Whole-exome sequencing identifies 5 novel genes associated with carpal tunnel syndrome.

Carpal tunnel syndrome (CTS), a common peripheral nerve entrapment disorder, has a high estimated heritability index. Although previous genome-wide association studies have assessed common genetic components of CTS, the risk contributed by coding variants is still not well understood. Here, we performed the largest exome-wide analyses using UK Biobank data from 350 770 participants to find coding variants associated with CTS. We then explored the relative contribution of both rare mutations and polygenic risk score (PRS) to CTS risk in survival analyses. Finally, we investigated the functional pathways of the CTS-related coding genes identified above. Aside from conforming 6 known CTS genes, 5 novel genes were identified (SPSB1, SYNC, ITGB5, MUC13 and LOXL4). The associations of most genes we identified with incident CTS were striking in survival analyses. Additionally, we provided evidence that combining rare coding alleles and polygenic risk score can improve the genetic prediction of CTS. Functional enrichment analyses revealed potential roles of the identified coding variants in CTS pathogenesis, where they contributed to extracellular matrix organization. Our results evaluated the contribution to CTS etiology from quantities of coding variants accessible to exome sequencing data.