Importance Although depression is a common psychiatric disorder, its underlying biological basis remains poorly understood. Pairing depression polygenic scores with the results of clinical laboratory tests can reveal biological processes involved in depression etiology and in the physiological changes resulting from depression. Objective To characterize the association between depression polygenic scores and an inflammatory biomarker, ie, white blood cell count. Design, Setting, and Participants This genetic association study was conducted from May 19, 2019, to June 5, 2021, using electronic health record data from 382 452 patients across 4 health care systems. Analyses were conducted separately in each health care system and meta-analyzed across all systems. Primary analyses were conducted in Vanderbilt University Medical Center's biobank. Replication analyses were conducted across 3 other PsycheMERGE sites: Icahn School of Medicine at Mount Sinai, Mass General Brigham, and the Million Veteran Program. All patients with available genetic data and recorded white blood cell count measurements were included in the analyses. Primary analyses were conducted in individuals of European descent and then repeated in a population of individuals of African descent. Exposures Depression polygenic scores. Main Outcomes and Measures White blood cell count. Results Across the 4 PsycheMERGE sites, there were 382 452 total participants of European ancestry (18.7% female; median age, 57.9 years) and 12 383 participants of African ancestry (61.1% female; median age, 39.0 [range, birth-90.0 years]). A laboratory-wide association scan revealed a robust association between depression polygenic scores and white blood cell count (β, 0.03; SE, 0.004; P = 1.07 × 10-17), which was replicated in a meta-analysis across the 4 health care systems (β, 0.03; SE, 0.002; P = 1.03 × 10-136). Mediation analyses suggested a bidirectional association, with white blood cell count accounting for 2.5% of the association of depression polygenic score with depression diagnosis (95% CI, 2.2%-20.8%; P = 2.84 × 10-70) and depression diagnosis accounting for 9.8% of the association of depression polygenic score with white blood cell count (95% CI, 8.4%-11.1%; P = 1.78 × 10-44). Mendelian randomization provided additional support for an association between increased white blood count and depression risk, but depression modeled as the exposure showed no evidence of an influence on white blood cell counts. Conclusions and Relevance This genetic association study found that increased depression polygenic scores were associated with increased white blood cell count, and suggests that this association may be bidirectional. These findings highlight the potential importance of the immune system in the etiology of depression and may motivate future development of clinical biomarkers and targeted treatment options for depression.

中文翻译：

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使用 PsycheMERGE 网络调查抑郁症多基因评分与白细胞计数之间的关联。

重要性 尽管抑郁症是一种常见的精神疾病，但其潜在的生物学基础仍知之甚少。将抑郁症多基因评分与临床实验室测试结果相结合，可以揭示抑郁症病因学和抑郁症引起的生理变化中涉及的生物学过程。目的 描述抑郁症多基因评分与炎症生物标志物（即白细胞计数）之间的关联。设计、设置和参与者这项遗传关联研究于 2019 年 5 月 19 日至 2021 年 6 月 5 日进行，使用了来自 4 个医疗保健系统的 382,​​452 名患者的电子健康记录数据。分析在每个医疗保健系统中分别进行，并对所有系统进行荟萃分析。初步分析在范德比尔特大学医学中心的生物库中进行。复制分析在其他 3 个 PsycheMERGE 站点进行：西奈山伊坎医学院、布里格姆麻省将军和百万退伍军人计划。所有具有可用遗传数据和记录的白细胞计数测量值的患者都包括在分析中。主要分析是在欧洲人后裔的个体中进行的，然后在非洲人后裔的人群中重复进行。暴露抑郁多基因评分。主要成果和措施 白细胞计数。结果 在 4 个 PsycheMERGE 站点中，共有 382452 名欧洲血统参与者（18.7% 女性；中位年龄 57.9 岁）和 12383 名非洲血统参与者（61.1% 女性；中位年龄 39.0 [范围，出生 90.0 岁） ]). 实验室范围内的关联扫描显示抑郁症多基因评分与白细胞计数之间存在稳健关联（β，0.03；SE，0.004；P = 1.07 × 10-17），这在 4 个医疗保健机构的荟萃分析中得到重复系统（β，0.03；SE，0.002；P = 1.03 × 10-136）。中介分析表明存在双向关联，白细胞计数占抑郁症多基因评分与抑郁症诊断关联的 2.5%（95% CI，2.2%-20.8%；P = 2.84 × 10-70），抑郁症诊断占9.8% 的抑郁症多基因评分与白细胞计数相关（95% CI，8.4%-11.1%；P = 1.78 × 10-44）。孟德尔随机化为白细胞计数增加与抑郁风险之间的关联提供了额外的支持，但是以暴露为模型的抑郁症没有显示出对白细胞计数有影响的证据。结论和相关性 这项遗传关联研究发现，抑郁症多基因评分增加与白细胞计数增加相关，并表明这种关联可能是双向的。这些发现突出了免疫系统在抑郁症病因学中的潜在重要性，并可能推动临床生物标志物的未来发展和抑郁症的靶向治疗选择。