Yukihiro Ohya

Abstract Understanding the influence of both genetics and environment on human health, especially early in life, is essential for shaping long-term health. Here, we utilize a nationwide prospective birth cohort, the Japan Environment and Children’s Study (JECS), to conduct a large-scale population-based genetic study using biannual questionnaire surveys and biological and physical measurements collected from both parents and their children up to the age of 4, since the participant mothers were pregnant. Analyses of genome-wide genotyping for 80,639 child participants with parental consent and sufficient DNA from cord blood samples represent the genetic diversity of the general population in Japan. Systematic genome-wide association studies of 1,255 child health and developmental traits (including, e.g., food allergy, anthropometry measurements or ASQ-3 developmental screening) and parental environmental exposure traits (including, e.g., mercury or PFAS exposure) identify 6,073 common genomic loci (2,332 of which passed the phenome-wide significance threshold 𝑃 = 4.0 × 10 ^-1 ), of which 18-20% of loci represent novel associations not previously reported, including loci with potential therapeutic relevance. Additional longitudinal GWAS of BMI, using Gaussian process regression, identified 29 novel dynamic genetic associations throughout child development. These associations can also be used to predict an individual’s growth trajectory based on their genetic background. In addition, genetic correlation analysis suggested potential associations between maternal environmental exposures during pregnancy and child traits after birth. Together with studies of genetic risk factors and environmental exposures, across time and multiple outcomes, these demonstrate the uniqueness and value of the JECS data.