The long-term mediation role of cytokines on the causal pathway from maternal gestational age to offspring eye diseases: Lifecourse-Network Mendelian randomization

Abstract

Background: Gestational duration has a significant impact on eye diseases. A large number of evidences suggest that cytokines are associated with gestational duration and eye diseases. However, the causal relationships among cytokines, maternal gestational impairment and offspring eye diseases remain unclear.

Methods: We performed lifecourse-network Mendelian randomization (MR) to explore the causal relationships between maternal gestational duration (from the Early Growth Genetics (EGG) Consortium and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study, 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 methods were the main analysis methods, and the other 15 pleiotropy-robust methods, weak IV-robust methods, and outliers-robust methods were used as auxiliary methods.

Results: Maternal gestational age (early preterm birth, preterm birth, gestational duration, and post-term birth) had a causal relationship with 42 eye diseases. Four neonatal cytokines, Tumor Necrosis Factor-α(TNF-α), IL10, GROA, and CTACK, as well as four adult cytokines, CTACK, IL10, IL12p70 and IL6 are mediators in the causal relationships between early preterm birth and preterm birth in eight eye diseases. However, after adjusting for these mediators, a null direct causal effect of early preterm birth and preterm birth on eight eye diseases was found. In addition, there was no mediator in the causal relationship between gestational duration and post-term birth to eye diseases.

Conclusion: The effects of maternal gestational duration on offspring eye diseases through cytokines are long-term and life-course effects.

Keywords: Eye diseases; Lifecourse mendelian randomization; Maternal gestational duration; Neonatal/adult cytokines; Network mendelian randomization.