Experience of stressful life events is associated with risk of depression. Yet many exposed individuals do not become depressed. A controversial hypothesis is that genetic factors influence vulnerability to depression following stress. This hypothesis is often tested with a “diathesis-stress” model, in which genes confer excess vulnerability. The authors tested an alternative formulation of this model: genes may buffer against depressogenic effects of life stress.

The hypothesized genetic buffer was measured using a polygenic score derived from a published genome-wide association study of subjective well-being. The authors tested whether married older adults who had higher polygenic scores were less vulnerable to depressive symptoms following the death of their spouse compared with age-matched peers who had also lost their spouse and who had lower polygenic scores. Data were analyzed from 8,588 non-Hispanic white adults in the Health and Retirement Study (HRS), a population-representative longitudinal study of older adults in the United States.

HRS adults with higher well-being polygenic scores experienced fewer depressive symptoms during follow-up. Those who survived the death of their spouses (N=1,647) experienced a sharp increase in depressive symptoms following the death and returned toward baseline over the following 2 years. Having a higher well-being polygenic score buffered against increased depressive symptoms following a spouse’s death.

The effects were small, and the clinical relevance is uncertain, although polygenic score analyses may provide clues to behavioral pathways that can serve as therapeutic targets. Future studies of gene-environment interplay in depression may benefit from focus on genetics discovered for putative protective factors.

压力生活事件的经历与抑郁症的风险相关。然而，许多暴露的人并没有变得抑郁。一个有争议的假设是，遗传因素会影响压力后抑郁的脆弱性。这一假设经常用“素质-压力”模型进行检验，在该模型中，基因赋予了过度的脆弱性。作者测试了该模型的另一种表述：基因可以缓冲生活压力的抑郁效应。

假设的遗传缓冲是使用源自已发表的主观幸福感全基因组关联研究的多基因评分来测量的。作者测试了与同样失去配偶且多基因得分较低的同龄人相比，具有较高多基因得分的已婚老年人在配偶去世后是否更不容易出现抑郁症状。健康与退休研究 (HRS) 是一项针对美国老年人的人口代表性纵向研究，对 8,588 名非西班牙裔白人成年人的数据进行了分析。

幸福感多基因得分较高的 HRS 成年人在随访期间经历的抑郁症状较少。那些在配偶去世后幸存下来的人（N = 1,647）在死亡后经历了抑郁症状的急剧增加，并在接下来的两年内恢复到基线水平。拥有较高的幸福感多基因评分可以缓冲配偶去世后抑郁症状的增加。

尽管多基因评分分析可能提供可作为治疗目标的行为途径的线索，但效果很小，临床相关性尚不确定。未来对抑郁症中基因与环境相互作用的研究可能会受益于对假定保护因素的遗传学的关注。