Introduction: Age-related alterations in muscle tissue morphology and function, as well as chronic pro-inflammatory conditions, contribute to the development of sarcopenia. To elucidate the multidimensional pathogenesis of sarcopenia, we performed a comprehensive genetic analysis, including common variants, rare variants, and human leukemia antigen (HLA). Methods: A total of 129 older adults were analyzed using whole-genome sequencing (WGS), including 67 sarcopenia patients and 62 normal controls. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 consensus. WGS data and associated clinical data were obtained from the National Center for Geriatrics and Gerontology Biobank in Japan. We performed logistic regression adjusted for age, sex, and body mass index for common variant (minor allele frequency [MAF] ≧0.01), rare variant (MAF <0.01), and HLA analyses. For the functional analysis, we performed RNA interference using human myoblasts and estimated gene expressions (MYOG, MYMK, MYMG) by quantitative PCR. Results: Rare variant analysis identified five rare coding variants of genes – SLC41A3, SYNRG, CLUAP1, CCHCR1, and ALDH2 – expressed in skeletal muscle. Of these, a deleterious frameshift deletion in SLC41A3 was associated with the pathogenesis of sarcopenia (p = 0.0012, odds ratio [OR] = 11.52, 95% confidence interval [CI] = 2.62–50.69). This deletion significantly reduced expression of myogenin (MYOG), a factor involved in myoblast differentiation (p = 0.0094), but did not affect the fusion of myogenic cells. We also discovered a new protective allele, HLA-DPB1*02:01 associated with sarcopenia (OR = 0.17, 95% CI = 0.060–0.51, p = 0.0015), which has a high occurrence rate in the Northeast Asian population. Conclusion: Rare variant analysis identified a deleterious frameshift deletion in SLC41A3 as a risk factor for sarcopenia. Our findings suggest that the suppression of MYOG could play a role in myogenesis or muscle maintenance, although this mutation did not impact the terminal differentiation of human myoblasts. Additionally, HLA analysis revealed that HLA-DPB1*02:01 has a protective effect, especially in Northeast Asian populations. Our study enhances the understanding of the etiology of sarcopenia and provides new insights into the mechanisms of its pathogenesis.

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