S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Theses (Master's Degree_분자의학 및 바이오제약학과)
Identification of risk factors for sarcopenia and its roles in Koreans through Genome Wide Association Study
전장유전체연관성분석을 통한 한국인에서의 근감소증의 위험인자 발굴 및 역할 규명
- 융합과학기술대학원 분자의학 및 바이오제약학과
- Issue Date
- 서울대학교 융합과학기술대학원
- 학위논문 (석사)-- 서울대학교 융합과학기술대학원 분자의학 및 바이오제약학과, 2017. 8. 박경수.
- Sarcopenia, the progressive decrease of skeletal muscle mass and function, is related to functional impairment in the elderly. Muscle mass, mainly composed of lean body mass, is known to be a heritable trait. Sarcopenia has been a subject of increasing genetic researches. However, genetic risk factors in Koreans were not thoroughly evaluated. The aim of this study is to identify genetic variants associated with lean body mass in Koreans.
We performed a genome-wide association analysis of the two cohorts (Stage I), then did a joint analysis to discover common SNPs (Single Nucleotide Polymorphisms) in both cohorts (Stage II). A total of 13,105 participants (5,817 from Ansung-Ansan cohort and 7,288 form Gangnam center cohort) were analyzed. Joint analysis was conducted using METAL. We performed linear regression analysis including sex, age, height and body fat mass as covariates. Arbitrarily defined P value threshold of less than 0.00001 was used for suggestive evidence of association.
In joint analysis, none of the SNP markers passed genome-wide significance threshold of P < 5 x 10-8. There are nine loci (in/near FTO, GALNT16, ERH, PLCE1, STK39, PRF1 and ADAMTS14 genes) which were associated with lean body mass with suggestive genome-wide significance.
Among them, five variants including the most significant loci (rs3751812) were located in FTO. The most recent study showed that FTO expression increased during myoblasts differentiation, while the silence of FTO inhibited the differentiation. So, we planned to evaluate the correlation between FTO expression and muscle protein degradation, which is another muscle atrophy phenotype in sarcopenia model. After 2 days of FTO siRNA transfection in our study, there were no significant difference of MuRF-1 and Atrogin-1 expression, the two muscle-specific ubiquitin ligases that are important regulators of ubiquitin-mediated protein degradation in skeletal muscle.
In this first genome-wide association joint analysis study for lean body mass in Korean participants including the representative cohorts of Korea, we identified nine loci (in/near FTO, GALNT16, ERH, PLCE1, STK39, PRF1 and ADAMTS14 genes) for lean body mass which are crucial in sarcopenia diagnosis.
The actual function of the variants and the underlying mechanisms of the most suggestive gene, as well as FTOs involvement in skeletal muscle biology still need to be further elucidated by in vitro and animal experiments.