Rare genetic variants impact muscle strength

Muscle strength is highly heritable and predictive for multiple adverse health outcomes including mortality. Here, we present a rare protein-coding variant association study in 340,319 individuals for hand grip strength, a proxy measure of muscle strength. We identify six significant genes ( KDM5B, OBSCN, GIGYF1, TTN, RB1CC1, EIF3J ), propose shared mechanisms between brain and muscle function and demonstrate additive effects between rare and common genetic variation on muscle strength. ### Competing Interest Statement Y.H., D.B., C.C., J.S., K.G.M., E.A.T. and H.R. are employees of Biogen. M.E.H. is a co-founder, shareholder, non-executive director of Congenica, and an advisor to Astra-Zeneca. ### Funding Statement We did not receive any external funding. ### 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: Collection of the UK Biobank (UKBB) data was approved by the UKBB's Research Ethics Committee. UKBB individual-level, phenotypic data and whole exome sequencing data used in the present work were obtained under application ID 26041. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary-level association results produced in the present study are contained in the Supplementary Materials. Additional data produced in the present study are available upon reasonable request to the authors.