Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene

Eur J Hum Genet. 2011 Feb;19(2):208-15. doi: 10.1038/ejhg.2010.173. Epub 2010 Nov 10.


Muscle strength is important in functional activities of daily living and the prevention of common pathologies. We describe the two-staged fine mapping of a previously identified linkage peak for knee strength on chr12q12-14. First, 209 tagSNPs in/around 74 prioritized genes were genotyped in 500 Caucasian brothers from the Leuven Genes for Muscular Strength study (LGfMS). Combined linkage and family-based association analyses identified activin receptor 1B (ACVR1B) and inhibin β C (INHBC), part of the transforming growth factor β pathway regulating myostatin - a negative regulator of muscle mass - signaling, for follow-up. Second, 33 SNPs, selected in these genes based on their likelihood to functionally affect gene expression/function, were genotyped in an extended sample of 536 LGfMS siblings. Strong associations between ACVR1B genotypes and knee muscle strength (P-values up to 0.00002) were present. Of particular interest was the association with rs2854464, located in a putative miR-24-binding site, as miR-24 was implicated in the inhibition of skeletal muscle differentiation. Rs2854464 AA individuals were ∼2% stronger than G-allele carriers. The strength increasing effect of the A-allele was also observed in an independent replication sample (n=266) selected from the Baltimore Longitudinal Study of Aging and a Flemish Policy Research Centre Sport, Physical Activity and Health study. However, no genotype-related difference in ACVR1B mRNA expression in quadriceps muscle was observed. In conclusion, we applied a two-stage fine mapping approach, and are the first to identify and partially replicate genetic variants in the ACVR1B gene that account for genetic variation in human muscle strength.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics*
  • Activin Receptors, Type I / metabolism
  • Adolescent
  • Adult
  • Chromosome Mapping / methods*
  • Chromosomes, Human, Pair 12 / genetics*
  • Genetic Linkage
  • Genome-Wide Association Study / methods*
  • Genotype
  • Humans
  • Knee / physiology
  • Male
  • Muscle Strength / genetics*
  • Muscle, Skeletal / physiology
  • Myostatin / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Siblings
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Whites / genetics
  • Young Adult


  • Myostatin
  • Transforming Growth Factor beta
  • ACVR1B protein, human
  • Activin Receptors, Type I