scholarly journals DNA Methylation of the LY86 Gene is Associated With Obesity, Insulin Resistance, and Inflammation

2014 ◽  
Vol 17 (3) ◽  
pp. 183-191 ◽  
Author(s):  
Shaoyong Su ◽  
Haidong Zhu ◽  
Xiaojing Xu ◽  
Xin Wang ◽  
Yanbin Dong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Dna Methylation ◽  
General Population ◽  
Association Studies ◽  
Cross Sectional Study ◽  
Genome Wide Association Studies ◽  
Cross Sectional ◽  
Multi Stage ◽  
Genome Wide ◽  
And Gender

Background: Previous genome-wide association studies (GWAS) have identified a large number of genetic variants for obesity and its related traits, representing a group of potential key genes in the etiology of obesity. Emerging evidence suggests that epigenetics may play an important role in obesity. It has not been explored whether the GWAS-identified loci contribute to obesity through epigenetics (e.g., DNA (deoxyribonucleic acid) methylation) in addition to genetics. Method: A multi-stage cross-sectional study was designed. We did a literature search and identified 117 genes discovered by GWAS for obesity and its related traits. Then we analyzed whether the methylation levels of these genes were also associated with obesity in two genome-wide methylation panels. We examined an initial panel of seven adolescent obese cases and seven age-matched lean controls, followed by a second panel of 48 adolescent obese cases and 48 age- and gender-matched lean controls. The validated CpG sites were further replicated in two independent replication panels of youth (46 vs. 46 and 230 cases vs. 413 controls, respectively) and a general population of youth, including 703 healthy subjects. Results: One CpG site in the lymphocyte antigen 86 (LY86) gene, which showed higher methylation in the obese in both the initial (p = .009) and second genome-wide DNA methylation panel (p = .008), was further validated in both replication panels (meta p = .00016). Moreover, in the general population of youth, the methylation levels of this region were significantly correlated with adiposity indices (p ≤ .02), insulin resistance (p = .001), and inflammatory markers (p < .001). Conclusion: By focusing on recent GWAS findings in genome-wide methylation profiles, we identified a solid association between LY86 gene DNA methylation and obesity.

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Identification of six novel susceptibility loci for dyslipidemia by longitudinal exome-wide association studies in Japanese

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Oguri ◽  
K Kato ◽  
H Horibe ◽  
T Fujimaki ◽  
J Sakuma ◽  
...  
Keyword(s):  
Serum Lipid ◽  
Ldl Cholesterol ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Cross Sectional ◽  
Genome Wide

Abstract Background The circulating concentrations of triglycerides, high density lipoprotein (HDL)-cholesterol, and low density lipoprotein (LDL)-cholesterol have a substantial genetic component. Although previous genome-wide association studies identified various genes and loci related to plasma lipid levels, those studies were conducted in a cross-sectional manner. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to hypertriglyceridemia, hypo-HDL-cholesterolemia, and hyper-LDL-cholesterolemia in Japanese. We have now performed longitudinal exome-wide association studies (EWASs) to identify novel loci for dyslipidemia by examining temporal changes in serum lipid profiles. Methods Longitudinal EWASs (mean follow-up period, 5 years) for hypertriglyceridemia (2056 case, 3966 controls), hypo-HDL-cholesterolemia (698 cases, 5324 controls), and hyper-LDL-cholesterolemia (2769 cases, 3251 controls) were performed with Illumina Human Exome arrays. The relation of genotypes of 24,691 single nucleotide polymorphisms (SNPs) that passed quality control to dyslipidemia-related traits was examined with the generalized estimating equation (GEE). To compensate for multiple comparisons of genotypes with each of the three conditions, we applied Bonferroni's correction for statistical significance of association. Replication studies with cross-sectional data were performed for hypertriglyceridemia (2685 cases, 4703 controls), hypo-HDL-cholesterolemia (1947 cases, 6146 controls), and hyper-LDL-cholesterolemia (1719 cases, 5833 controls). Results Longitudinal EWASs revealed that 30 SNPs were significantly (P&lt;2.03 × 10–6 by GEE) associated with hypertriglyceridemia, 46 SNPs with hypo-HDL-cholesterolemia, and 25 SNPs with hyper-LDL-cholesterolemia. After examination of the relation of identified SNPs to serum lipid profiles, linkage disequilibrium, and results of the previous genome-wide association studies, we newly identified rs74416240 of TCHP, rs925368 of GIT2, rs7969300 of ATXN2, and rs12231744 of NAA25 as a susceptibility loci for hypo-HDL-cholesterolemia; and rs34902660 of SLC17A3 and rs1042127 of CDSN for hyper-LDL-cholesterolemia. These SNPs were not in linkage disequilibrium with those previously reported to be associated with dyslipidemia, indicating independent effects of the SNPs identified in the present study on serum concentrations of HDL-cholesterol or LDL-cholesterol in Japanese. According to allele frequency data from the 1000 Genomes project database, five of the six identified SNPs were monomorphic or rare variants in European populations. In the replication study, all six SNPs were associated with dyslipidemia-related phenotypes. Conclusion We have thus identified six novel loci that confer susceptibility to hypo-HDL-cholesterolemia or hyper-LDL-cholesterolemia. Determination of genotypes for these SNPs at these loci may prove informative for assessment of the genetic risk for dyslipidemia in Japanese. Funding Acknowledgement Type of funding source: None

