病例（548 [69.5%] 男性；平均 [SD] 年龄，38.2 [10.8] 岁）和 522 名对照者（151 [28.9.%] 男性；年龄 [SD]，43.9 [11.6] 岁）科加；来自 SAGE 的 631 例病例（333 [52.8%] 男性；年龄 [SD]，35.0 [7.7] 岁）和 756 例对照（260 [34.4%] 男性；年龄 [SD] 36.1 [7.7] 岁）；来自耶鲁-宾夕法尼亚大学的 2135 例病例（1375 [64.4%] 男性；年龄 [SD]，39.4 [11.5] 岁）和 350 名对照者（126 [36.0%] 男性；年龄 [SD]，43.5 [13.9] 岁）；来自 NHRVS 的 317 例病例（295 [93.1%] 男性；年龄 [SD]，59.1 [13.1] 岁）和 1719 例对照（1545 [89.9%] 男性；年龄 [SD]，64.5 [13.3] 岁）。在所有样本中，较高的 MDD PRS 与 AD 风险显着增加相关（COGA：最佳 P = 1.7 × 10−6，R2 = 0.026；SAGE：最佳 P = 0.001，R2 = 0.01；耶鲁-宾夕法尼亚大学：最佳 P = .035，R2 = 0.0018；NHHRVS：最佳 P = .004，R2 = 0.0074），对 4 个样本进行荟萃分析后有更强的关联证据（最佳 P = 3.3 × 10−9）。在 3 个 AD GWAS 数据集中针对 MDD 状态进行调整的分析中，观察到类似的关联模式（COGA：最佳 P = 7.6 × 10−6，R2 = 0.023；耶鲁-宾夕法尼亚大学：最佳 P = 0.08，R2 = 0.0013；以及NHRVS：最佳 P = .006，R2 = 0.0072）。使用没有合并 MDD-AD 病例的 MDD GWAS 数据集重新计算 MDD PRS 后，在对 3 个没有 MDD 病例的 GWAS AD 样本进行荟萃分析时，观察到 MDD PRS 和 AD 之间存在关联的重要证据（最佳 P = .007）。

结论和相关性这些结果表明，共同的遗传易感性对 MDD 和 AD 合并症的影响不大。患有 MDD 多基因风险较高的个体也可能面临 AD 风险。