School of Basic Medical Science, Institute of Bioinformatics, Southern Medical University, Guangzhou, People's Republic of China.
Hum Genet. 2013 Feb;132(2):189-99. doi: 10.1007/s00439-012-1236-5. Epub 2012 Oct 30.
Bone and muscle, two major tissue types of musculoskeletal system, have strong genetic determination. Abnormality in bone and/or muscle may cause musculoskeletal diseases such as osteoporosis and sarcopenia. Bone size phenotypes (BSPs), such as hip bone size (HBS), appendicular bone size (ABS), are genetically correlated with body lean mass (mainly muscle mass). However, the specific genes shared by these phenotypes are largely unknown. In this study, we aimed to identify the specific genes with pleiotropic effects on BSPs and appendicular lean mass (ALM). We performed a bivariate genome-wide association study (GWAS) by analyzing ~690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) followed by a replication study in 2,286 unrelated US Caucasians (558 males and 1,728 females). We identified 14 interesting single nucleotide polymorphisms (SNPs) that may contribute to variation of both BSPs and ALM, with p values <10(-6) in discovery stage. Among them, the association of three SNPs (rs2507838, rs7116722, and rs11826261) in/near GLYAT (glycine-N-acyltransferase) gene was replicated in US Caucasians, with p values ranging from 1.89 × 10(-3) to 3.71 × 10(-4) for ALM-ABS, from 5.14 × 10(-3) to 1.11 × 10(-2) for ALM-HBS, respectively. Meta-analyses yielded stronger association signals for rs2507838, rs7116722, and rs11826261, with pooled p values of 1.68 × 10(-8), 7.94 × 10(-8), 6.80 × 10(-8) for ALB-ABS and 1.22 × 10(-4), 9.85 × 10(-5), 3.96 × 10(-4) for ALM-HBS, respectively. Haplotype allele ATA based on these three SNPs was also associated with ALM-HBS and ALM-ABS in both discovery and replication samples. Interestingly, GLYAT was previously found to be essential to glucose metabolism and energy metabolism, suggesting the gene's dual role in both bone development and muscle growth. Our findings, together with the prior biological evidence, suggest the importance of GLYAT gene in co-regulation of bone phenotypes and body lean mass.
骨骼和肌肉是肌肉骨骼系统的两种主要组织类型，它们具有很强的遗传决定因素。骨骼和/或肌肉的异常可能导致肌肉骨骼疾病，如骨质疏松症和肌肉减少症。骨骼大小表型（BSPs），如髋骨大小（HBS）、附肢骨大小（ABS），与身体瘦体重（主要是肌肉质量）有遗传相关性。然而，这些表型共享的特定基因在很大程度上尚不清楚。在这项研究中，我们旨在鉴定具有骨骼大小表型和附肢瘦体重（ALM）多效性的特定基因。我们通过分析 1627 名无血缘关系的汉族成年人（802 名男性和 825 名女性）中的约 690,000 个 SNP 进行了双变量全基因组关联研究（GWAS），随后在 2286 名无血缘关系的美国白种人中进行了复制研究（558 名男性和 1,728 名女性）。我们在发现阶段鉴定出了 14 个有趣的单核苷酸多态性（SNPs），这些 SNP 可能导致 BSPs 和 ALM 的变化，其 p 值<10(-6)。其中，在 GLYAT（甘氨酸-N-酰基转移酶）基因内/附近的三个 SNP（rs2507838、rs7116722 和 rs11826261）与 US 白种人的 ALM-ABS、ALM-HBS 的相关性分别为 1.89×10(-3)至 3.71×10(-4)和 5.14×10(-3)至 1.11×10(-2)。rs2507838、rs7116722 和 rs11826261 的荟萃分析得出了更强的关联信号，其合并 p 值分别为 1.68×10(-8)、7.94×10(-8)和 6.80×10(-8)用于 ALB-ABS，分别为 1.22×10(-4)、9.85×10(-5)和 3.96×10(-4)用于 ALM-HBS。这三个 SNP 基于的单倍型等位基因 ATA 也与发现和复制样本中的 ALM-HBS 和 ALM-ABS 相关。有趣的是，GLYAT 先前被发现对葡萄糖代谢和能量代谢至关重要，这表明该基因在骨骼发育和肌肉生长中具有双重作用。我们的发现，加上先前的生物学证据，表明 GLYAT 基因在骨骼表型和身体瘦体重的共同调节中具有重要意义。
