Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene.
Eur J Hum Genet
; 19(2): 208-15, 2011 Feb.
Article
in En
| MEDLINE
| ID: mdl-21063444
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 ß C (INHBC), part of the transforming growth factor ß 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 â¼2% 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Chromosomes, Human, Pair 12
/
Chromosome Mapping
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Activin Receptors, Type I
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Muscle Strength
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Genome-Wide Association Study
Type of study:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Adolescent
/
Adult
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Humans
/
Male
Language:
En
Journal:
Eur J Hum Genet
Journal subject:
GENETICA MEDICA
Year:
2011
Document type:
Article
Affiliation country:
Belgium
Country of publication:
United kingdom