Estimating heritability of glycaemic response to metformin using nationwide electronic health records and population-sized pedigree

Background Variability of response to medication is a well-known phenomenon, determined by both environmental and genetic factors. Understanding the heritable component of the response to medication is of great interest but challenging due to several reasons, including small study cohorts and computational limitations.Methods Here, we study the heritability of variation in the glycaemic response to metformin, first-line therapeutic agent for type 2 diabetes (T2D), by leveraging 18 years of electronic health records (EHR) data from Israel's largest healthcare service provider, consisting of over five million patients of diverse ethnicities and socio-economic background. Our cohort consists of 80,788 T2D patients treated with metformin, with an accumulated number of 1,611,591 HbA1C measurements and 4,581,097 metformin prescriptions. We estimate the explained variance of glycated hemoglobin (HbA1c%) reduction due to inheritance by constructing a six-generation population-size pedigree from national registries and linking it to medical health records.Results Using Linear Mixed Model-based framework, a common-practice method for heritability estimation, we calculate a heritability measure of h2 = 12.6% (95% CI, 6.1%-19.1%) for absolute reduction of HbA1c% after metformin treatment in the entire cohort, h(2) = 21.0% (95% CI, 7.8%-34.4%) for males and h(2) = 22.9% (95% CI, 10.0%-35.7%) in females. Results remain unchanged after adjusting for pre-treatment HbA1c%, and in proportional reduction of HbA1c%.Conclusions To the best of our knowledge, our work is the first to estimate heritability of drug response using solely EHR data combining a pedigree-based kinship matrix. We demonstrate that while response to metformin treatment has a heritable component, most of the variation is likely due to other factors, further motivating non-genetic analyses aimed at unraveling metformin's action mechanism.