Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

Sara M Willems,Tom White,Yannis Pitsiladis,Paweł Cięszczyk,Martin D Tobin,Søren Brage,John A Morris,Jun Liu,Mette Aadahl,Kay‐Tee Khaw ,Haruka Murakami,Po−Ru Loh ,Alejandro Lucía ,Cornelia M Van Duijn,Craig Sale,Massimo Mangino,Karen A Mather,Braxton D Mitchell,Nick Wareham ,Klaus North ,Ioannis Papadimitriou,Krista G Austin ,Yu‐Ching Cheng ,Katerina Trajanoska,Ian Varley,Deepak K Rajpal,Amy M Matteini,Oluf Pedersen,Joanne M Murabito,Niels Grarup,Beben Benyamin,J Brent Richards,Kyle J Gaulton,Allan Linneberg,Nick Shrine,Fleur Garton ,Felix R Day,Douglas P Kiel,Guan Wang,Nikolay Oskolkov,Christopher Oldmeadow,Anbupalam Thalamuthu,John R B Perry,Manuel A Rivas,Tim D Spector ,Peter K Joshi,Eri Miyamoto‐Mikami ,Deil S Wright ,Paul W Franks,Noriyuki Fuku,Li‐Wen Xu ,Ashutosh Kumar Pandey ,Claudia Langenberg,Fernando Rivadeneira,Daniel G Macarthur,Francesco Sessa,Myosotis Massidda,Mark I Mccarthy,Sandosh Padmanabhan,Luca A Lotta,Theresia M Schnurr,Karl-Fredrik Eriksson,John Attia ,Wim Derave,Louise V Wain,Dawn Waterworth ,Ayşe Demirkan ,Monkol Lek,Motohiko Miyachi,Cecilia M Lindgren,Naomi R Wray,Nir Eynon,Najaf Amin,Torben Hansen,Ola Hansson,Robert A Scott

doi:10.1038/ncomms16015

Abstract

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10−8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

Highlights

Due to the well-established observational associations of grip strength with mortality and incident CHD it has been hypothesized that improvement of muscle strength might increase longevity and reduce risk of adverse cardiovascular events[7]
Our Mendelian randomization (MR) analyses do not find evidence supportive of a causal role of muscular strength in mortality risk, nor in risk of cardiovascular events (CHD and myocardial infarction (MI)), leaving open the possibility that these observational associations may be attributable to confounding and/or reverse causality. Regardless, this does not negate the importance of maintaining strength and muscle mass during ageing as a strategy to maintain physical function[59], and we acknowledge the potential limitations of our MR
We saw evidence for shared genetic aetiology of bone mineral density and lean mass with grip strength, and MR results suggested a causal role for higher muscular strength in lower risk of fracture

Summary

Introduction

Within the UKB discovery cohort, the association of all three loci with grip strength persisted at genome-wide significance even after sensitivity analyses restricted to participants without any form of self-reported condition which might affect muscle mass or function. Association of haplotypes (inverted versus non-inverted, continuous structural variant [a/b/g] copy number, and 9 common haplotypes as a categorical exposure) with grip strength was modelled using linear regression adjusted for age, sex, height (m), BMI (kg m À 2) and UKB genotype chip in up to 111,860 unrelated genetic white Europeans defined centrally by UKB (see URLs).

Results

Conclusion