Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease
Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease
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DOI：
10.1038/s41380-019-0614-y
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发表时间：
2021-08-01
影响因子：
11
通讯作者：
Davis, Lea K.
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文献类型：
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作者：
Dennis, Jessica;Sealock, Julia;Davis, Lea K.
重度抑郁症（MDD）和孤独感在表型和遗传上都与冠状动脉疾病（CAD）相关，但这些关联是否可以用多效性遗传变异或共有的合并症来解释尚不清楚。为了梳理这些情况，我们首先通过对范德比尔特大学医学中心生物银行（BioVU）的18385名欧洲血统个体进行全现象关联研究，评估了与MDD和孤独感遗传风险因素相关的医学发病率模式。使用先前发表的meta-GWAS汇总统计数据为每个人开发了重度抑郁症和孤独感的多基因评分，并通过电子健康记录中的账单代码测试了与882种临床诊断的关联。我们发现了与心脏病诊断的强烈关联，然后开始对3893例和4197例对照的CAD进行针对性分析。我们发现，MDD和孤独感的多基因评分每增加1个sd，比值比分别为1.11 （95% CI, 1.04-1.18; P 8.43 × 10(-4)）和1.13 （95% CI, 1.07-1.20; P 4.51 × 10(-6)）。在没有精神症状的患者中结果相似，即使在调整了多种传统危险因素和CAD的多基因评分后，女性的风险仍然增加。在最后的敏感性分析中，我们统计调整了重度抑郁症和孤独感之间的遗传相关性，并重新计算了多基因得分。孤独特有的多基因评分仍然与CAD相关（OR 1.09, 95% CI 1.03-1.15; P 0.002），而MDD特有的多基因评分则不相关（OR 1.00, 95% CI 0.95-1.06; P 0.97）。我们的复制样本是社区动脉粥样硬化风险（ARIC）队列的7197名欧洲血统参与者（1598例冠心病事件）。在ARIC中，MDD和孤独感的多基因评分的风险比分别为1.07 （95% CI, 0.99-1.14, P = 0.07）和1.07 (1.01-1.15,P = 0.03)，我们重复了BioVU敏感性分析的结果。我们得出结论，重度抑郁症和孤独感的遗传危险因素多效性地增加女性冠心病的风险。
Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 x 10(-4)) and 1.13 (95% CI, 1.07-1.20; P 4.51 x 10(-6)) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.