Population scale whole genome sequencing provides novel insights into cardiometabolic health

In addition to its coverage of the non-coding genome, whole genome sequencing (WGS) may better capture the coding genome than exome sequencing. We sought to exploit this and identify novel rare, protein-coding variants associated with metabolic health in newly released WGS data (N=708,956) from the UK Biobank and All of Us studies. Identified genes highlight novel biological mechanisms, including protein truncating variants (PTVs) in the DNA double-strand break repair gene RIF1 that have a substantial effect on body mass index (BMI, 2.66 kg/m2, s.e. 0.43, P = 3.7x10-10). UBR3 is an intriguing example where PTVs independently increase BMI and type 2 diabetes (T2D) risk. Furthermore, PTVs in IRS2 have a substantial effect on T2D (OR 6.4 [3.7-11.3], P = 9.9x10-14, 34% case prevalence among carriers) and were unexpectedly also associated with chronic kidney disease independent of diabetes status, suggesting an important role for IRS-2 in maintaining renal health. We identified genetic evidence of functional heterogeneity in IRS1 and IRS2, suggesting a greater role for IRS-1 in mediating the growth promoting effects of insulin and IGF-I, while IRS-2 has a greater impact on glucose homeostasis likely through its actions in the pancreatic islet and insulin target tissues. Our study demonstrates that large-scale WGS provides novel mechanistic insights into human metabolic phenotypes through improved capture of coding sequences.