Three genes associated with anterior and posterior cruciate ligament injury : a genome-wide association analysis.

AIMS: The aim of this study was to screen the entire genome for genetic markers associated with risk for anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) injury. METHODS: Genome-wide association (GWA) analyses were performed using data from the Kaiser Permanente Research Board (KPRB) and the UK Biobank. ACL and PCL injury cases were identified based on electronic health records from KPRB and the UK Biobank. GWA analyses from both cohorts were tested for ACL and PCL injury using a logistic regression model adjusting for sex, height, weight, age at enrolment, and race/ethnicity using allele counts for single nucleotide polymorphisms (SNPs). The data from the two GWA studies were combined in a meta-analysis. Candidate genes previously reported to show an association with ACL injury in athletes were also tested for association from the meta-analysis data from the KPRB and the UK Biobank GWA studies. RESULTS: There was a total of 2,214 cases of ACL and PCL injury and 519,869 controls within the two cohorts, with three loci demonstrating a genome-wide significant association in the meta-analysis: INHBA, AEBP2, and LOC101927869. Of the eight candidate genes previously studied in the literature, six were present in the current dataset, and only COL3A1 (rs1800255) showed a significant association (p = 0.006). CONCLUSION: Genetic markers in three novel loci in this study and one previously-studied candidate gene were identified as potential risk factors for ACL and PCL injury and deserve further validation and investigation of molecular mechanisms. Cite this article: Bone Jt Open 2021;2(6):414-421.

Association of COA1 with Patellar Tendonitis: A Genome-wide Association Analysis.

PURPOSE: It is unknown why some athletes develop patellar tendinopathy and others do not, even when accounting for similar workloads between individuals. Genetic differences between these two populations may be a contributing factor. The purpose of this work was to screen the entire genome for genetic markers associated with patellar tendinopathy. METHODS: Genome-wide association (GWA) analyses were performed utilizing data from the Kaiser Permanente Research Board (KPRB) and the UK Biobank. Patellar tendinopathy cases were identified based on electronic health records from KPRB and UK Biobank. GWA analyses from both cohorts were tested for patellar tendinopathy using a logistic regression model adjusting for sex, height, weight, age, and race/ethnicity using allele counts for single nucleotide polymorphisms. The data from the two GWA studies (KPRB and UK Biobank) were combined in a meta-analysis. RESULTS: There were a total of 1670 cases of patellar tendinopathy and 293,866 controls within the two cohorts. Two single nucleotide polymorphisms located in the intron of the cytochrome c oxidase assembly factor 1 (COA1) gene showed a genome-wide significant association in the meta-analysis. CONCLUSIONS: Genetic markers in COA1 seem to be associated with patellar tendinopathy and are potential risk factors for patellar tendinopathy that deserve further validation regarding molecular mechanisms.

Identification of Three Loci Associated with Achilles Tendon Injury Risk from a Genome-wide Association Study.

PURPOSE: This study aimed to screen the entire genome for genetic markers associated with risk for Achilles tendon injury. METHODS: A genome-wide association analysis was performed using data from the Kaiser Permanente Research Board and the UK Biobank. Achilles tendon injury cases were identified based on electronic health records from the Kaiser Permanente Research Board databank and the UK Biobank from individuals of European ancestry. Genome-wide association analyses from both cohorts were tested for Achilles tendon injury using a logistic regression model adjusting for sex, height, weight, and race/ethnicity using allele counts for single nucleotide polymorphisms (SNP). Previously identified genes within the literature were also tested for association with Achilles tendon injury. RESULTS: There were a total of 12,354 cases of Achilles tendon injury and 483,080 controls within the two combined cohorts, with 67 SNP in three chromosomal loci demonstrating a genome-wide significant association with Achilles tendon injury. The first locus contains a single SNP (rs183364169) near the CDCP1 and TMEM158 genes on chromosome 3. The second locus contains 65 SNP in three independently segregating sets near the MPP7 gene on chromosome 10. The last locus contains a single SNP (rs4454832) near the SOX21 and GPR180 genes on chromosome 13. The current data were used to test 14 candidate genes previously reported to show an association with Achilles tendon injury, but none showed a significant association (all P > 0.05). CONCLUSION: Three loci were identified as potential risk factors for Achilles tendon injury and deserve further validation and investigation of molecular mechanisms.

A genome-wide association study for shoulder impingement and rotator cuff disease.

BACKGROUND: The purpose of the study was to identify genetic variants associated with rotator cuff disease by performing a genome-wide association study (GWAS) for shoulder impingement using the UK Biobank (UKB) cohort and then combining the GWAS data with a prior GWAS for rotator cuff tears. The loci identified by the GWAS and meta-analysis were examined for changes in expression following rotator cuff tearing using RNA sequencing. METHODS: A GWAS was performed using data from UKB with 3864 cases of shoulder impingement. The summary statistics from shoulder impingement and a prior study on rotator cuff tears were combined in a meta-analysis. Also, the previous association of 2 single-nucleotide polymorphisms (SNPs) with shoulder impingement from a published GWAS using the UKB was tested. Rotator cuff tendon biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humeral fracture (controls). Total RNA was extracted and differential gene expression was measured by RNA sequencing for genes with variants associated with rotator cuff tearing. RESULTS: The shoulder impingement GWAS identified 4 new loci: LOC100506457, LSP1P3, LOC100506207, and MIS18BP1/LINC00871. Combining data with a prior GWAS for rotator cuff tears in a meta-analysis resulted in the identification of an additional 7 loci: SLC39A8/UBE2D3, C5orf63, ASTN2, STK24, FRMPD4, ACOT9/SAT1, and LINC00890/ALG13. Many of the identified loci have known biologic functions or prior associations with diseases, suggesting possible biologic pathways leading to rotator cuff disease. RNA sequencing experiments show that expression of STK24 increases whereas expression of SAT1 and UBE2D3 decreases following rotator cuff tearing. Two SNPs previously reported to show an association with shoulder impingement from a prior UKB GWAS were not validated in our study. CONCLUSION: This is the first GWAS for shoulder impingement in which new data from UKB enabled the identification of 4 loci showing a genetic association. A meta-analysis with a prior GWAS for rotator cuff tearing identified an additional 7 loci. The known biologic roles of many of the 11 loci suggest plausible biologic mechanisms underlying the etiology of rotator cuff disease. The risk alleles from each of the genetic loci can be used to assess the risk for rotator cuff disease in individual patients, enabling preventative or restorative actions via personalized medicine.