scholarly journals Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

2020 ◽  
Author(s):  
Julia Goodrich ◽  
Moriel Singer-Berk ◽  
Rachel Son ◽  
Abigail Sveden ◽  
Jordan Wood ◽  
...  
Keyword(s):  
Rare Variants ◽  
Standard Of Care ◽  
Monogenic Diabetes ◽  
Polygenic Scores ◽  
Monogenic Diseases ◽  
Metabolic Conditions ◽  
The Uk ◽  
Control Study ◽  
Polygenic Variation

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.

scholarly journals Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Julia K. Goodrich ◽  
Moriel Singer-Berk ◽  
Rachel Son ◽  
Abigail Sveden ◽  
Jordan Wood ◽  
...  
Keyword(s):  
Case Control Study ◽  
Rare Variants ◽  
Standard Of Care ◽  
Polygenic Scores ◽  
Monogenic Diseases ◽  
Metabolic Conditions ◽  
The Uk ◽  
Control Study ◽  
Polygenic Variation

AbstractHundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

scholarly journals Diabetes and Insulin Therapy, but Not Metformin, Are Related to Hepatocellular Cancer Risk

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Luca Miele ◽  
Cristina Bosetti ◽  
Federica Turati ◽  
Gianlodovico Rapaccini ◽  
Antonio Gasbarrini ◽  
...  
Keyword(s):  
Hepatocellular Cancer ◽  
Excess Risk ◽  
Diabetes Diagnosis ◽  
Logistic Regression Models ◽  
Metabolic Conditions ◽  
Never Smokers ◽  
Fold Excess ◽  
Control Study

Introduction. Metabolic conditions, including type 2 diabetes, have been related to hepatocellular carcinoma (HCC) risk. We have further analyzed the role of diabetes and antidiabetic treatments on HCC.Methods. Data derived from a hospital-based case-control study (Italy, 2005–2012) on 224 HCC patients and 389 controls. Odds ratios (ORs) were estimated using multiple logistic regression models.Results. Sixty-nine (30.9%) cases versus 52 (13.5%) controls reported a diabetes diagnosis, corresponding to a multivariate OR of 2.25 (95% confidence interval, CI = 1.42–3.56). A stronger excess risk emerged for a longer time since diabetes diagnosis (OR = 2.96 for <10 years and 5.33 for ≥10 years). Oral therapies were inversely, though not significantly, related to HCC risk, OR being 0.44 for metformin and 0.88 for sulfonylureas; conversely, insulin was nonsignificantly directly associated (OR = 1.90). Compared to nondiabetic subjects who were never smokers, those who were diabetics and ever smokers had an OR of 6.61 (95% CI 3.31–13.25).Conclusion. Our study confirms an over 2-fold excess HCC risk in diabetics, with a stronger excess risk in diabetic subjects who are also tobacco smokers. Metformin may decrease the risk of HCC, whereas insulin may increase the risk.

scholarly journals Oxytocin pathway polygenic risk scores for severe mental disorder and metabolic phenotypes in the UK Biobank

2021 ◽  
Author(s):  
Adriano Winterton ◽  
Francesco Bettella ◽  
Ann-Marie G de Lange ◽  
Marit Haram ◽  
Nils Eiel Steen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bipolar Disorder ◽  
Social Cognition ◽  
Mental Illnesses ◽  
Risk Scores ◽  
Uk Biobank ◽  
Polygenic Scores ◽  
The Uk ◽  
And Behavior

Oxytocin is a neuromodulator and hormone that is typically associated with social cognition and behavior. In light of its purported effects on social cognition and behavior, research has investigated its potential as a treatment for psychiatric illnesses characterised by social dysfunction, such as schizophrenia and bipolar disorder. While the results of these trials have been mixed, more recent evidence suggests that the oxytocin system is also linked with cardiometabolic conditions for which individuals with severe mental disorders are at a higher risk for developing. To investigate whether the oxytocin system plays a pleiotropic role in the aetiology of severe mental illness and cardiometabolic conditions, we explored oxytocin’s role in the shared genetic liability of schizophrenia, bipolar disorder, type 2 diabetes and several phenotypes linked with cardiovascular disease and type 2 diabetes risk using a polygenic pathway-specific approach. Analysis of a large sample with 488,377 individuals (UK Biobank) revealed statistically significant associations across the range of phenotypes analysed. By comparing these effects to those of polygenic scores calculated from 100 random gene-sets, we also demonstrated the specificity of many of these significant results. Altogether, our results suggest that the shared effect of oxytocin system dysfunction could help explain the co-occurrence of social and cardiometabolic dysfunction in severe mental illnesses.

Effect of waist-to-hip ratio on the association between type 2 diabetes and depression: an exploratory study using the polygenic scores approach in the UK Biobank

The Lancet ◽  
2017 ◽  
Vol 389 ◽  
pp. S53
Author(s):  
Carol Kan ◽  
Jonathan Coleman ◽  
Anubha Mahajan ◽  
Mark McCarthy ◽  
Gerome Breen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Exploratory Study ◽  
Uk Biobank ◽  
Waist To Hip Ratio ◽  
Polygenic Scores ◽  
The Uk

scholarly journals Clinical conditions and their impact on utility of genetic scores for prediction of acute coronary syndrome

2020 ◽  
Author(s):  
Jiwoo Lee ◽  
Tuomo Kiiskinen ◽  
Nina Mars ◽  
Sakari Jukarainen ◽  
Erik Ingelsson ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
P Value ◽  
Coronary Syndrome ◽  
Polygenic Scores ◽  
Hernia Inguinal ◽  
Asymptomatic Individuals ◽  
The Uk ◽  
Clinical Conditions ◽  
Incident Cases

Early prediction of acute coronary syndrome (ACS) is a major goal for prevention of coronary heart disease (CHD). Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual's genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS. We explored the association between 405 clinical conditions diagnosed before baseline and 9,080 incident cases of ACS in 387,832 individuals from the UK Biobank. We identified 80 conventional (e.g., stable angina pectoris (SAP), type 2 diabetes mellitus) and unconventional (e.g., diaphragmatic hernia, inguinal hernia) associations with ACS. Results were replicated in 6,430 incident cases of ACS in 177,876 individuals from FinnGen. The association between PS and ACS was consistent in individuals with and without most clinical conditions. However, a diagnosis of SAP yielded a differential association between PS and ACS. PS was associated with a significantly reduced (interaction p-value=2.87×10-8) risk for ACS in individuals with SAP (HR=1.163 [95% CI: 1.082-1.251]) compared to individuals without SAP (HR=1.531 [95% CI: 1.497-1.565]). These findings were replicated in FinnGen (interaction p-value=1.38×10-6). In summary, while most clinical conditions did not impact utility of PS for prediction of ACS, we found that PS was substantially less predictive of ACS in individuals with prevalent stable CHD. PS for ACS may be more appropriate for asymptomatic individuals than symptomatic individuals with clinical suspicion for CHD.

Abstract #841: Association of Depression with Type 2 Diabetes in Bangladeshi Adults- A Case Control Study

2016 ◽  
Vol 22 ◽  
pp. 183
Author(s):  
Shahjada Selim ◽  
Shahjada Selim ◽  
Shahabul Chowdhury ◽  
Mohammad Saifuddin ◽  
Marufa Mustary ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Case Control Study ◽  
Case Control ◽  
Control Study
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