A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor
Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic va...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-06-01
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| Series: | PLoS Genetics |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191964/?tool=EBI |
| _version_ | 1798035115855577088 |
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| author | Harry D. Green Alistair Jones Jonathan P. Evans Andrew R. Wood Robin N. Beaumont Jessica Tyrrell Timothy M. Frayling Christopher Smith Michael N. Weedon |
| author_facet | Harry D. Green Alistair Jones Jonathan P. Evans Andrew R. Wood Robin N. Beaumont Jessica Tyrrell Timothy M. Frayling Christopher Smith Michael N. Weedon |
| author_sort | Harry D. Green |
| collection | DOAJ |
| description | Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16–1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren’s disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02–1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren’s disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition. Author summary Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes but it is known to be more common in people with diabetes. In a dataset of 500,000 people, we used a genome-wide association study to find genetic causes and a genetic technique called Mendelian randomisation to test if diabetes causes frozen shoulder. We found five new genetic variants that associate with frozen shoulder, and showed genetic overlap with Dupuytren’s Disease, a similar condition that affects the fingers. We found an association with diabetes and obesity, but that the obesity association disappeared when we accounted for diabetes status, suggesting the condition is glycaemic rather than mechanical. Our Mendelian randomisation study showed evidence that type 1 diabetes has a causal effect on development of frozen shoulder, likely through a pathway involving long-term high blood glucose levels. |
| first_indexed | 2024-04-11T20:53:46Z |
| format | Article |
| id | doaj.art-743bd257e1b14cf6b5f8eab1ed15787d |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-11T20:53:46Z |
| publishDate | 2021-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-743bd257e1b14cf6b5f8eab1ed15787d2022-12-22T04:03:46ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042021-06-01176A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factorHarry D. GreenAlistair JonesJonathan P. EvansAndrew R. WoodRobin N. BeaumontJessica TyrrellTimothy M. FraylingChristopher SmithMichael N. WeedonFrozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16–1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren’s disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02–1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren’s disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition. Author summary Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes but it is known to be more common in people with diabetes. In a dataset of 500,000 people, we used a genome-wide association study to find genetic causes and a genetic technique called Mendelian randomisation to test if diabetes causes frozen shoulder. We found five new genetic variants that associate with frozen shoulder, and showed genetic overlap with Dupuytren’s Disease, a similar condition that affects the fingers. We found an association with diabetes and obesity, but that the obesity association disappeared when we accounted for diabetes status, suggesting the condition is glycaemic rather than mechanical. Our Mendelian randomisation study showed evidence that type 1 diabetes has a causal effect on development of frozen shoulder, likely through a pathway involving long-term high blood glucose levels.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191964/?tool=EBI |
| spellingShingle | Harry D. Green Alistair Jones Jonathan P. Evans Andrew R. Wood Robin N. Beaumont Jessica Tyrrell Timothy M. Frayling Christopher Smith Michael N. Weedon A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor PLoS Genetics |
| title | A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor |
| title_full | A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor |
| title_fullStr | A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor |
| title_full_unstemmed | A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor |
| title_short | A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor |
| title_sort | genome wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191964/?tool=EBI |
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