Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA19104, USA.
EBioMedicine. 2024 Mar;101:105038. doi: 10.1016/j.ebiom.2024.105038. Epub 2024 Feb 27.
Carpal tunnel syndrome (CTS) is a common disorder caused by compression of the median nerve in the wrist, resulting in pain and numbness throughout the hand and forearm. While multiple behavioural and physiological factors influence CTS risk, a growing body of evidence supports a strong genetic contribution. Recent genome-wide association study (GWAS) efforts have reported 53 independent signals associated with CTS. While GWAS can identify genetic loci conferring risk, it does not determine which cell types drive the genetic aetiology of the trait, which variants are "causal" at a given signal, and which effector genes correspond to these non-coding variants. These obstacles limit interpretation of potential disease mechanisms.
We analysed CTS GWAS findings in the context of chromatin conformation between gene promoters and accessible chromatin regions across cellular models of bone, skeletal muscle, adipocytes and neurons. We identified proxy variants in high LD with the lead CTS sentinel SNPs residing in promoter connected open chromatin in the skeletal muscle and bone contexts.
We detected significant enrichment for heritability in skeletal muscle myotubes, as well as a weaker correlation in human mesenchymal stem cell-derived osteoblasts. In myotubes, our approach implicated 117 genes contacting 60 proxy variants corresponding to 20 of the 53 GWAS signals. In the osteoblast context we implicated 30 genes contacting 24 proxy variants coinciding with 12 signals, of which 19 genes shared. We subsequently prioritized BZW2 as a candidate effector gene in CTS and implicated it as novel gene that perturbs myocyte differentiation in vitro.
Taken together our results suggest that the CTS genetic component influences the size, integrity, and organization of multiple tissues surrounding the carpal tunnel, in particular muscle and bone, to predispose the nerve to being compressed in this disease setting.
This work was supported by NIH Grant UM1 DK126194 (SFAG and WY), R01AG072705 (SFAG & KDH) and the Center for Spatial and Functional Genomics at CHOP (SFAG & ADW). SFAG is supported by the Daniel B. Burke Endowed Chair for Diabetes Research. WY is supported by the Perelman School of Medicine of the University of Pennsylvania.
腕管综合征（CTS）是一种常见疾病，由正中神经在腕管中受压引起，导致手部和前臂疼痛和麻木。虽然多种行为和生理因素会影响 CTS 的发病风险，但越来越多的证据表明其发病具有很强的遗传因素。最近的全基因组关联研究（GWAS）结果报告了与 CTS 相关的 53 个独立信号。GWAS 虽然可以确定具有风险的遗传基因座，但无法确定哪些细胞类型驱动该特征的遗传病因，哪些变体在给定信号中是“因果”的，以及哪些效应基因对应于这些非编码变体。这些障碍限制了对潜在疾病机制的解释。
我们在骨骼、骨骼肌、脂肪细胞和神经元的细胞模型中，分析了 CTS GWAS 研究结果在基因启动子和开放染色质区域之间的染色质构象。我们在骨骼肌和骨骼背景下，确定了与 CTS 先导单核苷酸多态性密切相关的、位于启动子连接的开放染色质中的替代变体。
我们在骨骼肌肌管中检测到遗传力的显著富集，而在人类间充质干细胞衍生的成骨细胞中相关性较弱。在肌管中，我们的方法表明有 117 个基因与 60 个替代变体接触，这些变体对应于 53 个 GWAS 信号中的 20 个。在成骨细胞背景下，我们表明有 30 个基因与 24 个替代变体接触，与 12 个信号重合，其中 19 个基因共享。随后，我们将 BZW2 作为 CTS 的候选效应基因进行优先级排序，并表明它是一种新型基因，可干扰体外肌细胞分化。
综上所述，我们的研究结果表明，CTS 的遗传成分影响腕管周围的多种组织的大小、完整性和组织，特别是肌肉和骨骼，使神经在这种疾病环境中易受压迫。
这项工作得到了 NIH 基金 UM1 DK126194（SFAG 和 WY）、R01AG072705（SFAG & KDH）和费城儿童医院空间和功能基因组中心（SFAG & ADW）的支持。SFAG 由 Daniel B. Burke 糖尿病研究教授职位支持。WY 由宾夕法尼亚大学佩雷尔曼医学院支持。
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