Abstract
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10−17), arthritis (GDF5p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
Highlights
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people
The primary analysis was based on the established 2010 European Working Group on Sarcopenia in Older People (EWGSOP) definition of low grip strength, and results were compared to an analysis of the alternative Foundations of the National Institutes of Health (FNIH) definition based on its association with functional outcomes, with additional analyses stratified by sex
Our primary analysis of EWGSOP definition low grip strength will be described first, with subsequent additional analyses described in later sections: these include analysis of males and females separately and use of the alternative low grip strength criteria provided by the FNIH data
Summary
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Another study on maximum hand grip strength (divided by weight) in mostly middle-aged UK Biobank participants (334,925 people aged 40–70, mean aged 56) identified and replicated 64 loci, many of which are known to have a role in determining anthropometric measures of body size[9,10] These previous studies that considered grip strength as a continuous phenotype across young and old individuals may not provide insights into the age related loss of muscle strength that leads to a magnitude of weakness sufficient to call it a disease. The associated loci and subsequent pathway and Mendelian randomization analysis reveal causal pathways to weakness at older ages distinct from overall strength during the life course, highlighting specific diseases (such as osteoarthritis) and link to hallmark aging mechanisms such as cell cycle control
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