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

Abstract

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. Key words: maternal gestational duration, neonatal/adult cytokines, eye diseases, lifecourse mendelian randomization, network mendelian randomization