Objectives: The objectives of this study are to 1) identify individuals that required surgery for thumb carpometacarpal osteoarthritis (CMCJ OA), 2) determine if CMCJ OA clusters in multigenerational families, 3) define the magnitude of familial risk of CMCJ OA, 4) identify risk factors associated with CMCJ OA and 5) identify rare genetic variants that segregate with familial CMCJ OA. Methods: We searched the Utah Population Database to identify a cohort of CMCJ OA patients that required a surgical procedure (CMC fusion or arthroplasty). Affected individuals were mapped to pedigrees to identify high-risk multigenerational families with excess clustering of CMCJ OA. Cox regression models were used to calculate familial risk of CMCJ OA in related individuals. Risk factors were evaluated using logistic regression models. Whole exome sequencing was used to identify a rare coding variant associated with familial CMCJ OA. Results: We identified 550 pedigrees with excess clustering of severe CMCJ OA. The relative risk of developing CMCJ OA requiring surgical treatment was significantly elevated in first- and third-degree relatives of affected individuals, and significant associations with advanced age, female sex, obesity, and tobacco use were observed. A dominantly segregating, rare variant in CHSY3 was associated with familial CMCJ OA. Conclusions: Familial clustering of severe CMCJ OA was observed in a statewide population. Identification of a candidate gene indicates a genetic contribution to the etiology of the disease. Our data indicate the genetic and environmental factors contribute to the disease process, further highlighting the multifactorial nature of the disease.

The authors have declared no competing interest.

This study was funded by the Skaggs Foundation for Research (MJJ and NHK), the Arthritis National Research Foundation (MJJ), the Utah Genome Project (MJJ and NHK), and National Institutes of Health R21AG063534-01A1 (MJJ). The UPDB is supported by the Pedigree and Population Resource, the Program in Personalized Health and Center for Clinical and Translational Science, and the National Cancer Institute at the National Institutes of Health grant P30 CA2014.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Boards of the University of Utah (IRB # 79442) and Intermountain Healthcare (IRB # 1050554), and the Resource for Genetic and Epidemiologic Research approved this study.

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All data produced in the present study are available upon reasonable request to the authors