scholarly journals Quantifying the extent to which index event biases influence large genetic association studies

2016 ◽  
Author(s):  
Hanieh Yaghootkar ◽  
Michael P. Bancks ◽  
Sam E. Jones ◽  
Aaron McDaid ◽  
Robin Beaumont ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Association ◽  
Genetic Risk ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Population Based ◽  
Uk Biobank ◽  
Index Event ◽  
Risk Alleles

AbstractAs genetic association studies increase in size to 100,000s of individuals, subtle biases may influence conclusions. One possible bias is “index event bias” (IEB), also called “collider bias”, caused by the stratification by, or enrichment for, disease status when testing associations between gene variants and a disease-associated trait. We first provided a statistical framework for quantifying IEB then identified real examples of IEB in a range of study and analytical designs. We observed evidence of biased associations for some disease alleles and genetic risk scores, even in population-based studies. For example, a genetic risk score consisting of type 2 diabetes variants was associated with lower BMI in 113,203 type 2 diabetes controls from the population based UK Biobank study (−0.010 SDs BMI per allele, P=5E-4), entirely driven by IEB. Three of 11 individual type 2 diabetes risk alleles, and 10 of 25 hypertension alleles were associated with lower BMI at p<0.05 in UK Biobank when analyzing disease free individuals only, of which six hypertension alleles remained associated at p<0.05 after correction for IEB. Our analysis suggested that the associations between CCND2 and TCF7L2 diabetes risk alleles and BMI could (at least partially) be explained by IEB. Variants remaining associated after correction may be pleiotropic and include those in CYP17A1 (allele associated with hypertension risk and lower BMI). In conclusion, IEB may result in false positive or negative associations in very large studies stratified or strongly enriched for/against disease cases.

scholarly journals The genetic susceptibility profile of type 2 diabetes and reflection of its possible role related to reproductive dysfunctions in the southern Indian population of Hyderabad

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kumuda Irgam ◽  
Battini Sriteja Reddy ◽  
Sai Gayathri Hari ◽  
Swathi Banapuram ◽  
Battini Mohan Reddy
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Association ◽  
Large Scale ◽  
Indian Population ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Significant Snps ◽  
Allelic Association ◽  
Gender Specific

Abstract Background The genetic association studies of type 2 diabetes mellitus (T2DM) hitherto undertaken among the Indian populations are grossly inadequate representation of the ethnic and geographic heterogeneity of the country. In view of this and due to the inconsistent nature of the results of genetic association studies, it would be prudent to undertake large scale studies in different regions of India considering wide spectrum of variants from the relevant pathophysiological pathways. Given the reproductive dysfunctions associated with T2DM, it would be also interesting to explore if some of the reproductive pathway genes are associated with T2DM. The present study is an attempt to examine these aspects in the southern Indian population of Hyderabad. Methods A prioritized panel of 92 SNPs from a large number of metabolic and reproductive pathway genes was genotyped on 500 cases and 500 controls, matched for ethnicity, age and BMI, using AGENA MassARRAYiPLEX™ platform. Results The allelic association results suggested 14 SNPs to be significantly associated with T2DM at P ≤ 0.05 and seven of those—rs2241766-G (ADIPOQ), rs6494730-T (FEM1B), rs1799817-A and rs2059806-T (INSR), rs11745088-C (FST), rs9939609-A and rs9940128-A (FTO)—remained highly significant even after correction for multiple testing. A great majority of the significant SNPs were risk in nature. The ROC analysis of the risk scores of the significant SNPs yielded an area under curve of 0.787, suggesting substantial power of our study to confer these genetic variants as predictors of risk for T2DM. Conclusions The associated SNPs of this study are known to be specifically related to insulin signaling, fatty acid metabolism and reproductive pathway genes and possibly suggesting the role of overlapping phenotypic features of insulin resistance, obesity and reproductive dysfunctions inherent in the development of diabetes. Large scale studies involving gender specific approach may be required in order to identify the precise nature of population and gender specific risk profiles for different populations, which might be somewhat distinct.

