Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.
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TOPMed Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for NHLBI TOPMed: FHS (phs000974) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-12S2). WGS for NHLBI TOPMed: CHS (phs001368) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201600033I). WGS for NHLBI TOPMed: Amish (phs000956) was performed at the Broad Institute of MIT and Harvard (3R01HL121007-01S1). WGS for NHLBI TOPMed: ARIC (phs001211) was performed at the Baylor College of Medicine Human Genome Sequencing Center (3U54HG003273-12S2, HHSN268201500015C) and the Broad Institute for MIT and Harvard (3R01HL092577-06S1). WGS for NHLBI TOPMed: WHI (phs001237) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C). WGS for NHLBI TOPMed: HyperGEN (phs001293) was performed at the University of Washington Northwest Genomics Center (3R01HL055673-18S1). The Genome Sequencing Program (GSP) was funded by the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Eye Institute (NEI). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. ARIC is part of the Centers for Common Disease Genomics (CCDG) program, a large-scale genome sequencing effort to identify rare risk and protective alleles that contribute to a range of common disease phenotypes. The CCDG program was supported by NHGRI and NHLBI, and whole genome sequencing was performed at the Baylor College of Medicine Human Genome Sequencing Center (UM1 HG008898 and R01HL059367). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The Analysis Commons was funded by R01HL131136. Study-specific acknowledgements FHS: The FHS acknowledges the support of contracts N01-HC-25195 and HHSN268201500001I from the National Heart, Lung and Blood Institute and grant supplement R01 HL092577-06S1 for this research. We also acknowledge the dedication of the FHS study participants without whom this research would not be possible. CHS: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Amish: The TOPMed component of the Amish Research Program was supported by NIH grants R01 HL121007, U01 HL072515, and R01 AG18728, P30 DK072488. We gratefully acknowledge our Amish liaisons and field workers and the extraordinary cooperation and support of the Amish community, without which these studies would not have been possible. ARIC: The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. HyperGEN: The HyperGEN Study is part of the NHLBI Family Blood Pressure Program; collection of the data represented here was supported by grants U01 HL054472 (MN Lab), U01 HL054473 (DCC), U01 HL054495 (AL FC), and U01 HL054509 (NC FC). The HyperGEN: Genetics of Left Ventricular Hypertrophy Study was supported by NHLBI grant R01 HL055673 with whole-genome sequencing made possible by supplement -18S1. Individual grants Dr. Jeffrey R. O’Connell grant U01 HL137181 NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). UK Biobank This research has been conducted using the UK Biobank Resource under Application Number 42614.
The data used in this study are available through dbGaP but with restrictions as approved by the individual study IRBs as these data contain potentially identifying and sensitive patient information. Requesting individual(s) must have IRB approval to use the data, and obtain a letter of collaboration from each study's principal investigator. The NHLBI Data Access Committee (email@example.com) handles data requests for the TOPMed study accessions via the dbGaP Data Access Request system. The summary statistics from the association analyses that support the findings of this study will be posted on the TOPMed Genomic Summary Results dbGaP accession phs001974, “NHLBI TOPMed: Genomic Summary Results for the Trans-Omics for Precision Medicine Program” and made accessible, via controlled access and a General Research Use (GRU) consent designation, to applicants via the normative dbGaP application process.
Sarnowski, Chloé; Chen, Han; Biggs, Mary L.; Wassertheil-Smoller, Sylvia; Bressler, Jan; Irvin, Marguerite R.; Ryan, Kathleen A.; Karasik, David; Arnett, Donna K.; Cupples, L. Adrienne; Fardo, David W.; Gogarten, Stephanie M.; Heavner, Benjamin D.; Jain, Deepti; Kang, Hyun Min; Kooperberg, Charles; Mainous, Arch G.; Mitchell, Braxton D.; Morrison, Alanna C.; and O'Connell, Jeffrey R., "Identification of Novel and Rare Variants Associated with Handgrip Strength Using Whole Genome Sequence Data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program" (2021). Epidemiology and Environmental Health Faculty Publications. 76.
S1 File. Materials. https://doi.org/10.1371/journal.pone.0253611.s001
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S2 File. Longevity wkgp list. https://doi.org/10.1371/journal.pone.0253611.s002
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S3 File. TOPMed banner authorship. https://doi.org/10.1371/journal.pone.0253611.s003
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S4 File. S11 and S12 Tables. https://doi.org/10.1371/journal.pone.0253611.s004