Lapinska Sandra, Pimplaskar Aditya, Shi Zhuozheng, Ding Yi, Frydman-Gani Clara, Hou Kangcheng, Venkateswaran Vidhya, Boulier Kristin, Olde Loohuis Loes M, Pasaniuc Bogdan
Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.
Am J Hum Genet. 2025 Aug 7;112(8):1877-1891. doi: 10.1016/j.ajhg.2025.06.003. Epub 2025 Jun 27.
Treatment-resistant depression (TRD), usually defined as limited or no response to at least two antidepressants, occurs in approximately one-third of individuals diagnosed with major depressive disorder (MDD). Studies of individuals of European ancestry highlight a genetic overlap between TRD and MDD. We analyzed two large and diverse biobanks, the UCLA ATLAS Community Health Study (ATLAS) and the All of Us Research Program (AoU), to test for associations between a polygenic score for major depression (MDD-PGS) and TRD. Compared to treatment responders, TRD individuals have higher MDD-PGS across all ancestries. MDD-PGS was significantly associated with response to selective serotonin reuptake inhibitors in individuals of European and Hispanic/Latin American genetic ancestries in both biobanks. In AoU, a decreased MDD-PGS was observed in response to tricyclics or serotonin modulators in individuals of European American ancestry and in response to serotonin and norepinephrine reuptake inhibitors in individuals of African American ancestry. ATLAS found that MDD-PGS showed lower odds of responding to atypical agents than did TRD in MDD-affected individuals belonging to the Hispanic/Latin American group, MDD-PGS was associated with atypical agents. Overall, by leveraging larger sample sizes from two diverse biobanks, we provide new insights into antidepressant response and treatment specificity for MDD in individuals of diverse genetic ancestries.
难治性抑郁症（TRD）通常定义为对至少两种抗抑郁药反应有限或无反应，约三分之一被诊断为重度抑郁症（MDD）的患者会出现这种情况。对欧洲血统个体的研究突出了TRD和MDD之间的遗传重叠。我们分析了两个大型且多样的生物样本库，即加州大学洛杉矶分校地图集社区健康研究（ATLAS）和全民研究计划（AoU），以测试重度抑郁症多基因评分（MDD-PGS）与TRD之间的关联。与治疗反应者相比，TRD个体在所有血统中都有更高的MDD-PGS。在两个生物样本库中，欧洲和西班牙裔/拉丁裔遗传血统个体的MDD-PGS与对选择性5-羟色胺再摄取抑制剂的反应显著相关。在AoU中，在欧裔美国人个体中观察到三环类药物或5-羟色胺调节剂治疗后MDD-PGS降低，在非裔美国人个体中观察到5-羟色胺和去甲肾上腺素再摄取抑制剂治疗后MDD-PGS降低。ATLAS发现，在属于西班牙裔/拉丁裔群体的MDD患者中，MDD-PGS显示对非典型药物反应的几率低于TRD，MDD-PGS与非典型药物有关。总体而言，通过利用来自两个不同生物样本库的更大样本量，我们为不同遗传血统个体的MDD抗抑郁反应和治疗特异性提供了新的见解。
