The Long-term Mediation Role of Cytokines on the Causal Pathway from Maternal Gestational Age to Offspring Visual System: Lifecourse-Network Mendelian Randomization

Background Gestational duration has a non-negligible impact on eye diseases. However, the long-term role of cytokines on the causal relationship of maternal gestational age on offspring visual impairment remains unclear. Methods We perform a lifecourse-network Mendelian randomization (MR) to explore the causal relationships among maternal gestational duration (from EGG and iPSYCH, N=84,689), neonatal/adult cytokines (from the NHGRI-EBI Catalog, N=764/4,618) and adult eye diseases (from FinnGen consotium, N=309,154) using summary-level data from large genome-wide association studies. Multiplicative random effects inverse variance weighted (IVW) and multivariable-IVW method are the main analysis methods and the other 15 pleiotropy-robust methods, weak IV-robust methods and outliers-robust methods are performed as auxiliary methods. Results We find that maternal gestational age (early preterm birth, preterm birth, gestational duration and postterm birth) has causal relationships with 42 eye diseases. Specially, four neonatal cytokines: TNF-α, IL10, GROA and CTACK, as well as four adult cytokines: CTACK, IL10, IL12p70 and IL6.26 are mediators in the causal relationships between early preterm birth and preterm birth to 8 eye diseases. However, after adjusting for these mediators, null direct causal effect of early preterm birth and preterm birth on 8 eye diseases can be found. In addition, there is no mediator in the causal relationships from gestational duration and postterm birth to eye diseases. Conclusion The influences of maternal gestational duration on the offspring eye diseases through cytokines are long-term and lifecourse.