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

Abstract

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.