Exploring Rare Genetic Variation Underlying Metabolic Traits in the Fenland Cohort

Recent large-scale whole-exome sequencing (WES) studies in population biobanks have transformed our understanding of the role of rare protein coding on human health. However, the size and design of these biobanks limit deep phenotyping and genotype-targeted follow-up. To address this, we present new WES in the Fenland study, a population-based cohort of 11,458 individuals with extended metabolic phenotyping. Using this resource, we performed the first large-scale rare variant association analysis of measured Resting Energy Expenditure (REE) and fasting/post-challenge measures of glucose and insulin. We identified damaging variants in BRSK2, NID2 and PC influencing glycaemic traits; and in COL8A1 and CASQ1 reducing REE. Notably, the CASQ1 association was sex- and menopause status-dependent, highlighting a potential estrogen-mediated mechanism by which menopause may contribute to declining metabolic health. Collectively, our findings demonstrate the utility of the Fenland study as a resource for genetic discovery.