Sex-differences in the intergenerational transmission of mental disorders among schizophrenia probands: familial risk and protective factors in a population-based study

Summary Background Parental schizophrenia confers intergenerational mental health risks. The sex-specific transmission patterns remain poorly quantified. This study examined parent-reported transmission rate and familial risk factors among Chinese offspring of schizophrenia probands. Methods In this cross-sectional study, we enrolled 27,315 schizophrenia probands and 35,772 offspring. Psychiatric disorder diagnoses of offspring were parent-reported and subsequently verified via the medical management system. Age- and sex-standardized rate referenced China's 2020 census. Robust Poisson regression generated adjusted rate ratios (aRR). Multivariable logistic models were used to identify risk factors for young offspring. This study was registered with ClinicalTrials (NCT07005245). Findings The parent-reported transmission rate in offspring was 2.68% (95% CI, 2.52%–2.85%), dominated by schizophrenia spectrum disorders (1.42%). Standardized rates reached 2.53% (95% CI, 2.01%–3.05%) after demographic standardization. Offspring risk increased by 86.0% when conception occurred post-parental illness onset. Firstborn status (aRR = 1.67), low-income household (aRR = 1.43), and being a male child (aRR = 1.14) were significantly associated with elevated risk. Sex-specific parental age effects were also observed. In the subgroup analysis of underage (<17 years) offspring, maternal transmission was associated with post-parental-onset birth (OR = 2.48, p < 0.001), lower household income (OR = 2.32, p < 0.001), and prenatal antipsychotic exposure (OR = 1.69, p < 0.001). Paternal transmission was related to father-only caregiving (OR = 2.15, p < 0.001), lower household income (OR = 1.97, p < 0.001), and male offspring (OR = 1.79, p = 0.001). Dual-parent care demonstrated a robust protective effect across both maternal and paternal schizophrenia groups (OR = 0.75, 95% CI, 0.51–1.10). Interpretation Our findings highlighted critical interactions between familial aggregation, sex-differentiated perinatal exposures, and caregiving environments. Policy priorities should integrate sex-stratified genetic counselling, prenatal medication monitoring, and family support programs targeting caregiving inequalities. Funding This study was supported by the National Natural Science Foundation of China (32070589).