Zhang Xiaoyu, Su Kuan-Jui, Banerjee Bodhisattwa, Eres Ittai, Hsu Yi-Hsiang, Crandall Carolyn J, Donaka Rajashekar, Han Zhe, Jackson Rebecca D, Liu Hanhan, Luo Zhe, Mitchell Braxton D, Qiu Chuan, Tian Qing, Shen Hui, Tsai Ming-Ju, Wiggins Kerri L, Xu Hanfei, Yau Michelle, Zhao Lan-Juan, Zhang Xiao, Montasser May E, Kiel Douglas P, Deng Hong-Wen, Liu Ching-Ti, Karasik David
Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
Center for Biomedical Informatics and Genomics, Tulane University, New Orleans, LA, 70112, USA.
Genome Biol. 2025 Apr 28;26(1):106. doi: 10.1186/s13059-025-03520-x.
Lean body mass is a crucial physiological component of body composition. Although lean body mass has a high heritability, studies evaluating the genetic determinants of lean mass (LM) have to date been limited largely to genome-wide association studies (GWAS) and common variants. Using whole genome sequencing (WGS)-based studies, we aimed to discover novel genetic variants associated with LM in population-based cohorts with multiple ancestries.
We describe the largest WGS-based meta-analysis of lean body mass to date, encompassing 10,729 WGS samples from six TOPMed cohorts and the Louisiana Osteoporosis Study (LOS) cohort, measured with dual-energy X-ray absorptiometry. We identify seven genome-wide loci significantly associated with LM not reported by previous GWAS. We partially replicate these associations in UK Biobank samples. In rare variant analysis, we discover one novel protein-coding gene, DMAC1, associated with both whole-body LM and appendicular LM in females, and a long non-coding RNA gene linked to appendicular LM in males. Both genes exhibit notably high expression levels in skeletal muscle tissue. We investigate the functional roles of two novel lean-mass-related genes, EMP2 and SSUH2, in animal models. EMP2 deficiency in Drosophila leads to significantly reduced mobility without altering muscle tissue or body fat morphology, whereas an SSUH2 gene mutation in zebrafish stimulates muscle fiber growth.
Our comprehensive analysis, encompassing a large-scale WGS meta-analysis and functional investigations, reveals novel genomic loci and genes associated with lean mass traits, shedding new insights into pathways influencing muscle metabolism and muscle mass regulation.
瘦体重是身体组成的关键生理成分。尽管瘦体重具有较高的遗传力，但迄今为止，评估瘦体重（LM）遗传决定因素的研究在很大程度上仅限于全基因组关联研究（GWAS）和常见变异。通过基于全基因组测序（WGS）的研究，我们旨在发现与多个祖先的人群队列中LM相关的新遗传变异。
我们描述了迄今为止基于WGS的最大规模瘦体重荟萃分析，涵盖了来自六个TOPMed队列和路易斯安那骨质疏松症研究（LOS）队列的10,729个WGS样本，采用双能X线吸收法测量。我们确定了七个全基因组位点与LM显著相关，这些位点以前的GWAS未报道。我们在英国生物银行样本中部分重复了这些关联。在罕见变异分析中，我们发现一个新的蛋白质编码基因DMAC1与女性的全身LM和附属LM相关，以及一个长链非编码RNA基因与男性的附属LM相关。这两个基因在骨骼肌组织中均表现出显著高表达水平。我们在动物模型中研究了两个与瘦体重相关的新基因EMP2和SSUH2的功能作用。果蝇中EMP2缺乏导致运动能力显著降低，而不改变肌肉组织或体脂形态，而斑马鱼中的SSUH2基因突变刺激肌肉纤维生长。
我们的综合分析，包括大规模WGS荟萃分析和功能研究，揭示了与瘦体重特征相关的新基因组位点和基因，为影响肌肉代谢和肌肉质量调节的途径提供了新见解。
