Sex differences in rates of depression are thought to contribute to sex differences in smoking initiation (SI) and number of cigarettes smoked per day (CPD). One hypothesis is that women smoke as a strategy to cope with anxiety and depression, and have difficulty quitting because of concomitant changes in hypothalamic-pituitary-adrenocortical (HPA) axis function during nicotine withdrawal states. Despite evidence of biological ties, research has not examined whether genetic factors that contribute to depression-smoking comorbidity differ by sex. We utilized two statistical aggregation techniques-polygenic scores (PGSs) and sequence kernel association testing-to assess the degree of pleiotropy between these behaviors and moderation by sex in the Health and Retirement Study (N = 8,086). At the genome-wide level, we observed associations between PGSs for depressive symptoms and SI, and measured SI and depressive symptoms (all p < .01). At the gene level, we found evidence of pleiotropy in FKBP5 for SI (p = .028), and sex-specific pleiotropy in females in NR3C2 (p = .030) and CHRNA5 (p = .025) for SI and CPD, respectively. Results suggest bidirectional associations between depression and smoking may be partially accounted for by shared genetic factors, and genetic variation in genes related to HPA-axis functioning and nicotine dependence may contribute to sex differences in SI and CPD.

中文翻译：

---

使用多基因和基因区域聚合技术检查抑郁症和吸烟的多效性效应的性别差异。


抑郁症发生率的性别差异被认为是导致吸烟开始（SI）和每天吸烟数量（CPD）的性别差异的原因之一。一种假设是，女性吸烟是一种应对焦虑和抑郁的策略，但由于尼古丁戒断状态下下丘脑-垂体-肾上腺皮质 (HPA) 轴功能的伴随变化，女性很难戒烟。尽管存在生物联系的证据，但研究尚未检验导致抑郁症-吸烟合并症的遗传因素是否因性别而异。我们利用两种统计聚合技术——多基因评分 (PGS) 和序列核关联测试——来评估健康与退休研究 (N = 8,086) 中这些行为与性别调节之间的多效性程度。在全基因组水平上，我们观察了抑郁症状的 PGS 与 SI 之间的关联，并测量了 SI 和抑郁症状（所有 p < .01）。在基因水平上，我们发现 FKBP5 中 SI 多效性的证据 (p = .028)，以及女性中 NR3C2 (p = .030) 和 CHRNA5 (p = .025) 中 SI 和 CPD 的性别特异性多效性的证据。 。结果表明，抑郁症和吸烟之间的双向关联可能部分是由共同的遗传因素造成的，与 HPA 轴功能和尼古丁依赖相关的基因的遗传变异可能导致 SI 和 CPD 的性别差异。