TY - JOUR
T1 - Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene
AU - Windelinckx, An
AU - De Mars, Gunther
AU - Huygens, Wim
AU - Peeters, Maarten W.
AU - Vincent, Barbara
AU - Wijmenga, Cisca
AU - Lambrechts, Diether
AU - Delecluse, Christophe
AU - Roth, Stephen M.
AU - Metter, E. Jeffrey
AU - Ferrucci, Luigi
AU - Aerssens, Jeroen
AU - Vlietinck, Robert
AU - Beunen, Gaston P.
AU - Thomis, Martine A.
PY - 2011/2
Y1 - 2011/2
N2 - 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.
AB - 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.
KW - combined linkage and association analyses
KW - complex trait
KW - family-based association
KW - genotype/phenotype association
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U2 - 10.1038/ejhg.2010.173
DO - 10.1038/ejhg.2010.173
M3 - Article
C2 - 21063444
AN - SCOPUS:78651406683
VL - 19
SP - 208
EP - 215
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 2
ER -