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

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.

Genes encoding agrin (AGRN) and neurotrypsin (PRSS12) are associated with muscle mass, strength and plasma C-terminal agrin fragment concentration

“…Unfortunately, the current paucity of data surrounding potential differences in the genetic architecture of left hand vs right hand grip strength impedes our interpretation of these findings. This dearth is somewhat due to existing studies considering only the mean grip strength of both hands [9] or maximum grip strength from either hand [42,43], eliminating the potential to elucidate genetic differences between hands. Interestingly however, a recent study based upon UKBB data identified 160 SNPs for right hand grip strength and 136 SNPs for left hand grip strength [44], demonstrating hand-specific differences in the genetic basis of grip strength.…”