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

An Windelinckx, Gunther De Mars, Wim Huygens, Maarten W. Peeters, Barbara Vincent, Cisca Wijmenga, Diether Lambrechts, Christophe Delecluse, Stephen M. Roth, E. Jeffrey Metter, Luigi Ferrucci, Jeroen Aerssens, Robert Vlietinck, Gaston P. Beunen, Martine A. Thomis

Research output: Contribution to journalArticlepeer-review


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 (n266) 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.

Original languageEnglish (US)
Pages (from-to)208-215
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number2
StatePublished - Feb 2011
Externally publishedYes


  • combined linkage and association analyses
  • complex trait
  • family-based association
  • genotype/phenotype association

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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