1134-P: Polygenic Risk Score of Type 2 Diabetes as a Predictive Factor for Macrovascular Complications: A Prospective Population-Based UK Biobank Study

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 1134-P
Author(s):  
SANGHYUK JUNG ◽  
DOKYOON KIM ◽  
MANU SHIVAKUMAR ◽  
HONG-HEE WON ◽  
JAE-SEUNG YUN
Keyword(s):  
Type 2 Diabetes ◽  
Risk Score ◽  
Predictive Factor ◽  
Population Based ◽  
Macrovascular Complications ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Polygenic Risk

scholarly journals Night Shift Work, Genetic Risk, and Type 2 Diabetes in the UK Biobank

Diabetes Care ◽  
2018 ◽  
Vol 41 (4) ◽  
pp. 762-769 ◽  
Author(s):  
Céline Vetter ◽  
Hassan S. Dashti ◽  
Jacqueline M. Lane ◽  
Simon G. Anderson ◽  
Eva S. Schernhammer ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Shift Work ◽  
Genetic Risk ◽  
Night Shift ◽  
Uk Biobank ◽  
Night Shift Work ◽  
The Uk

scholarly journals Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case–control study and meta-analysis

2010 ◽  
Vol 163 (3) ◽  
pp. 427-434 ◽  
Author(s):  
José Miguel Dora ◽  
Walter Escouto Machado ◽  
Jakeline Rheinheimer ◽  
Daisy Crispim ◽  
Ana Luiza Maia
Keyword(s):  
Type 2 Diabetes ◽  
Case Control Study ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Association Studies ◽  
Case Control ◽  
Increased Risk ◽  
Key Enzyme ◽  
Control Study

ObjectiveThe type 2 deiodinase (D2) is a key enzyme for intracellular triiodothyronine (T3) generation. A single-nucleotide polymorphism in D2 (Thr92Ala) has been associated with increased insulin resistance in nondiabetic and type 2 diabetes (DM2) subjects. Our aim was to evaluate whether the D2 Thr92Ala polymorphism is associated with increased risk for DM2.Design and methodsA case–control study with 1057 DM2 and 516 nondiabetic subjects was performed. All participants underwent genotyping of the D2 Thr92Ala polymorphism. Additionally, systematic review and meta-analysis of the literature for genetic association studies of D2 Thr92Ala polymorphism and DM2 were performed in Medline, Embase, LiLacs, and SciELO, and major meeting databases using the terms ‘rs225014’ odds ratio (OR) ‘thr92ala’ OR ‘T92A’ OR ‘dio2 a/g’.ResultsIn the case–control study, the frequencies of D2 Ala92Ala homozygous were 16.4% (n=173) versus 12.0% (n=62) in DM2 versus controls respectively resulting in an adjusted OR of 1.41 (95% confidence intervals (CI) 1.03–1.94, P=0.03). The literature search identified three studies that analyzed the association of the D2 Thr92Ala polymorphism with DM2, with the following effect estimates: Mentuccia (OR 1.40 (95% CI 0.78–2.51)), Grarup (OR 1.09 (95% CI 0.92–1.29)), and Maia (OR 1.22 (95% CI 0.78–1.92)). The pooled effect of the four studies resulted in an OR 1.18 (95% CI 1.03–1.36, P=0.02).ConclusionsOur results indicate that in a case–control study, the homozygosity for D2 Thr92Ala polymorphism is associated with increased risk for DM2. These results were confirmed by a meta-analysis including 11 033 individuals, and support a role for intracellular T3 concentration in skeletal muscle on DM2 pathogenesis.

scholarly journals Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies

Cephalalgia ◽  
2014 ◽  
Vol 35 (6) ◽  
pp. 489-499 ◽  
Author(s):  
Dale R Nyholt ◽  
Verneri Anttila ◽  
Bendik S Winsvold ◽  
Tobias Kurth ◽  
Hreinn Stefansson ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Association Studies ◽  
Population Based ◽  
Significant Heterogeneity ◽  
Single Nucleotide ◽  
Disease Spectrum ◽  
Genome Wide ◽  
Genetic Overlap

Background There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls. Methods Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migraine subgroups was performed for the 12 independent SNP loci significantly associated ( p < 5 × 10−8; thus surpassing the threshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNP effect concordance analysis (SECA) at over 23,000 independent SNPs. Results Significant heterogeneity of SNP effects ( phet < 1.4 × 10−3) was observed between the MA and MO subgroups (for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 and rs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genome-wide SNP effects to be in the same direction across the subgroups. Conclusions Any differences in common genetic risk across these subgroups are outweighed by the similarities. Meta-analysis of additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibility loci for migraine.

