Variant to gene mapping for carpal tunnel syndrome risk loci implicates skeletal muscle regulatory elementsResearch in context
Matthew C. Pahl,
Lin Liu,
James A. Pippin,
Yadav Wagley,
Keith Boehm,
Kurt D. Hankenson,
Andrew D. Wells,
Wenli Yang,
Struan F.A. Grant
Affiliations
Matthew C. Pahl
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
Lin Liu
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
James A. Pippin
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
Yadav Wagley
Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Keith Boehm
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
Kurt D. Hankenson
Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Andrew D. Wells
Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA, USA
Wenli Yang
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; Corresponding author. Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Struan F.A. Grant
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 Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author. Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Summary: Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: 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.
