Feng Yen-Chen A, Chen Wei J, Lin Mei-Chen, Hsu Jacob Shujui, Cheng Chi-Fung, Liu Chih-Min, Hwu Hai-Gwo, Huang Yen-Tsung, Lu Tzu-Pin, Wang Shi-Heng
Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan.
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
Mol Psychiatry. 2025 Mar 5. doi: 10.1038/s41380-025-02942-0.
Whether delaying fatherhood leads to more mutations, thereby resulting in adverse psychiatric outcomes in offspring, remains under debate. No study has directly examined the role of de novo mutations (DNMs) between paternal age and offspring psychiatric outcomes. This study aimed to explore the association between paternal age, the number of DNMs, and age at onset of schizophrenia by sequencing the whole genome of multiplex schizophrenia families. Whole-genome sequencing (30x) was performed in 5 Taiwanese families, each comprising 3 co-affected siblings and healthy parents. Causal mediation analyses were used to explore the mediating role of DNMs in the paternal age effect. Paternal age predicted increased DNMs (+1.50 DNMs/year, 95% CI: 0.81, 2.19, p < 0.0001) over maternal age (+0.09 DNMs/year, 95% CI: -1.01, 1.19, p = 0.87). The effect of paternal age on the number of DNMs varied across families. Each additional DNM resulted in a 0.16-year earlier onset age of schizophrenia (95% CI: 0.04, 0.27, p = 0.009). The estimated direct effect of paternal age on the onset of schizophrenia was -0.82 (95% CI: -0.90, -0.73), while the indirect effect through DNMs was -0.32 (95% CI: -0.47, -0.17). The proportion mediated via DNMs was 28.04% (95% CI: 18.19%, 37.89%). The mediation analyses showed that 30% of the observed association of paternal age with onset age of schizophrenia might be mediated through paternal age-related DNMs. Our study, the first to directly quantify the mediating effect of DNMs, provides support for a causal role of paternal age-related mutations in the increased psychiatric risk in offspring.
推迟生育是否会导致更多突变，进而导致后代出现不良精神状况，这一问题仍存在争议。尚无研究直接考察新生突变（DNM）在父亲年龄与后代精神状况之间所起的作用。本研究旨在通过对多个精神分裂症家庭的全基因组进行测序，探究父亲年龄、DNM数量与精神分裂症发病年龄之间的关联。对5个台湾家庭进行了全基因组测序（30倍覆盖度），每个家庭包括3名共同患病的兄弟姐妹及其健康的父母。采用因果中介分析来探究DNM在父亲年龄效应中的中介作用。与母亲年龄（每年增加0.09个DNM，95%置信区间：-1.01, 1.19，p = 0.87）相比，父亲年龄可预测DNM数量增加（每年增加1.50个DNM，95%置信区间：0.81, 2.19，p < 0.0001）。父亲年龄对DNM数量的影响在不同家庭中有所差异。每增加一个DNM，精神分裂症发病年龄提前0.16年（95%置信区间：0.04, 0.27，p = 0.009）。估计父亲年龄对精神分裂症发病的直接效应为-0.82（95%置信区间：-0.90, -0.73），而通过DNM的间接效应为-0.32（95%置信区间：-0.47, -0.17）。通过DNM介导的比例为28.04%（95%置信区间：18.19%, 37.89%）。中介分析表明，观察到的父亲年龄与精神分裂症发病年龄之间的关联中，约30%可能是通过与父亲年龄相关的DNM介导的。我们的研究首次直接量化了DNM的中介效应，为与父亲年龄相关的突变在增加后代精神疾病风险中的因果作用提供了支持。