scholarly journals Evidence for Association of the E23K Variant ofKCNJ11Gene with Type 2 Diabetes in Tunisian Population: Population-Based Study and Meta-Analysis

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Khaled Lasram ◽  
Nizar Ben Halim ◽  
Sana Hsouna ◽  
Rym Kefi ◽  
Imen Arfa ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Association Studies ◽  
Meta Analysis ◽  
Population Based ◽  
Case Control ◽  
Tunisian Population ◽  
Allelic Association ◽  
Meta Analyses

Aims. Genetic association studies have reported the E23K variant ofKCNJ11gene to be associated with Type 2 diabetes. In Arab populations, only four studies have investigated the role of this variant. We aimed to replicate and validate the association between the E23K variant and Type 2 diabetes in Tunisian and Arab populations.Methods. We have performed a case-control association study including 250 Tunisian patients with Type 2 diabetes and 267 controls. Allelic association has also been evaluated by 2 meta-analyses including all population-based studies among Tunisians and Arabs (2 and 5 populations, resp.).Results. A significant association between the E23K variant and Type 2 diabetes was found (OR = 1.6, 95% CI = 1.14–2.27, andP=0.007). Furthermore, our meta-analysis has confirmed the significant role of the E23K variant in susceptibility of Type 2 diabetes in Tunisian and Arab populations (OR = 1.29, 95% CI = 1.15–1.46, andP<10-3and OR = 1.33, 95% CI = 1.13–1.56, andP=0.001, resp.).Conclusion. Both case-control and meta-analyses results revealed the significant association between the E23K variant ofKCNJ11and Type 2 diabetes among Tunisians and Arabs.

scholarly journals Daily Yogurt Consumption Improves Glucose Metabolism and Insulin Sensitivity in Young Nondiabetic Japanese Subjects with Type-2 Diabetes Risk Alleles

Nutrients ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 1834 ◽  
Author(s):  
Daiki Watanabe ◽  
Sachi Kuranuki ◽  
Akiko Sunto ◽  
Naoki Matsumoto ◽  
Teiji Nakamura
Keyword(s):  
Type 2 Diabetes ◽  
Test Meal ◽  
Genetic Risk ◽  
Serum Insulin ◽  
Genetic Risk Score ◽  
Postprandial Plasma Glucose ◽  
Risk Alleles ◽  
Weighted Genetic Risk Score ◽  
Insulin Responses

This study investigated whether the association between postprandial plasma glucose (PPG) is affected by five type 2 diabetes mellitus (T2DM) susceptibility genes, and whether four weeks of yogurt consumption would affect these responses. We performed a single-arm intervention study in young nondiabetic Japanese participants, who consumed 150 g yogurt daily for four weeks, after which a rice test meal containing 50 g carbohydrate was administered. PPG and postprandial serum insulin (PSI) were measured between 0 and 120 mins at baseline and after the intervention. Genetic risk was evaluated by weighted genetic risk score (GRS) according to published methodology, and participants were assigned to one of two groups (n = 17: L-GRS group and n = 15: H-GRS group) according to the median of weighted GRS. At baseline, the H-GRS group had higher glucose area under the curve0–120 min after intake of the test meal than the L-GRS group (2175 ± 248 mg/dL.min vs. 1348 ± 199 mg/dL.min, p < 0.001), but there were no significant differences after the yogurt intervention. However, there was an improvement in PSI in the H-GRS group compared with baseline. These results suggest that habitual yogurt consumption may improve glucose and insulin responses in nondiabetic subjects who have genetically higher PPG.

scholarly journals Ghrelin in Diabetes and Metabolic Syndrome

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Leena Pulkkinen ◽  
Olavi Ukkola ◽  
Marjukka Kolehmainen ◽  
Matti Uusitupa
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Complex Disease ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Public Health Problem ◽  
Basic Research ◽  
Global Public Health

Metabolic syndrome is a cluster of related risk factors for cardiovascular disease, type 2 diabetes and liver disease. Obesity, which has become a global public health problem, is one of the major risk factors for development of metabolic syndrome and type 2 diabetes. Obesity is a complex disease, caused by the interplay between environmental and genetic factors. Ghrelin is one of the circulating peptides, which stimulates appetite and regulates energy balance, and thus is one of the candidate genes for obesity and T2DM. During the last years both basic research and genetic association studies have revealed association between the ghrelin gene and obesity, metabolic syndrome or type 2 diabetes

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