Abstract

Skeletal muscle is a major component of the human body. Age-related loss of muscle mass and function contributes to some public health problems such as sarcopenia and osteoporosis. Skeletal muscle, mainly composed of appendicular lean mass (ALM), is a heritable trait. Copy number variation (CNV) is a common type of human genome variant which may play an important role in the etiology of many human diseases. In this study, we performed genome-wide association analyses of CNV for ALM in 2,286 Caucasian subjects. We then replicated the major findings in 1,627 Chinese subjects. Two CNVs, CNV1191 and CNV2580, were detected to be associated with ALM (p = 2.26×10−2 and 3.34×10−3, respectively). In the Chinese replication sample, the two CNVs achieved p-values of 3.26×10−2 and 0.107, respectively. CNV1191 covers a gene, GTPase of the immunity-associated protein family (GIMAP1), which is important for skeletal muscle cell survival/death in humans. CNV2580 is located in the Serine hydrolase-like protein (SERHL) gene, which plays an important role in normal peroxisome function and skeletal muscle growth in response to mechanical stimuli. In summary, our study suggested two novel CNVs and the related genes that may contribute to variation in ALM.

Highlights

  • Loss and function impairment of skeletal muscle, especially in the elderly, are related to a number of public health problems and increased mortality [1,2]

  • Genome wide association studies have identified a number of variants that may account for variation in Appendicular lean mass (ALM) [9,10]

  • CNV1191 and CNV2580 were replicated in the Chinese sample

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Summary

Introduction

Loss and function impairment of skeletal muscle, especially in the elderly, are related to a number of public health problems (such as sarcopenia, osteoporosis) and increased mortality [1,2]. Genome wide association studies have identified a number of variants that may account for variation in ALM [9,10]. CNV may influence gene expression, phenotypic variation and adaptation by disrupting coding or altering gene dosage [16,17,18,19] It may affect gene expression indirectly through position effects, predispose to deleterious genetic changes, or provide substrates for chromosome change in evolution [15,20,21,22]. A recent GWAS of CNVs in Chinese identified the gremlin gene that was associated with LBM variation [23]. We performed a CNV-based GWAS to identify genetic loci influencing variation in ALM in 2,286 Caucasian subjects. Note: The numbers within parentheses are standard deviation (SD). doi:10.1371/journal.pone.0089776.t001

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