scholarly journals Insulin resistance indices and coronary risk in adults from Maracaibo city, Venezuela: A cross sectional study

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 44 ◽  
Author(s):  
Juan Salazar ◽  
Valmore Bermúdez ◽  
Luis Carlos Olivar ◽  
Wheeler Torres ◽  
Jim Palmar ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adult Population ◽  
Cross Sectional Study ◽  
Coronary Risk ◽  
Sectional Study ◽  
Predictive Capacity ◽  
Cross Sectional ◽  
Multi Stage ◽  
Risk Event ◽  
Hs Crp

Background: Insulin resistance (IR) is a metabolic disorder related to atherosclerosis. Its measurement is of great importance not only as a marker of diabetes but also for cardiovascular disease. The aim of this research study was to evaluate the relationship between various IR indices and coronary risk in an adult population from Maracaibo city, Venezuela. Methods: The Maracaibo City Metabolic Syndrome Prevalence Study is a descriptive, cross-sectional study with random and multi-stage sampling. In this sub study, 1272 individuals of both genders were selected with the measurement of basal insulin and coronary risk according to the Framingham-Wilson formula calibrated for our population. The insulin resistance indices evaluated were HOMA2-IR, triglycerides and glucose index (TyG) and triglycerides/HDL ratio (TG/HDL). The predictive capacity and association between each index and the coronary risk event in 10 years were determined. Results: Of the evaluated population, 55.2% were female, 34.8% had a coronary risk ≥5% in 10 years, with the TG/HDL and TyG indices showing the highest AUC 0.712 (0.681-0.743) and 0.707 (0.675-0.739), respectively; compared to HOMA2-IR. Both were also the indices most associated with increased coronary risk, especially TG/HDL ≥3 with a higher association [OR = 2.83 (1.74-4.61); p<0.01] after multivariable adjustment. Conclusions: TyG (≥4.5) and TG/HDL (≥3) indices showed a great predictive capacity of higher coronary risk, with being TG/HDL more associated even after adjusting for abdominal obesity and hs-CRP. Therefore, these represent useful tools for determining IR.

scholarly journals Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tianxiao Huan ◽  
Roby Joehanes ◽  
Ci Song ◽  
Fen Peng ◽  
Yichen Guo ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Dna Methylation ◽  
Whole Blood ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Disease Associations ◽  
Independent Replication ◽  
Functional Mechanisms

Abstract Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population

2016 ◽  
Vol 29 (2) ◽  
pp. e12923 ◽  
Author(s):  
F. Bonfiglio ◽  
P. G. Hysi ◽  
W. Ek ◽  
V. Karhunen ◽  
N. V. Rivera ◽  
...  
Keyword(s):  
General Population ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals M88. EVIDENCE FOR INFLAMMATION AS A PUTATIVE SHARED MECHANISM FOR INSULIN RESISTANCE AND SCHIZOPHRENIA

