Paternal age, de novo mutation, and age at onset among co-affected schizophrenia sib-pairs: whole-genome sequencing in multiplex families.

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.