Genetic Epidemiology of Rotator Cuff Tears: The cuffGEN Study

Last updated: October 23, 2025
Sponsor: University of Michigan
Overall Status: Active - Recruiting

Phase

N/A

Condition

N/A

Treatment

NA (not an interventional study)

Clinical Study ID

NCT04831164
STU-2020-0689
1R01AR074989-01A1
  • Ages 40-85
  • All Genders

Study Summary

Rotator cuff tear is one of the most common reasons to seek musculoskeletal care, and cuff repair is one of the fastest growing ambulatory surgery procedures. However, the etiology of cuff tears, reasons for variability treatment success, and causes of FI are poorly understood. A large-scale genome-wide association studies (GWAS) using imaging-verified rotator cuff tear cases and controls can address limitations in rigor of prior research and assess the genetic basis of FI and functional outcomes of cuff tear treatments.

Primary Objective: To conduct a case-control GWAS of imaging-verified symptomatic rotator cuff tear in approximately 3000-6000 individuals and replicate findings in an independent set of 3000-6000 or more imaging-verified individuals to identify common variants in several genetic loci that increase risk for rotator cuff tears.

Hypothesis: Common variants in several genetic loci increase risk for rotator cuff tears.

Secondary Objectives:

  1. To perform an imputed transcriptome-wide association study (TWAS) to identify and prioritize gene targets associated with rotator cuff tear by integrating GWAS summary statistics and gene-expression weights from muscle and adipose tissue available in the GTEx project.

    Hypothesis: Genetically predicted gene expression of multiple genes in muscle and adipose tissue are associated with rotator cuff tear.

  2. To identify if single nucleotide polymorphisms (SNPs) associated with rotator cuff tear and their genetic risk score (GRS) predict improved pain and function as measured by American Shoulder and Elbow Surgeons Standardized Form (ASES) and other outcome measures.

    Hypothesis: Select SNPs and GRS predict ASES outcome.

  3. To identify genetic variants associated with Fatty Infiltration (FI) in patients with cuff tears in a two stage GWAS of imaged rotator cuffs and to prioritize gene targets through an imputed-TWAS in muscle and adipose tissue.

Hypothesis: Multiple genetic variants are associated with FI and some exert their influence by altering gene expression in the muscle and adipose tissue.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  • Aged ≥40 years to < 85 years

  • Confirmed diagnosis of partial or full-thickness cuff tear on MRI (Cases) OR absenceof rotator cuff tear on shoulder MRI (Controls)

  • Ability and willingness to provide informed consent

  • Ability to complete questionnaires in English (to maintain scientific integritysince standardized questionnaires are extensively validated in English)

Exclusion

Exclusion Criteria:

  • Acute rotator cuff tear caused by a severe trauma

Study Design

Total Participants: 3500
Treatment Group(s): 1
Primary Treatment: NA (not an interventional study)
Phase:
Study Start date:
March 04, 2021
Estimated Completion Date:
December 31, 2031

Study Description

Participants will complete a structured questionnaire (Appendix B) that includes medical and musculoskeletal comorbidities, Mental Health Inventory-5148, Fear Avoidance Beliefs Questionnaire (FABQ)149, and expectations of improvement from treatment. The primary patient-reported outcome (Aim 2) of our study is American Shoulder and Elbow Surgeons Standardized Form (ASES), which is a composite pain and function measure. ASES was chosen because it is widely used; is shoulder-specific and takes 2 minutes to complete; has an established minimally clinically important difference (MCID) of >9 points151; and has good psychometric properties152-155. We will use the Shoulder Pain and Disability Index (SPADI)as a secondary outcome. SPADI has good psychometric properties and an established MCID of >10 points.

We will perform a genome-wide association meta-analysis (GWAMA) in approximately 10,000 imaging-verified rotator cuff tear cases and imaging-verified controls. Discovery meta-analysis will consist of samples from cuffGEN cohort with MRI imaging (N=1,250 cases and 1,250 controls) and samples from BioVU based on MRI report-confirmed cases and controls (N ~ 2400 with equal cases and controls). Targeted variants showing some evidence of association (P < 5 x 10-6) will be replicated in an independent cohort of imaging confirmed cuff tear cases (N > 2,500) and controls (N > 2,500) from the GERA study. In addition to providing careful selection of cases via imaging confirmation, equal attention to the confirmation of lack of tears via imaging greatly reduces misclassification of cases and controls and allows for detection of effect estimates that are likely larger (away from the null). Adhering to the same stringent criteria for discovery and replication greatly improves our ability over previous studies to identify variants associated with cuff tears.

Connect with a study center

  • University of Iowa

    Iowa City, Iowa 52242
    United States

    Site Not Available

  • University of Iowa

    Iowa City 4862034, Iowa 4862182 52242
    United States

    Active - Recruiting

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts 02215
    United States

    Site Not Available

  • Boston Medical Center

    Boston, Massachusetts 02118
    United States

    Site Not Available

  • Brigham and Women's Hospital

    Boston, Massachusetts 02115
    United States

    Site Not Available

  • Beth Israel Deaconess Medical Center

    Boston 4930956, Massachusetts 6254926 02215
    United States

    Completed

  • Boston Medical Center

    Boston 4930956, Massachusetts 6254926 02118
    United States

    Completed

  • Brigham and Women's Hospital

    Boston 4930956, Massachusetts 6254926 02115
    United States

    Completed

  • University of Michigan

    Ann Arbor, Michigan 48108
    United States

    Site Not Available

  • University of Michigan

    Ann Arbor 4984247, Michigan 5001836 48108
    United States

    Active - Recruiting

  • Ohio State University

    Columbus, Ohio 43202
    United States

    Site Not Available

  • Ohio State University

    Columbus 4509177, Ohio 5165418 43202
    United States

    Site Not Available

  • Orthopedic Institute

    Sioux Falls, South Dakota 57117
    United States

    Site Not Available

  • Orthopedic Institute

    Sioux Falls 5231851, South Dakota 5769223 57117
    United States

    Completed

  • Vanderbilt University Medical Center

    Nashville, Tennessee 37232
    United States

    Site Not Available

  • Vanderbilt University Medical Center

    Nashville 4644585, Tennessee 4662168 37232
    United States

    Completed

  • Parkland Health and Hospital System

    Dallas, Texas 75390
    United States

    Active - Recruiting

  • University of Texas Southwestern Medical Center

    Dallas, Texas 75390
    United States

    Site Not Available

  • Parkland Health and Hospital System

    Dallas 4684888, Texas 4736286 75390
    United States

    Completed

  • University of Texas Southwestern Medical Center

    Dallas 4684888, Texas 4736286 75390
    United States

    Active - Recruiting

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