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S168-S168
Author(s):  
Benjamin Perry ◽  
Stephen Burgess ◽  
Hannah Jones ◽  
Stanley Zammit ◽  
Rachel Upthegrove ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Genetic Variants ◽  
Cardiometabolic Risk ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Cardiometabolic Risk Factors ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Cardiometabolic Disorders

Abstract Background Insulin Resistance (IR) predisposes to cardiometabolic disorders, which are common in schizophrenia and are associated with excess morbidity and mortality. The mechanisms of association remain unknown. We aimed 1) To use genetic data to examine the direction of association between IR and related cardiometabolic risk factors, and schizophrenia; 2) To examine whether inflammation could be a shared mechanism for IR and schizophrenia. Methods We used two-sample uni-variable Mendelian randomization (MR) to examine whether genetically-predicted IR-related cardiometabolic risk factors (Fasting insulin (FI), high-density lipoprotein (HDL), triglycerides (TG), low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance and type 2 diabetes) may be causally associated with schizophrenia. We used the most recent summary statistics for genetic variants associated with schizophrenia and IR-related cardiometabolic risk factors from publicly-available large genome-wide association studies (GWAS). We used bi-directional MR to examine direction of association. To examine whether inflammation could be a shared mechanism for IR and schizophrenia, we first conducted a sensitivity analysis by performing MR using only cardiometabolic genetic variants that were also associated with inflammation, at genome-wide significance. Second, we used multi-variable MR (MVMR) to examine associations between cardiometabolic risk factors and schizophrenia after adjusting for genetically-predicted levels of C-reactive protein. Results In analyses using all associated genetic variants, genetically predicted levels of leptin were associated with risk of schizophrenia (OR=2.54 per SD increase in leptin; 95% CI, 1.02–6.31). In analyses using inflammation-related variants, genetically predicted levels of FI (OR=2.76 per SD increase in FI; 95% C.I., 1.31–6.17), TG (OR=2.90 per SD increase in TG; 95% C.I., 1.36–6.17), and HDL (OR=0.56 per SD increase in HDL; 95% C.I., 0.37–0.83) were associated with schizophrenia. The associations completely attenuated in MVMR analyses controlling for CRP. There was no evidence of an association between genetically-predicted schizophrenia liability and cardiometabolic factors. Discussion The IR phenotype of FI, TG and HDL could be associated with schizophrenia over and above common sociodemographic and lifestyle factors. This association is likely explained by a common inflammatory mechanism. Interventional studies are required to test whether inflammation could represent a putative therapeutic target for the treatment and prevention of cardiometabolic disorders in schizophrenia.

scholarly journals Multimorbidity Patterns in the General Population: Results from the EpiChron Cohort Study

2020 ◽  
Vol 17 (12) ◽  
pp. 4242
Author(s):  
Ignatios Ioakeim-Skoufa ◽  
Beatriz Poblador-Plou ◽  
Jonás Carmona-Pírez ◽  
Jesús Díez-Manglano ◽  
Rokas Navickas ◽  
...  
Keyword(s):  
General Population ◽  
Large Scale ◽  
Musculoskeletal Diseases ◽  
Epidemiological Studies ◽  
Population Based ◽  
Cross Sectional Study ◽  
Real World Data ◽  
Cross Sectional ◽  
Complex Interactions ◽  
And Gender

The correct management of patients with multimorbidity remains one of the main challenges for healthcare systems worldwide. In this study, we analyze the existence of multimorbidity patterns in the general population based on gender and age. We conducted a cross-sectional study of individuals of all ages from the EpiChron Cohort, Spain (1,253,292 subjects), and analyzed the presence of systematic associations among chronic disease diagnoses using exploratory factor analysis. We identified and clinically described a total of 14 different multimorbidity patterns (12 in women and 12 in men), with some relevant differences in the functions of age and gender. The number and complexity of the patterns was shown to increase with age in both genders. We identified associations of circulatory diseases with respiratory disorders, chronic musculoskeletal diseases with depression and anxiety, and a very consistent pattern of conditions whose co-occurrence is known as metabolic syndrome (hypertension, diabetes, obesity, and dyslipidaemia), among others. Our results demonstrate the potential of using real-world data to conduct large-scale epidemiological studies to assess the complex interactions among chronic conditions. This could be useful in designing clinical interventions for patients with multimorbidity, as well as recommendations for healthcare professionals on how to handle these types of patients in clinical practice.

