Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness
Authors: Willems Sara M. , Wright Daniel J. , Day Felix R. , Trajanoska Katerina , Joshi Peter K. , Morris John A. , Matteini Amy M. , Garton Fleur C. , Grarup Niels , Oskolkov Nikolay , Thalamuthu Anbupalam , Mangino Massimo , Liu Jun , Demirkan Ayse , Lek Monkol , Xu Liwen , Wang Guan , Oldmeadow Christopher , Gaulton Kyle J. , Lotta Luca A. , Miyamoto-Mikami Eri , Rivas Manuel A. , White Tom , Loh Po-Ru , Aadahl Mette , Amin Najaf , Attia John R. , Austin Krista , Benyamin Beben , Brage Søren , Cheng Yu-Ching , Cięszczyk Paweł , Derave Wim , Eriksson Karl-Fredrik , Eynon Nir , Linneberg Allan , Lucia Alejandro , Massidda Myosotis , Mitchell Braxton D. , Miyachi Motohiko , Murakami Haruka , Padmanabhan Sandosh , Pandey Ashutosh , Papadimitriou Ioannis , Rajpal Deepak K. , Sale Craig , Schnurr Theresia M. , Sessa Francesco , Shrine Nick , Tobin Martin D. , Varley Ian , Wain Louise V. , Wray Naomi R. , Lindgren Cecilia M. , MacArthur Daniel G. , Waterworth Dawn M. , McCarthy Mark I. , Pedersen Oluf , Khaw Kay-Tee , Kiel Douglas P. ,   GEFOS Any-Type of Fracture Consortium, Oei Ling , Zheng Hou-Feng , Forgetta Vincenzo , Leong Aaron , Ahmad Omar S. , Laurin Charles , Mokry Lauren E. , Ross Stephanie , Elks Cathy E. , Bowden Jack , Warrington Nicole M. , Murray Anna , Ruth Katherine S. , Tsilidis Konstantinos K. , Medina-Gómez Carolina , Estrada Karol , Bis Joshua C. , Chasman Daniel I. , Demissie Serkalem , Enneman Anke W. , Hsu Yi-Hsiang , Ingvarsson Thorvaldur , Kähönen Mika , Kammerer Candace , Lacroix Andrea Z. , Li Guo , Liu Ching-Ti , Liu Yongmei , Lorentzon Mattias , Mägi Reedik , Mihailov Evelin , Milani Lili , Moayyeri Alireza , Nielson Carrie M. , Sham Pack Chung , Siggeirsdotir Kristin , Sigurdsson Gunnar , Stefansson Kari , Trompet Stella , Thorleifsson Gudmar , Vandenput Liesbeth , van der Velde Nathalie , Viikari Jorma , Xiao Su-Mei , Zhao Jing Hua , Evans Daniel S. , Cummings Steven R. , Cauley Jane , Duncan Emma L. , de Groot Lisette C. P. G. M. , Esko Tonu , Gudnason Vilmundar , Harris Tamara B. , Jackson Rebecca D. , Jukema J Wouter , Ikram Arfan M. A. , Karasik David , Kaptoge Stephen , Kung Annie Wai Chee , Lehtimäki Terho , Lyytikäinen Leo-Pekka , Lips Paul , Luben Robert , Metspalu Andres , van Meurs Joyce B. J. , Minster Ryan L. , Orwoll Erick , Oei Edwin , Psaty Bruce M. , Raitakari Olli T. , Ralston Stuart W. , Ridker Paul M. , Robbins John A. , Smith Albert V. , Styrkarsdottir Unnur , Tranah Gregory J. , Thorstensdottir Unnur , Uitterlinden Andre G. , Zmuda Joseph , Zillikens M Carola , Ntzani Evangelia E. , Evangelou Evangelos , Ioannidis John P. A. , Evans David M. , Ohlsson Claes , Pitsiladis Yannis , Fuku Noriyuki , Franks Paul W. , North Kathryn N. , van Duijn Cornelia M. , Mather Karen A. , Hansen Torben , Hansson Ola , Spector Tim , Murabito Joanne M. , Richards J. Brent , Rivadeneira Fernando , Langenberg Claudia , Perry John R. B. , Wareham Nick J. , Scott Robert A. 
Published: July 2017

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.