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

Abstract

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 b C (INHBC), part of the transforming growth factor b 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 B2% stronger than G-allele carriers. The strength increasing effect of the A-allele was also observed in an independent replication sample (n¼266) 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.

Serum concentrations of insulin-like growth factor-1, members of the TGF-beta superfamily and follistatin do not reflect different stages of dynapenia and sarcopenia in elderly women

“…2013). Recently, it has been suggested that activin A receptors could serve as targets in order to treat muscle wasting (Chen et al, 2014a) and that genetic variations in the in the activin A receptor type-1B gene are associated with differences in knee extensor strength (Windelinckx et al, 2011), but studies focusing on activin A in the context of skeletal muscle mass and especially function are scarce. In an experimental model it has been shown that enhancing circulating activin A levels in C57BL/6 mice results in loss of muscle mass and function (Chen et al, 2014b).…”

Genetic aspects of skeletal muscle strength and mass with relevance to sarcopenia

“…54 Significant linkages were reported on four chromosomal regions with knee muscle strength measures. Most recently, Windelinckx and colleagues 55 performed a focused fine mapping of chromosome 12q12-14 and identified ACVR1B as a candidate gene for muscle strength.…”

“…89 -91 Because the common polymorphisms have rare allele frequencies, any public health significance of MSTN genetic variation is unlikely, though it may be important for those individuals. Subsequently genes within the myostatin-signaling pathway have been examined, including the myostatin receptors ( ACVR1B and ACVR2B ) and follistatin, a myostatin inhibitor, 55,92,93 but again, the sample sizes of the genotype groups with significant findings were generally small, making the clinical relevance of these findings uncertain but generally not striking.…”

Molecular genetic studies of gene identification for sarcopenia

“…Santiago et al (2011) recently found that the MSTN K153R polymorphism is associated with the ability to produce 'peak' power during muscle contractions in 281 healthy young adults. Importantly, the contribution of MSTN gene to skeletal muscle traits variation was supported by the linkage at 2q32.2 for knee extension peak torque (Huygens et al 2004a) as discussed above, indicating an important role for this gene in explaining inter-individual variation for muscle traits, in addition to three myostatin-related genes activin receptor type 2B (ACVR2B) and follistatin genes Kostek et al 2009), and activin receptor type 1B (ACVR1B) (Windelinckx et al 2011).…”