scholarly journals Trans-ethnic meta-analysis identifies new loci associated with longitudinal blood pressure traits

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mateus H. Gouveia ◽  
Amy R. Bentley ◽  
Hampton Leonard ◽  
Karlijn A. C. Meeks ◽  
Kenneth Ekoru ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Association Studies ◽  
Meta Analysis ◽  
Regulatory Function ◽  
Genome Wide Association Studies ◽  
The Novel ◽  
Cross Sectional ◽  
Age Related ◽  
Genome Wide ◽  
The Us

AbstractGenome-wide association studies (GWAS) have identified thousands of genetic loci associated with cross-sectional blood pressure (BP) traits; however, GWAS based on longitudinal BP have been underexplored. We performed ethnic-specific and trans-ethnic GWAS meta-analysis using longitudinal and cross-sectional BP data of 33,720 individuals from five cohorts in the US and one in Brazil. In addition to identifying several known loci, we identified thirteen novel loci with nine based on longitudinal and four on cross-sectional BP traits. Most of the novel loci were ethnic- or study-specific, with the majority identified in African Americans (AA). Four of these discoveries showed additional evidence of association in independent datasets, including an intergenic variant (rs4060030, p = 7.3 × 10–9) with reported regulatory function. We observed a high correlation between the meta-analysis results for baseline and longitudinal average BP (rho = 0.48). BP trajectory results were more correlated with those of average BP (rho = 0.35) than baseline BP(rho = 0.18). Heritability estimates trended higher for longitudinal traits than for cross-sectional traits, providing evidence for different genetic architectures. Furthermore, the longitudinal data identified up to 20% more BP known associations than did cross-sectional data. Our analyses of longitudinal BP data in diverse ethnic groups identified novel BP loci associated with BP trajectory, indicating a need for further longitudinal GWAS on BP and other age-related traits.

Utilising multi-large omics data to elucidate biological mechanisms within multiple sclerosis genetic susceptibly loci

2021 ◽  
pp. 135245852110044
Author(s):  
Yuan Zhou ◽  
Gabriel Cuellar-Partida ◽  
Steve Simpson Yap ◽  
Xin Lin ◽  
Suzi Claflin ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dna Methylation ◽  
Whole Blood ◽  
Association Studies ◽  
Specific Effect ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Biological Mechanisms ◽  
Functional Variants ◽  
Genome Wide

Background: Genome-wide association studies (GWAS) have succeeded in identifying over 200 susceptibility loci for multiple sclerosis (MS). However, the potential functional variants and the mechanisms by which these loci affect MS risk remain largely unexplained. Objectives: We used summary data-based Mendelian randomisation to prioritise risk genes and infer potential biological mechanisms for MS risk loci. Methods: The data used consisted of DNA methylation ( n = 1980) QTL (mQTL) and gene expression ( n = 31,684) QTL (eQTL) derived from whole blood as well as MS GWAS summary statistics (14,802 cases, 26,703 controls). The findings were further evaluated using data derived from independent brain mQTL ( n = 1160) and eQTL ( n = 1194). Results: In whole blood, we identified two independent genomic loci (lincRNA: RP11-326C3.13 and TNFSF14) with consistent genome-wide significant pleiotropic associations across different omics layers. In brain tissue, a similar effect for the RP11-326C3.13 locus was observed but not for TNFSF14, indicating a potential tissue-specific effect for the TNFSF14 locus. Conclusion: We provide in silico evidence for the putative biological mechanisms by which the identified DNA methylation sites and target genes are functionally relevant to MS development in different tissues. Future research targeting these genes and DNA methylation sites will determine their roles in the pathophysiology of MS.

scholarly journals Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Adrienne Tin ◽  
Pascal Schlosser ◽  
Pamela R. Matias-Garcia ◽  
Chris H. L. Thio ◽  
Roby Joehanes ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Complex Traits ◽  
Cardiometabolic Risk ◽  
Association Studies ◽  
Meta Analysis ◽  
Elevated Serum ◽  
Complex Trait ◽  
Serum Urate ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractElevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

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