Muscle bulk in adult healthy humans is highly variable even after height, age, and sex are accounted for. Low muscle mass, due to fewer and/or smaller constituent muscle fibers, would exacerbate the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences muscle mass differences, but causative genes remain largely unknown. In a genome-wide association study (GWAS) on appendicular lean mass (ALM) in a population of 85,750 middle-aged (aged 38–49 years) individuals from the UK Biobank (UKB), we found 182 loci associated with ALM (p

/pdf/genome-wide-associations-reveal-human-mouse-genetic-4on09ff017.pdf

Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

The genetics underlying variation in health‐related musculoskeletal phenotypes can be investigated in a mouse model. Quantitative trait loci (QTLs) affecting musculoskeletal traits in the LG/J and SM/J strain lineage remain to be refined and corroborated. The aim of this study was to map muscle and bone traits in males ( n  = 506) of the 50th filial generation of advanced intercross lines (LG/SM AIL) derived from the two strains. Genetic contribution to variation in all musculoskeletal traits was confirmed; the SNP heritability of muscle mass ranged between 0.46 and 0.56; and the SNP heritability of tibia length was 0.40. We used two analytical software, GEMMA and QTLRel, to map the underlying QTLs. GEMMA required substantially less computation and recovered all the QTLs identified by QTLRel. Seven significant QTLs were identified for muscle weight (Chr 1, 7, 11, 12, 13, 15, and 16), and two for tibia length, (Chr 1 and 13). Each QTL explained 4–5% of phenotypic variation. One muscle and both bone loci replicated previous findings; the remaining six were novel. Positional candidates for the replicated QTLs were prioritized based on in silico analyses and gene expression in muscle tissue. In summary, we replicated existing QTLs and identified novel QTLs affecting muscle weight, and replicated bone length QTLs in LG/SM AIL males. Heritability estimates substantially exceed the cumulative effect of the QTLs, hence a richer genetic architecture contributing to muscle and bone variability could be uncovered with a larger sample size.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.14814/phy2.13561

Replication and discovery of musculoskeletal QTLs in LG/J and SM/J advanced intercross lines.

Genome wide association analyses (GWAS) in model organisms have numerous advantages compared to human GWAS, including the ability to use populations with well-defined genetic diversity, the ability to collect tissue for gene expression analysis and the ability to perform experimental manipulations. We examined behavioral, physiological, and gene expression traits in 1,063 male and female mice from a 50-generation intercross between two inbred strains (LG/J and SM/J). We used genotyping by sequencing in conjunction with whole genome sequence data from the two founder strains to obtain genotypes at 4.3M SNPs. As expected, all alleles were common (mean MAF=0.35) and linkage disequilibrium degraded rapidly, providing excellent power and sub-megabase mapping precision. We identified 126 genome-wide significant loci for 50 traits and integrated this information with 7,081 cis-eQTLs and 1,476 trans-eQTLs identified in hippocampus, striatum and prefrontal cortex. We replicated several loci that were identified using an earlier generation of this intercross, including an association between locomotor activity and a locus containing a single gene, Csmd1. We also showed that Csmd1 mutant mice recapitulated the locomotor phenotype. Our results demonstrate the utility of this population, identify numerous novel associations, and provide examples of replication in an independent cohort, which is customary in human genetics, and replication by experimental manipulation, which is a unique advantage of model organisms.

/pdf/genome-wide-association-study-of-behavioral-physiological-24wbgwudus.pdf

Genome wide association study of behavioral, physiological and gene expression traits in a multigenerational mouse intercross

Muscle bulk in adult healthy humans is highly variable even after accounting for height, age and sex. Low muscle mass, due to fewer and/or smaller constituent muscle fibres, would exacerbate the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences muscle mass differences, but causative genes remain largely unknown. In a genome-wide association study (GWAS) on appendicular lean mass (ALM) in a population of 95,545 middle-age (37-48 years) individuals from the UK Biobank we found 125 loci associated with ALM (P

https://www.biorxiv.org/content/biorxiv/early/2019/10/10/370312.full.pdf

Genome-wide associations reveal human-mouse genetic convergence and novel modifiers of myogenesis, CPNE1 and STC2

Muscle bulk in humans is highly variable even after accounting for differences in height, age and sex, hence the impact of aging-related muscle loss known as sarcopenia varies in a similar fashion. Although heritability estimates are 40-80%, only a small number of muscle mass affecting genes have been identified. In 95,545 genotyped individuals of predominantly British ancestry, aged 37-48 years, body composition was assessed using bioelectrical impedance. We aimed to identify the genetic architecture underlying variability in appendicular lean mass (ALM), a proxy for muscle mass. A genome wide-association study (GWAS) in the Discovery cohort containing 60% of individuals identified 209 single nucleotide polymorphisms (SNP) with significant (P < 5 x 10-8) effects on ALM. We confirmed 62% of the SNPs (P < 2 x 10-5) in the remaining sub-set, the Replication cohort. A subsequent GWAS in the Combined cohort revealed 132 significant quantitative trait loci (QTLs) that collectively explained 6.75% of ALM phenotypic variance. Sixteen novel genes with missense and frameshift polymorphisms and expressed in skeletal muscle emerged (THBS3, CEP120, STC2, WSCD2, CCDC92, AKAP13, CPNE1, PPM1J, ITSN2, C2orf16, FGFR4, MLXIPL, PTCH1, BDNF, NCOR2, WDR90). Furthermore, non-coding SNPs located in 74 regulatory elements suggest gene expression being an important contributor to variation in muscle mass. In conclusion, we identified genetic architecture explaining a significant fraction of the phenotypic variation in middle age human ALM. The highlighted genes and regulatory elements will help understand the mechanisms underlying differences in skeletal muscle mass that can affect the risk and impact of sarcopenia.

/pdf/genome-wide-analysis-in-uk-biobank-identifies-over-100-qtls-4k4wfq8doj.pdf

Genome-wide analysis in UK Biobank identifies over 100 QTLs associated with muscle mass variability in middle age individuals

Muscle fiber cross-sectional area (CSA) and proportion of different fiber types are important determinants of muscle function and overall metabolism. Genetic variation plays a substantial role in p...

/pdf/fine-mapping-of-genes-determining-extrafusal-fiber-2t3yp9deml.pdf

Fine-mapping of genes determining extrafusal fiber properties in murine soleus muscle.

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Fine-mapping of genes determining extrafusal fiber properties in murine soleus muscle.