A Mendelian randomization approach for advancing healthcare innovation: From pregnancy hypertension to schizophrenia

Background Schizophrenia, a severe mental disorder, is strongly associated with perinatal factors, including pregnancy hypertension, which affects fetal neurodevelopment. The causal relationship between pregnancy hypertension and schizophrenia remains unclear. Objective To investigate the causal relationship between pregnancy hypertension and schizophrenia using a two-sample Mendelian randomization (MR) study. Methods Pregnancy hypertension (cases/controls: 7686/115,8993) was considered as exposure and schizophrenia (cases/controls: 76755/243,649) as outcome. A two-sample MR study genetically estimated associations, with the inverse variance-weighted method as primary analysis. A two-step MR study explored potential mediators. Sensitivity tests assessed pleiotropy, heterogeneity, and stability. Results Four single nucleotide polymorphisms (SNPs) were identified as genetic instruments for pregnancy hypertension (P < 5 × 10 -8 , r² < 0.001). Pregnancy hypertension increased the risk of schizophrenia (odds ratio = 1.098, 95% CI = 1.025–1.173, P = 0.007), while reverse MR analysis found no significant link (odds ratio = 1.03, 95% CI = 0.980–1.082, P = 0.235). The two-step study revealed pregnancy hypertension elevated levels of 1,4-Dihydroxy-2-naphthoic acid (odds ratio = 1.351, 95% CI = 1.097–1.664, P = 0.004), which decreased schizophrenia risk (odds ratio = 0.97, 95% CI = 0.942–0.998, P = 0.040). Conclusion Pregnancy hypertension is a high-risk factor for schizophrenia, with 1,4-Dihydroxy-2-naphthoic acid potentially mitigating this effect. These findings offer insights for the prophylaxis of schizophrenia and highlight the need for further research into underlying mechanisms.