Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

Ana I. Hernandez Cordero, Natalia M. Gonzales, Clarissa C. Parker, Greta Sokoloff, David J. Vandenbergh, Riyan Cheng, Mark Abney, Andrew Sko, Alex Douglas, Abraham A. Palmer, Jennifer S. Gregory, Arimantas Lionikas* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)
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Muscle bulk in adult healthy humans is highly variable even after accounting for height, age and sex. Low muscle mass, due to fewer and/or smaller constituent muscle fibers, would exacerbate the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences muscle mass differences, but causative genes remain largely unknown. In a genome-wide association study (GWAS) on appendicular lean mass (ALM) in a population of 85,750 middle-age (38-49 years) individuals from the UK Biobank (UKB) we found 182 loci associated with ALM (P<5x10-8). We replicated associations for 78% of these loci (P<5x10-8) with ALM in a population of 181,862 elderly (60-74 years) individuals from UKB. We also conducted a GWAS on hindlimb skeletal muscle mass of 1,867 mice from an advanced intercross between two inbred strains (LG/J and SM/J) which identified 23 quantitative trait loci. 38 positional candidates distributed across 5 loci overlapped between the two species. In vitro studies of positional candidates confirmed CPNE1 and STC2 as modifiers of myogenesis. Collectively, these findings shed light on the genetics of muscle mass variability in humans and identify targets for the development of interventions for treatment of muscle loss. The overlapping results between humans and the mouse model GWAS point to shared genetic mechanisms across species.
Original languageEnglish
Pages (from-to)1222-1236
Number of pages15
JournalAmerican Journal of Human Genetics
Issue number6
Early online date21 Nov 2019
Publication statusPublished - 5 Dec 2019

Bibliographical note

The authors would like to acknowledge Dr David A. Blizard for his role in the development of the ideas that led to this study and feedback on the manuscript, Professor Helen Macdonald for valuable advice on study design, Dr Leslie R. Noble for help with the UK Biobank data, and Dr Joseph P. Gyekis for help genotyping cohort 2 mice. The authors would like to acknowledge funding from the University of Aberdeen for the Maxwell computer cluster, the Elphinstone and IMS studentship for AIHC; a Schweppe Foundation Career Development Award (AAP), and the NIH (NIAMS (AL: R01AR056280) and NIDA (AAP:R01DA021336, AAP:R21DA024845, AAP:T32MH020065, NMG:F31DA03635803), NIGMS (NMG:T32GM007197), NHGRI (MA:R01HG002899))


  • skeletal muscle
  • human and mouse GWAS
  • sarcopenia
  • UK Biobank


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