scholarly journals A Mendelian randomization study identified obesity as a causal risk factor of uterine endometrial cancer in Japanese

2020 ◽  
Vol 111 (12) ◽  
pp. 4646-4651
Author(s):  
Tatsuo Masuda ◽  
Kotaro Ogawa ◽  
Yoichiro Kamatani ◽  
Yoshinori Murakami ◽  
Tadashi Kimura ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Risk Factor ◽  
Mendelian Randomization ◽  
Causal Risk Factor ◽  
Uterine Endometrial Cancer

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 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 SUN-016 Mendelian Randomization Reveals That Polycystic Ovary Syndrome Is Not a Causal Risk Factor for Type 2 Diabetes, Coronary Heart Disease, or Stroke

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Tiantian Zhu ◽  
Mark O Goodarzi
Keyword(s):  
Type 2 Diabetes ◽  
Risk Factor ◽  
Polycystic Ovary Syndrome ◽  
Observational Studies ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Ovary Syndrome ◽  
Causal Risk Factor

Abstract Polycystic ovary syndrome (PCOS) is now recognized not only as a cosmetic and reproductive disorder, but also as a metabolic disorder with important consequences. The balance of the literature suggests that PCOS increases the risk of future type 2 diabetes (T2D); however, whether PCOS increases the risk of coronary heart disease (CHD) and/or stroke is more controversial. Despite a high burden of cardiovascular risk factors (which suggests a high risk of events), the mostly small and retrospective cohort studies have yielded conflicting results. Meta-analyses of these studies suggested at best a 1.4 to 2-fold increased risk of CHD and stroke, which attenuated to 1.2-1.6 when accounting for body mass index (BMI) (1,2). Given that observational studies may be biased by confounders between the risk factor and outcome (in this case, elevated BMI often present in PCOS), we performed Mendelian randomization (MR) analyses to examine the possible causal effect of polycystic ovary syndrome (PCOS) with T2D, CHD and stroke. MR uses genetic variants as instruments to represent exposures of interest to assess causality between exposures and outcomes (3). It is increasingly being used because it overcomes confounding and reverse causation, which often plague observational studies. The instrument variables for PCOS were constructed based on 14 SNPs derived from a published GWAS meta-analysis for PCOS conducted in European cohorts (10,074 cases and 103,164 controls) (4). The SNP to outcomes estimates were obtained from the DIAMANTE T2D GWAS (74,124 T2D cases and 824,006 controls) (5), the CHD GWAS meta-analysis of the UK Biobank plus CARDIoGRAMplusC4D (122,733 cases and 424,528 controls) (6) and the MEGASTROKE consortium GWAS (67,162 cases and 454,450 controls) (7). MR analyses were conducted using three methods: inverse variance weighted (IVW) (primary method), weighted median and MR Egger (sensitivity analyses). In our study, no significant association of genetically predicted PCOS with T2D (OR 0.97, CI 0.91-1.02), CHD (OR 0.99, CI 0.95-1.03) or stroke (OR 0.98, CI 0.93-1.02) was observed. Our findings suggest that PCOS is not a causal risk factor for T2D, CHD or stroke. The observed associations of PCOS with these three diseases from observational studies are likely due to confounding factors and small sample sizes. Given that MR has found that increasing BMI is causal for PCOS as well as T2D and CHD, overweight/obesity is the likely confounding variable. These results suggest a critical revision of how we counsel and manage women with PCOS. Reference: 1. Zhou Y, et al. Gynecol Endocrinol 2017; 33:904-910 2. De Groot PC, et al. Hum Reprod Update 2011; 17:495-500 3. Davey Smith G, et al. Hum Mol Genet. 2014; 23:R89-R98. 4. Day F, et al. PLoS Genet. 2018;14(12). 5. Mahajan A, et al. Nat Genet. 2018;50(11):1505-1513. 6. van der Harst P, et al. Circ Res. 2018;122(3):433-443. 7. Malik R, et al. Nat Genet. 2018;50(4):524-537.

scholarly journals Morning plasma cortisol as a cardiovascular risk factor: findings from prospective cohort and Mendelian randomization studies

2019 ◽  
Vol 181 (4) ◽  
pp. 429-438 ◽  
Author(s):  
Andrew A Crawford ◽  
Stefan Soderberg ◽  
Clemens Kirschbaum ◽  
Lee Murphy ◽  
Mats Eliasson ◽  
...  
Keyword(s):  
Risk Factor ◽  
Plasma Cortisol ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Positive Association ◽  
Case Control ◽  
Case Control Studies ◽  
Cvd Risk ◽  
Causal Risk Factor ◽  
Nested Case Control

Objective The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD). Design and methods Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses). Results In the two prospective nested case–control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06–1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06–1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98–1.15. Conclusions All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.

scholarly journals Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19

2021 ◽  
Author(s):  
Ana I. Hernández Cordero ◽  
Xuan Li ◽  
Stephen Milne ◽  
Chen Xi Yang ◽  
Yohan Bossé ◽  
...  
Keyword(s):  
Risk Factor ◽  
Plasma Protein ◽  
Causal Risk Factor

Causal associations of short and long sleep durations with 12 cardiovascular diseases: linear and nonlinear Mendelian randomization analyses in UK Biobank

2021 ◽  
Author(s):  
Sizhi Ai ◽  
Jihui Zhang ◽  
Guoan Zhao ◽  
Ningjian Wang ◽  
Guohua Li ◽  
...  
Keyword(s):  
Heart Disease ◽  
Arterial Hypertension ◽  
Ischaemic Heart Disease ◽  
Sleep Duration ◽  
Mendelian Randomization ◽  
Short Sleep Duration ◽  
Short Sleep ◽  
Causal Risk Factor ◽  
Long Sleep ◽  
Artery Disease

Abstract Aims Observational studies have suggested strong associations between sleep duration and many cardiovascular diseases (CVDs), but causal inferences have not been confirmed. We aimed to determine the causal associations between genetically predicted sleep duration and 12 CVDs using both linear and nonlinear Mendelian randomization (MR) designs. Methods and results Genetic variants associated with continuous, short (≤6 h) and long (≥9 h) sleep durations were used to examine the causal associations with 12 CVDs among 404 044 UK Biobank participants of White British ancestry. Linear MR analyses showed that genetically predicted sleep duration was negatively associated with arterial hypertension, atrial fibrillation, pulmonary embolism, and chronic ischaemic heart disease after correcting for multiple tests (P &lt; 0.001). Nonlinear MR analyses demonstrated nonlinearity (L-shaped associations) between genetically predicted sleep duration and four CVDs, including arterial hypertension, chronic ischaemic heart disease, coronary artery disease, and myocardial infarction. Complementary analyses provided confirmative evidence of the adverse effects of genetically predicted short sleep duration on the risks of 5 out of the 12 CVDs, including arterial hypertension, pulmonary embolism, coronary artery disease, myocardial infarction, and chronic ischaemic heart disease (P &lt; 0.001), and suggestive evidence for atrial fibrillation (P &lt; 0.05). However, genetically predicted long sleep duration was not associated with any CVD. Conclusion This study suggests that genetically predicted short sleep duration is a potential causal risk factor of several CVDs, while genetically predicted long sleep duration is unlikely to be a causal risk factor for most CVDs.

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