A Genetic Variant in 12q13, a Possible Risk Factor for Bipolar Disorder, Is Associated with Depressive State, Accounting for Stressful Life Events

Genome-wide association studies (GWASs) have identified a number of susceptibility genes for schizophrenia (SCZ) and bipolar disorder (BD). However, the identification of risk genes for major depressive disorder (MDD) has been unsuccessful because the etiology of MDD is more influenced by environmental factors; thus, gene–environment (G×E) interactions are important, such as interplay with stressful life events (SLEs). We assessed the G×E interactions and main effects of genes targeting depressive symptoms. Using a case–control design, 922 hospital staff members were evaluated for depressive symptoms according to Beck Depressive Inventory (BDI; “depression” and “control” groups were classified by scores of 10 in the BDI test), SLEs, and personality. A total of sixty-three genetic variants were selected on the basis of previous GWASs of MDD, SCZ, and BD as well as candidate-gene (SLC6A4, BDNF, DBH, and FKBP5) studies. Logistic regression analysis revealed a marginally significant interaction (genetic variant × SLE) at rs4523957 (Puncorrected = 0.0034) with depression and a significant association of single nucleotide polymorphism identified from evidence of BD GWAS (rs7296288, downstream of DHH at 12q13.1) with depression as the main effect (Puncorrected = 9.4×10−4, Pcorrected = 0.0424). We also found that SLEs had a larger impact on depression (odds ratio∼3), as reported previously. These results suggest that DHH plays a possible role in depression etiology; however, variants from MDD or SCZ GWAS evidence or candidate genes showed no significant associations or minimal effects of interactions with SLEs on depression.

全基因组关联研究（Genome-wide association studies, GWASs）已识别出多个精神分裂症（schizophrenia, SCZ）与双相情感障碍（bipolar disorder, BD）的易感基因。然而，针对重性抑郁障碍（major depressive disorder, MDD）的风险基因识别仍未取得成功，究其原因在于重性抑郁障碍的病因更多受环境因素影响，因此基因-环境（gene–environment, G×E）交互作用至关重要，例如与应激性生活事件（stressful life events, SLEs）的相互作用。本研究针对抑郁症状相关基因的G×E交互作用及主效应展开评估。研究采用病例-对照设计，对922名医院工作人员进行了评估：依据贝克抑郁量表（Beck Depressive Inventory, BDI，以BDI测试得分≥10作为分界，将受试者划分为“抑郁组”与“对照组”）评估其抑郁症状，并收集其应激性生活事件与人格特征数据。本研究基于既往针对MDD、SCZ、BD的GWAS研究以及候选基因（SLC6A4、BDNF、DBH及FKBP5）研究，共筛选得到63个遗传变异。Logistic回归分析结果显示，rs4523957位点的遗传变异与应激性生活事件的交互作用与抑郁存在临界显著关联（未校正P值=0.0034）；而源自双相情感障碍GWAS证据的单核苷酸多态性（single nucleotide polymorphism）rs7296288（位于12q13.1区域DHH基因下游）与抑郁的主效应存在显著关联（未校正P值=9.4×10⁻⁴，校正后P值=0.0424）。本研究同时证实，如既往研究所报道，应激性生活事件对抑郁的影响更大（优势比（odds ratio）≈3）。本研究结果提示，DHH基因可能在抑郁病因学（etiology）中发挥潜在作用；然而，源自MDD或SCZ GWAS证据的遗传变异以及候选基因，并未显示出与应激性生活事件交互作用对抑郁存在显著关联，或仅存在微弱的交互效应。