Suchergebnisse

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. ; This research has been conducted using the UK Biobank Resource. The Fenland Study is supported by the UK Medical Research Council (MRC) (MC_UU_12015/1; MC_UU_12015/2; MC_UU_12015/3). EPIC-Norfolk is supported by the MRC (G401527, G1000143) and Cancer Research UK (A8257). The HCS is gratefully supported by the University of Newcastle (Australia) and the Fairfax Family Foundation. Sydney MAS is supported by the Australian National Health and Medical Research Council (NHMRC), grants ID568969, ID350833 and ID109308. Sydney MAS DNA was extracted by Genetic Repositories Australia, funded by NHMRC Enabling Grant 401184. The GEFOS Study, used as controls for the US and Jamaican athletes, was supported in part by NIH grants U01 HG004436 and P30 DK072488, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). TwinsUK was funded by the Wellcome Trust (WT), MRC, and European Union. The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. SNP Genotyping was performed by The WT Sanger Institute and National Eye Institute via NIH/CIDR. M.McC is a WT Senior Investigator and receives support from WT 090532 and 098381. TW is the recipient of a studentship from MedImmune. Research by A. Lucia is supported by Fondo de Investigaciones Sanitarias and Fondos Feder (grant # PI15/0558). EM-M. was a recipient of a Grant-in-Aid for JSPS Fellow from the Japan Society for the Promotion of Science. This work was supported in part by grants from the Grant-in-Aid for Scientific Research (B) (15H03081 to NF) of the Japanese Ministry of Education, Culture, Sports, Science and Technology and by a grant-in-aid for scientific research (to M. Miyachi) from the Japanese Ministry of Health, Labor, and Welfare. This work was further supported by NIH grants R01 AR41398 and U24 AG051129.

Published ; Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism. ; Intramural Research Program of the NIH ; NCRR ; NHLBI ; MedStar Research Institute ; NINDS ; National Center of Advancing Translational Technologies CTSI ; National Institute of Diabetes and Digestive and Kidney Diseases ; Robert Dawson Evans Endowment ; Italian Ministry of Health ; University and Research of the Autonomous Province of Bolzano ; European Union's Seventh Framework Programme ; ENGAGE project ; EPIGENESYS ; BLUEPRINT ; Dutch Innovation-Oriented Research Program on Genomics ; Netherlands Organization for Scientific Research (NWO) ; South Tyrolean Sparkasse Foundation ; Radboud University Nijmegen Medical Centre ; University of Maryland General Clinical Research Center ; Johns Hopkins University General Clinical Research Center ; Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC) ; Netherlands Research Institute for Diseases in the Elderly ; Erasmus Medical Center and Erasmus University, Rotterdam ; Netherlands Organization for the Health Research and Development (ZonMw) ; Dutch Ministry for Health, Welfare and Sports ; European Commission ; Municipality of Rotterdam ; German Bundesministerium fuer Forschung und Technology ; Wellcome Trust ; English Department of Health, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre ; Canadian Institutes of Health Research, Canadian Foundation for Innovation ; Fonds de la Recherche en Santé Québec, Ministère du Développement Économique, de l'Innovation et de l'Exportation ; Lady Davis Institute of the Jewish General Hospital (JBR) ; Australian National Health and Medical Research Council ; Sir Charles Gairdner Hospital Research Fund ; Italian "Compagnia di San Paolo" ; Italian "Fondazione Cariplo" ; Leiden University Medical Centre ; Dutch Arthritis Association ; Pfizer, Groton, CT, USA ; Dutch Centre of Medical System Biology ; Netherlands Genomics Initiative (NGI), Netherlands Consortium of Healthy Aging ; Academy of Finland ; Finnish Diabetes Research Society ; Folkhälsan Research Foundation ; Novo Nordisk Foundation ; Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation ; University of Helsinki ; European Science Foundation (EUROSTRESS) ; Finnish Ministry of Education ; Ahokas Foundation ; Emil Aaltonen Foundation ; Juho Vainio Foundation ; BBSRC ; EPSRC ; ESRC ; MRC ; AXA Research Fund ; Help the Aged/Research Into Ageing (Disconnected Mind) ; Economic Structure Enhancing Fund (FES) of the Dutch government ; Dutch Ministry of Economic Affairs ; Dutch Ministry of Education, Culture and Science ; Northern Netherlands Collaboration of Provinces (SNN) ; Province of Groningen ; University of Groningen ; Dutch Kidney Foundation ; Dutch Diabetes Research Foundation ; Bristol-Myers Squibb ; Netherlands Heart Foundation ; National Computing Facilities Foundation (NCF), Netherlands ; Endocrine Research Fund