Trindade Pons Victória, Oldehinkel Albertine J, van Loo Hanna M
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Mol Psychiatry. 2025 Sep 19. doi: 10.1038/s41380-025-03265-w.
There is an elevated risk of depression and anxiety in offspring of parents with a history of these disorders. Beyond direct transmission, parental genes may also impact offspring outcomes through the environment, in a "genetic nurture" pathway. The scarcity of relevant data has limited studies in this area, resulting in an incomplete understanding of the indirect impact of parental genes on the familial transmission of depression and anxiety. We investigated genetic nurture effects in 15,231-17,186 Dutch adults with at least one genotyped parent from Lifelines, a large general population cohort. We computed polygenic scores for transmitted (PGS-T) and non-transmitted (PGS-NT) parental haplotypes using genome-wide association studies for depression. Using mixed-effect regression models, we analyzed PGS-T and PGS-NT associations with offspring outcomes, ranging from narrow (depressive and anxiety disorders according to diagnostic criteria) to broader definitions (depressive and anxiety symptoms, neuroticism, and negative affect), measured at multiple assessment waves. Our results demonstrate a pattern of significant associations between PGS-T and offspring outcomes, consistent with direct genetic transmission (OR = 1.2-1.5; β = 0.09-0.20, p < 0.001). PGS-NT effects were approaching null across all outcomes, with some exceptions in specific assessment waves. The lack of robust associations for PGS-NT across outcomes suggests a minimal role of genetic nurture in depressive and anxiety disorders, symptoms, and related traits through parental genetic liability for depression. Though the possibility of indirect genetic effects through other genetic risk factors remains, our findings point to the genetic transmission of depression and anxiety primarily occurring via direct inheritance.
有抑郁症和焦虑症病史的父母，其子女患抑郁症和焦虑症的风险会升高。除了直接遗传外，父母的基因也可能通过“遗传养育”途径，经环境因素影响后代的情况。相关数据的匮乏限制了该领域的研究，导致人们对父母基因对抑郁症和焦虑症家族遗传的间接影响理解不全面。我们对15231至17186名荷兰成年人进行了遗传养育效应调查，这些成年人至少有一位来自大型普通人群队列“生命线”项目的已进行基因分型的父母。我们利用抑郁症的全基因组关联研究，计算了传递的（PGS-T）和未传递的（PGS-NT）父母单倍型的多基因分数。使用混合效应回归模型，我们分析了PGS-T和PGS-NT与后代情况的关联，后代情况的范围从狭义的（根据诊断标准的抑郁和焦虑症）到广义的定义（抑郁和焦虑症状、神经质和消极情绪），在多个评估阶段进行测量。我们的结果表明，PGS-T与后代情况之间存在显著关联模式，这与直接遗传传递一致（OR = 1.2 - 1.5；β = 0.09 - 0.20，p < 0.001）。在所有结果中，PGS-NT的影响几乎为零，在特定评估阶段有一些例外。PGS-NT在所有结果中缺乏有力关联，这表明遗传养育在抑郁和焦虑症、症状及相关特质中，通过父母的抑郁遗传易感性所起的作用极小。尽管通过其他遗传风险因素产生间接遗传效应的可能性仍然存在，但我们的研究结果表明，抑郁症和焦虑症的遗传传递主要是通过直接遗传发生的。
