scholarly journals A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009577
Author(s):  
Harry D. Green ◽  
Alistair Jones ◽  
Jonathan P. Evans ◽  
Andrew R. Wood ◽  
Robin N. Beaumont ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Frozen Shoulder ◽  
Genome Wide Association ◽  
Biological Mechanisms ◽  
Painful Condition ◽  
Causal Risk Factor ◽  
Genome Wide ◽  
A Genome

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.

scholarly journals A genome wide association study of frozen shoulder identifies a common variant of WNT7B and diabetes as causal risk factors

2020 ◽  
Author(s):  
Harry D Green ◽  
Alistair Jones ◽  
Jonathan P Evans ◽  
Andrew R Wood ◽  
Robin N Beaumont ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Frozen Shoulder ◽  
Biological Mechanisms ◽  
Causal Gene ◽  
Painful Condition ◽  
Causal Risk Factor ◽  
Genome Wide ◽  
A Genome

AbstractFrozen 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 2064 cases identified from ICD-10 codes. We used data from FinnGen for replication. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder.We identified a single genome-wide significant locus (lead SNP rs62228062; OR=1.34 [1.28-1.41], p=2×10−16) that contained WNT7B. A recent transcriptome study identified WNT7B as amongst the most enriched transcripts in anterior capsule tissue in patients undergoing arthroscopic capsulotomy surgery for frozen shoulder suggesting WNT7B as a potential causal gene at the locus. The lead SNP was also strongly associated with Dupuytren’s contracture (OR=2.61 [2.50, 2.72], p<1×10−100). The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR=1.04 [1.02-1.07], p=6×10−5). 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 the first genetic variant associated with frozen shoulder. WNT7B is a potential causal gene at the locus. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.

scholarly journals A genome wide association study identifies a lncRna as risk factor for pathological inflammatory responses in leprosy

PLoS Genetics ◽  
2017 ◽  
Vol 13 (2) ◽  
pp. e1006637 ◽  
Author(s):  
Vinicius M. Fava ◽  
Jeremy Manry ◽  
Aurélie Cobat ◽  
Marianna Orlova ◽  
Nguyen Van Thuc ◽  
...  
Keyword(s):  
Risk Factor ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Inflammatory Responses ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals Genetics of symptom remission in outpatients with COVID-19

2021 ◽  
Author(s):  
Marie-Pierre Dubé ◽  
Audrey Lemaçon ◽  
Amina Barhdadi ◽  
Louis-Philippe Lemieux Perreault ◽  
Essaïd Oussaïd ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Risk Factor ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Mechanistic Pathway ◽  
Genome Wide ◽  
A Genome ◽  
Symptom Remission

ABSTRACTWe conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10−8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10−8) in interaction with colchicine (P = 1.19 × 10−5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.

scholarly journals Genetics of symptom remission in outpatients with COVID-19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie-Pierre Dubé ◽  
Audrey Lemaçon ◽  
Amina Barhdadi ◽  
Louis-Philippe Lemieux Perreault ◽  
Essaïd Oussaïd ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Risk Factor ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Mechanistic Pathway ◽  
Genome Wide ◽  
A Genome ◽  
Symptom Remission

AbstractWe conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10–8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10–8) in interaction with colchicine (P = 1.19 × 10–5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.

scholarly journals Association of Serum Magnesium Levels With Risk of Intracranial Aneurysm: A Mendelian Randomization Study

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012244
Author(s):  
Susanna C. Larsson ◽  
Dipender Gill
Keyword(s):  
Confidence Interval ◽  
Intracranial Aneurysm ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Serum Magnesium ◽  
Genome Wide Association ◽  
Magnesium Concentration ◽  
Genome Wide ◽  
A Genome

ObjectiveMagnesium has been implicated in regulating blood pressure and vascular endothelial cell function, but its role in the pathophysiology of intracranial aneurysm is not known. Here we performed a Mendelian randomization analysis to investigate the association between serum magnesium concentration and risk of intracranial aneurysm.MethodsFive single-nucleotide polymorphisms strongly associated with serum magnesium concentrations in a genome-wide association study in 23 829 individuals of European ancestry were used as genetic instruments. Genetic association estimates for intracranial aneurysm were obtained from a genome-wide association study in 79 429 individuals (7495 cases and 71 934 controls). The inverse-variance weighted method was used in the primary analyses to obtain the causal estimates.ResultsHigher genetically predicted serum magnesium concentrations were associated with lower risk of intracranial aneurysm. The odds ratios per 0.1 mmol/L increment in genetically predicted serum magnesium concentrations were 0.66 (95% confidence interval: 0.49-0.91) for intracranial aneurysm (unruptured and ruptured combined), 0.57 (95% confidence interval: 0.30-1.06) for unruptured intracranial aneurysm, and 0.67 (95% confidence interval: 0.48-0.92) for aneurysmal subarachnoid hemorrhage.ConclusionThis study provides evidence to support that increased serum magnesium concentrations reduce the risk of intracranial aneurysm and associated hemorrhage.

Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization

Rheumatology ◽  
2019 ◽  
Vol 59 (5) ◽  
pp. 940-947 ◽  
Author(s):  
Zhen Zeng ◽  
Wanting Zhang ◽  
Yu Qian ◽  
Huijun Huang ◽  
David J H Wu ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Causal Association ◽  
Genome Wide ◽  
Inverse Variance ◽  
A Genome ◽  
Mean Differences

Abstract Objective To evaluate the telomere length (TL) in patients with RA relative to that in controls and to test whether TL is causally associated with risk of RA. Methods Systematic review and meta-analysis of relevant literature was conducted to evaluate the association between TL and RA. Standardized mean differences with 95% CIs of TL in RA patients relative to controls were pooled using fixed or random-effects models. TL-related single-nucleotide polymorphisms were selected from a genome-wide association study of 37 684 individuals, and summary statistics of RA were obtained from a genome-wide association study meta-analysis including 14 361 RA patients and 43 923 controls. Mendelian randomization was performed using the inverse-variance weighted, weighted-median and likelihood-based methods. Sensitivity analyses were performed to test the robustness of the association. Results In the meta-analysis of 911 RA patients and 2498 controls, we found that patients with RA had a significantly shorter TL compared with controls (standardized mean differences = −0.50; 95% CI −0.88, −0.11; P = 0.012). In the Mendelian randomization analysis, we found that genetically predicted longer TL was associated with a reduced risk of RA [odds ratio = 0.68; 95% CI 0.54, 0.86; P = 0.002 using the inverse-variance weighted method]. Sensitivity analyses using alternative Mendelian randomization approaches yielded similar findings, suggesting the robustness of the causal association. Conclusion Our study provides evidence for a negative causal association of TL with risk of RA. Further studies are warranted to elucidate the underlying mechanism for the role of telomeres in the development of RA.

scholarly journals A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis

2020 ◽  
Vol 139 (8) ◽  
pp. 1077-1090 ◽  
Author(s):  
Cristina M. Justice ◽  
◽  
Araceli Cuellar ◽  
Krithi Bala ◽  
Jeremy A. Sabourin ◽  
...  
Keyword(s):  
Risk Factor ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Metopic Craniosynostosis

scholarly journals Association Between Environmental Factors and Asthma Using Mendelian Randomization: Increased Effect of Body Mass Index on Adult-Onset Moderate-to-Severe Asthma Subtypes

2021 ◽  
Vol 12 ◽  
Author(s):  
Tae-Woong Ha ◽  
Hae-Un Jung ◽  
Dong Jun Kim ◽  
Eun Ju Baek ◽  
Won Jun Lee ◽  
...  
Keyword(s):  
Risk Factor ◽  
Environmental Factors ◽  
Severe Asthma ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effects ◽  
Genome Wide Association ◽  
Adult Onset ◽  
Uk Biobank ◽  
Genome Wide

Although asthma is one of the most common chronic diseases throughout all age groups, its etiology remains unknown, primarily due to its heterogeneous characteristics. We examined the causal effects of various environmental factors on asthma using Mendelian randomization and determined whether the susceptibility to asthma due to the causal effect of a risk factor differs between asthma subtypes, based on age of onset, severity of asthma, and sex. We performed Mendelian randomization analyses (inverse variance weighted, weighted median, and generalized summary-data-based Mendelian randomization) using UK Biobank data to estimate the causal effects of 69 environmental factors on asthma. Additional sensitivity analyses (MR-Egger regression, Cochran’s Q test, clumping, and reverse Mendelian randomization) were performed to ensure minimal or no pleiotropy. For confirmation, two-sample setting analyses were replicated using BMI SNPs that had been reported by a meta-genome-wide association study in Japanese and European (GIANT) populations and a genome-wide association study in control individuals from the UK Biobank. We found that BMI causally affects the development of asthma and that the adult-onset moderate-to-severe asthma subtype is the most susceptible to causal inference by BMI. Further, it is likely that the female subtype is more susceptible to BMI than males among adult asthma cases. Our findings provide evidence that obesity is a considerable risk factor in asthma patients, particularly in adult-onset moderate-to-severe asthma cases, and that weight loss is beneficial for reducing the burden of asthma.

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