Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations.

Background: Little is known about sex-based differences in anterior cruciate ligament (ACL) tissue quality in vivo or the association of ACL size (ie, volume) and tissue quality (ie, normalized signal intensity on magnetic resonance imaging [MRI]) with knee anatomy. Hypothesis: We hypothesized that (1) women have smaller ACLs and greater ACL normalized signal intensity compared with men, and (2) ACL size and normalized signal intensity are associated with age, activity levels, body mass index (BMI), bicondylar width, intercondylar notch width, and posterior slope of the lateral tibial plateau. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Knee MRI scans of 108 unique ACL-intact knees (19.7 ± 5.5 years, 62 women) were used to quantify the ACL signal intensity (normalized to cortical bone), ligament volume, mean cross-sectional area, and length. Independent t tests were used to compare the MRI-based ACL parameters between sexes. Univariate and multivariate linear regression analyses were used to investigate the associations between normalized signal intensity and size with age, activity levels, BMI, bicondylar width, notch width, and posterior slope of the lateral tibial plateau. Results: Compared with men, women had significantly smaller mean ACL volume (men vs women: 2028 ± 472 vs 1591 ± 405 mm3), cross-sectional area (49.4 ± 9.6 vs 41.5 ± 8.6 mm2), and length (40.8 ± 2.8 vs 38.1 ± 3.1 mm) ( P < .001 for all), even after adjusting for BMI and bicondylar width. There was no difference in MRI signal intensity between men and women (1.15 ± 0.24 vs 1.12 ± 0.24, respectively; P = .555). BMI, bicondylar width, and intercondylar notch width were independently associated with a larger ACL ( R 2 > 0.16, P < .001). Younger age and steeper lateral tibial slope were independently associated with shorter ACL length ( R 2 > 0.03, P < .04). The combination of BMI and bicondylar width was predictive of ACL volume and mean cross-sectional area ( R 2 < 0.3). The combination of BMI, bicondylar width, and lateral tibial slope was predictive of ACL length ( R 2 = 0.39). Neither quantified patient characteristics nor anatomic variables were associated with signal intensity. Conclusion: Men had larger ACLs compared with women even after adjusting for BMI and knee size (bicondylar width). No sex difference was observed in signal intensity, suggesting no difference in tissue quality. The association of the intercondylar notch width and lateral tibial slope with ACL size suggests that the influence of these anatomic features on ACL injury risk may be partially explained by their effect on ACL size. Registration: NCT02292004 and NCT02664545 ( ClinicalTrials.gov identifier).

Smaller anterior cruciate ligament (ACL) size in females has been hypothesized to be a key contributor to a higher incidence of ACL tears in that population, as a lower cross-sectional area (CSA) directly corresponds to a larger stress on the ligament for a given load. Prior studies have used a mid-length CSA measurement to quantify ACL size. In this study, we used magnetic resonance imaging to quantify the CSA along the entire length of the intact ACL. We hypothesized that changes in the ACL CSA along its length would have different patterns in males and females. We also hypothesized that changes in ACL CSA along its length would be associated with body size or knee size with different associations in females and males. MR images of contralateral ACL-intact knees of 108 patients (62 females, 13-35 years) undergoing ACL surgery were used to measure the CSA along the ACL length, using a custom program. For both females and males, the largest CSA was located at 37%-39% of ACL length from the tibial insertion.Compared to females, males had a significantly larger CSA only within the distal 41% of the ACL (p < 0.001). ACL CSA was associated with patient height and weight in males (r > 0.3; p < 0.05), whereas it was associated with intercondylar notch width in females (r > 0.3; p < 0.05). These findings highlight the importance of standardizing the location of measurement of ACL CSA.

Background: The cross-sectional area (CSA) of the anterior cruciate ligament (ACL) and reconstructed graft has direct implications on its strength and knee function. Little is known regarding how the CSA changes along the ligament length and how those changes vary between treated and native ligaments over time. Hypothesis: It was hypothesized that (1) the CSA of reconstructed ACLs and restored ACLs via bridge-enhanced ACL restoration (BEAR) is heterogeneous along the length. (2) Differences in CSA between treated and native ACLs decrease over time. (3) CSA of the surgically treated ACLs is correlated significantly with body size (ie, height, weight, body mass index) and knee size (ie, bicondylar and notch width). Study Design: Cohort study; Level of evidence, 2. Methods: Magnetic resonance imaging scans of treated and contralateral knees of 98 patients (n = 33 ACL reconstruction, 65 BEAR) at 6, 12, and 24 months post-operation were used to measure the ligament CSA at 1% increments along the ACL length (tibial insertion, 0%; femoral insertion, 100%). Statistical parametric mapping was used to evaluate the differences in CSA between 6 and 24 months. Correlations between body and knee size and treated ligament CSA along its length were also assessed. Results: Hamstring autografts had larger CSAs than native ACLs at all time points ( P < .001), with region of difference decreasing from proximal 95% of length (6 months) to proximal 77% of length (24 months). Restored ACLs had larger CSAs than native ACLs at 6 and 12 months, with larger than native CSA only along a small midsubstance region at 24 months ( P < .001). Graft CSA was correlated significantly with weight (6 and 12 months), bicondylar width (all time points), and notch width (24 months). Restored ACL CSA was significantly correlated with bicondylar width (6 months) and notch width (6 and 12 months). Conclusion: Surgically treated ACLs remodel continuously within the first 2 years after surgery, leading to ligaments/grafts with heterogeneous CSAs along the length, similar to the native ACL. While reconstructed ACLs remained significantly larger, the restored ACL had a CSA profile comparable with that of the contralateral native ACL. In addition to size and morphology differences, there were fundamental differences in factors contributing to CSA profile between the ACL reconstruction and BEAR procedures. Registration: NCT 02664545 ( ClinicalTrials.gov identifier).