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
Year: 2021
Type: article
Abstract: 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.
Source: PLoS ONE
Authors: Chloé Sarnowski, Han Chen, Mary L. Biggs, Sylvia Wassertheil-Smoller, Jan Bressler, Marguerite R. Irvin, Kathleen A. Ryan, David Karasik, Donna K. Arnett, L. Adrienne Cupples, David W. Fardo, Stephanie M. Gogarten, Benjamin D. Heavner, Deepti Jain, Hyun Min Kang, Charles Kooperberg, Arch G. Mainous, Braxton D. Mitchell, Alanna C. Morrison, Jeffrey R. O’Connell, Bruce M. Psaty, Kenneth Rice, Albert V. Smith, Ramachandran S. Vasan, B. Gwen Windham, Douglas P. Kiel, Joanne M. Murabito, Kathryn L. Lunetta, on behalf of the TOPMed Longevity and Healthy Aging Working Group
Institutions: Boston University, The University of Texas Health Science Center at Houston, University of Washington, Albert Einstein College of Medicine, University of Alabama at Birmingham, University of Maryland, Baltimore, Bar-Ilan University, Hebrew SeniorLife, University of Kentucky, National Heart, Lung, and Blood Institute, Framingham Heart Study, University of Michigan, Fred Hutch Cancer Center, University of Florida Health, University of Florida, Baltimore VA Medical Center, Kaiser Permanente Washington Health Research Institute, University of Mississippi Medical Center, Broad Institute, Beth Israel Deaconess Medical Center, Harvard University, Massachusetts Institute of Technology
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,749
Funders: Brown University, Memorial Sloan-Kettering Cancer Center, Northwestern University, Harvard University, University of Washington, National Jewish Health, Broad Institute, Karl-Franzens-Universität Graz, Medizinische Universität Graz, National Institutes of Health, University of California, Los Angeles, University of California, San Francisco, Anschutz Medical Campus, University of Colorado, Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Eye Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Awards: G1000630459, G105512408, G1114307781, G1129490614, G1220223050, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1609525565, CORONARY HEART DISEASE AND STROKE, G1851278524, Genomic Architecture of Common Disease in Diverse Populations, G2041673117, G2081319657, G2096685756, G2100737286, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2194386449, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G232264632, G2391884931, G247538147, Identification and Functional characterization of a gene influencing LDL-C on 5q, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G2663813066, G2731083040, G2739113967, G278200998, G2867897773, G3045517347, G3062349281, G3220743633, G3256118428, G334973597, G3405256882, G3406115797, CHS research resources for the cardiovascular health of older adults, G3643850837, G3973572274, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, G4091723164, G4115846997, The Human Genome Sequencing Center, Genomic Architecture of a Key Alzheimer's Disease Mimic: CARTS, G4747441672, G475755283, G4790942633, G483429595, G5153757918, G5164707915, G5479317095, G5484742928, G5544033492, Epidemiology of Venous Thrombosis and Pulmonary Embolism, Epigenetics of Successful Aging, G5770678025, G581887176, G581977066, G5847423356, G5850737185, G588227857, G5928944960, CHS Events Follow-up Study, G6226795708, HYPERGEN CENTRAL BIOCHEMISTRY LABORATORY, The Framingham Heart Study, G645632895, G6556565091, G6615318374, CHS-Transition Phase, G6837735701, Mid-Atlantic Nutrition Obesity Research Center, G7155745631, G7176672723, G7332203415, G747822814, G7518182772, G7535686976, G77860733, G7842000789, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, G8606882599, HyperGEN: Genetics of Left Ventricular Hypertrophy, G8635788653, G8738262636, G9000275289
OpenAlex ID: W3175877803