A GWAS for grip strength in cohorts of children, advantages of analysing young participants for this trait.

Grip strength (GS) is a proxy measure for muscular strength and a predictor for bone fracture risk among other diseases. Previous genomewide association studies (GWAS) have been conducted in large cohorts of adults focusing on scores collected for the dominant hand, therefore increasing the likelihood of confounding effects by environmental factors. Here, we perform the first GWAS meta-analyses on maximal GS with the dominant (GSD) and non-dominant (GSND) hand in two cohorts of children (ALSPAC, N = 5,450; age range = 10.65 / 13.61; Raine Study, N = 1,162, age range: 9.42 / 12.38 years). We identified a novel significant association for GSND (rs9546244, LINC02465, p = 3.43e-08) and replicated associations previously reported in adults including with a HOXB3 gene marker that shows an eQTL effect. Despite a much smaller sample (~3%) compared to the UK Biobank we replicated correlation and polygenic risk score (PRS) analyses previously reported in this much larger adult cohort. Specifically, we observed genetic correlations with coronary artery disease and a PRS association with the risk of overall fracture. Furthermore, we observed a higher SNP-heritability (24-41%) compared to previous studies (4-24%) in adults. Our results suggest that cohorts of children might be better suited for genetic studies of grip strength, possibly due to the shorter exposure to confounding environmental factors compared to adults. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Silvia Paracchini and Filippo Abbondanza are funded by the Royal Society (UF150663; RGF\EA\180141). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Silvia Paracchini will serve as guarantor for the contents of this paper. Genomewide genotyping data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Judith Schmitz is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 418445085) and supported by the Wellcome Trust [Institutional Strategic Support fund, grant code 204821/Z/16/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Support to the genetic analysis was provided by the St Andrews Bioinformatics Unit funded by the Wellcome Trust [grant 105621/Z/14/Z]. The Raine Study was supported by the National Health and Medical Research Council of Australia [Grant Numbers 572613, 403981, 1059711] and the Canadian Institutes of Health Research [Grant Number MOP-82893]. ### 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: ALSPAC Law and Ethics Committee of University of Bristol gave ethical approval for this work. Research Ethics Committee of King Edward Memorial Hospital, Princess Margaret Hospital, the University of Western Australia, and the Health Department of Western Australia gave ethical approval for this work. 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 ALSPAC study website contains details of all the data that is available through a fully searchable data dictionary (http://www.bris.ac.uk/alspac/researchers/data-access/data-dictionary/). The data access policy is described here https://www.bristol.ac.uk/alspac/researchers/access/. The Raine Study website contains details of all the data that is available https://rainestudy.org.au/information-for-researchers/available-data/. The data access policy is described here https://rainestudy.org.au/information-for-researchers/project-application-process/