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 = 3.7×10-10). 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 = 9.9×10-14, 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. ### Competing Interest Statement J.L., A.C., Y.L., J.D., C.B-D. and R.S. are employees and stockholders of GSK. J.R.B.P. and E.J.G. are employees and shareholders of Insmed. J.R.B.P. receives research funding from GSK. Y.Z. is a UK University worker at GSK. S.O.R. has undertaken remunerated consultancy work for Pfizer, Third Rock Ventures, AstraZeneca, NorthSea Therapeutics and Courage Therapeutics. The other authors declare no competing interests. ### Funding Statement We thank the participants and investigators in the UK Biobank study who made this work possible (resource application number 52293). Y.Z., E.J.G., K.A.K., K.K.O. and J.R.B.P. are supported by the UK MRC (Unit Programmes MC\_UU\_00006/1 and MC\_UU\_00006/2). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank has approval from the North West Multi-centre Research Ethics Committee (REC reference 13/NW/0157, ) as a Research Tissue Bank (RTB) approval and informed consent () was provided by each participant. Adults 18 years and older who have the capacity to consent and reside in the USA or a US territory at present are eligible to join the All of Us cohort. Informed consent for all participants is conducted in person or through an eConsent platform that includes primary consent, HIPAA Authorization for Research use of EHRs and other external health data, and Consent for Return of Genomic Results. The protocol was reviewed by the Institutional Review Board (IRB) of the All of Us Research Program. The All of Us IRB follows the regulations and guidance of the NIH Office for Human Research Protections for all studies, ensuring that the rights and welfare of research participants are overseen and protected uniformly. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The UK Biobank/All of Us cohort phenotype and WGS data described here are publicly available to registered researchers through the UK Biobank/All of Us cohort data access protocol.