title: Identification and prioritization of NUAK1 and PPP1CC as positional candidate loci for skeletal muscle strength phenotypes.
abstract: Muscle strength is an important determinant in elite sports performance as well as in the activities of daily living. Muscle metabolism also plays a role in the genesis, and therefore prevention, of common pathological conditions and chronic diseases. Even though heritability estimates between 31 and 78% suggest a significant genetic component in muscle strength, only a limited number of genes influencing muscle strength have been identified. This study aimed to identify and prioritize positional candidate genes within a skeletal muscle strength quantitative trait locus on chromosome 12q22-23 for follow-up. A two-staged gene-centered fine-mapping approach using 122 single nucleotide polymorphisms (SNPs) in stage 1 identified a family-based association (n=500) between several tagSNPs located in the ATPase, Ca2+ transporting, cardiac muscle, slow twitch 2 (ATP2A2; rs3026468), the NUAK family, SNF1-like kinase, 1 (NUAK1; rs10861553 and rs3741886), and the protein phosphatase 1, catalytic subunit, gamma isoform (PPP1CC; rs1050587 and rs7901769) genes and knee torque production (P values up to 0.00092). In stage 2, family-based association tests on additional putatively functional SNPs (e.g., exonic SNPs, SNPs in transcription factor binding sites or in conserved regions) in an enlarged sample (n=536; 464 individuals overlap with stage 1) did not identify additional associations with muscle strength characteristics. Further in-depth analyses will be necessary to elucidate the exact role of ATP2A2, PPP1CC, and NUAK1 in muscle strength and to find out which functional polymorphisms are at the base of the interindividual strength differences.
authors.affiliation: Research Center for Exercise and Health, Department of Biomedical Kinesiology, Faculty of Kinesiology and Rehabilitation Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Windelinckx
authors.forename: Gunther
authors.initials: G
authors.lastname: De Mars
authors.forename: Wim
authors.initials: W
authors.lastname: Huygens
authors.forename: Maarten W
authors.initials: MW
authors.lastname: Peeters
authors.forename: Barbara
authors.initials: B
authors.lastname: Vincent
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Jeroen
authors.initials: J
authors.lastname: Aerssens
authors.forename: Robert
authors.initials: R
authors.lastname: Vlietinck
authors.forename: Gaston
authors.initials: G
authors.lastname: Beunen
authors.forename: Martine A I
authors.initials: MA
authors.lastname: Thomis
mesh_terms: D000293:Adolescent; D000328:Adult; D005838:Genotype; D006801:Humans; D008297:Male; D053580:Muscle Strength / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics*; D054645:Protein Phosphatase 1 / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics; D055815:Young Adult
chemical_list: D012097:Repressor Proteins; D011494:Protein Kinases; C470845:NUAK1 protein, human; C517102:PPP1CC protein, human; D054645:Protein Phosphatase 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human