The Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging NGI NCHA

Rotterdam, Netherlands

The Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging NGI NCHA

Rotterdam, Netherlands
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Braun K.V.E.,Erasmus Medical Center | Dhana K.,Erasmus Medical Center | de Vries P.S.,Erasmus Medical Center | de Vries P.S.,University of Texas Health Science Center at Houston | And 10 more authors.
Clinical Epigenetics | Year: 2017

Background: DNA methylation is a key epigenetic mechanism that is suggested to be associated with blood lipid levels. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol in 725 participants of the Rotterdam Study, a population-based cohort study. Subsequently, we sought replication in a non-overlapping set of 760 participants. Results: Genome-wide methylation levels were measured in whole blood using the Illumina Methylation 450 array. Associations between lipid levels and DNA methylation beta values were examined using linear mixed-effect models. All models were adjusted for sex, age, smoking, white blood cell proportions, array number, and position on array. A Bonferroni-corrected p value lower than 1.08 × 10−7 was considered statistically significant. Five CpG sites annotated to genes including DHCR24, CPT1A, ABCG1, and SREBF1 were identified and replicated. Four CpG sites were associated with triglycerides, including CpG sites annotated to CPT1A (cg00574958 and cg17058475), ABCG1 (cg06500161), and SREBF1 (cg11024682). Two CpG sites were associated with HDL-C, including ABCG1 (cg06500161) and DHCR24 (cg17901584). No significant associations were observed with LDL-C or total cholesterol. Conclusions: We report an association of HDL-C levels with methylation of a CpG site near DHCR24, a protein-coding gene involved in cholesterol biosynthesis, which has previously been reported to be associated with other metabolic traits. Furthermore, we confirmed previously reported associations of methylation of CpG sites within CPT1A, ABCG1, and SREBF1 and lipids. These results provide insight in the mechanisms that are involved in lipid metabolism. © 2017, The Author(s).

Castano-Betancourt M.C.,Erasmus Medical Center | Castano-Betancourt M.C.,The Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging NGI NCHA | Oei L.,Erasmus Medical Center | Oei L.,The Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging NGI NCHA | And 10 more authors.
Bone | Year: 2013

Objective: To investigate the relation between lumbar disc degeneration (LDD) and all type of osteoporotic (OP) fractures including vertebral. Methods: This study is part of the Rotterdam study, a large prospective population-based cohort study among men and women aged 55. years and over. In 2819 participants spine radiographs were scored for LDD (osteophytes and disc space narrowing (DSN)) from L1 till S1, using the Lane atlas. Osteoporotic (OP) fracture data were collected and verified by specialists during 12.8. years. We considered two types of vertebral fractures (VFx): Clinical VFx (symptomatic fractures recorded by medical practitioners) and Radiographic VFx (using the McCloskey-Kanis method). Meta-analysis of published studies reporting an association of LDD features and VFx was performed. Differences in Bone Mineral Density (BMD) between participants with and without LDD features were analyzed using ANOVA. Risk of OP-fractures was analyzed using Cox regression. Results: In a total of 2385 participants, during 12.8. years follow-up, 558 suffered an OP-fracture. Subjects with LDD had an increased OP fracture risk compared to subjects without LDD (HR: 1.29, CI: 1.04-1.60). LDD-cases have between 0.3 and 0.72 standard deviations more BMD than non-cases in all analyzed regions including total body BMD and skull BMD (P. <. 0.001). Only males with LDD had increased risk for OP-fractures compared to males without LDD (adjusted-HR: 1.80, 95%CI: 1.20-2.70, P. = 0.005). The risk was also higher for VFx in males (HR: 1.64, CI: 1.03-2.60, P: 0.04). The association LDD-OP-fractures in females was lower and not significant (adjusted-HR: 1.08, 95%CI: 0.82-1.41). Meta-analyses showed that the risk of VFx in subjects with LDD has been studied only in women and there is not enough evidence to confidently analyze the relationship between LDD-features (DSN or/and OPH) and VFx due to low power and heterogeneity in phenotype definition in the collected studies. Conclusions: Male subjects with LDD have a higher osteoporotic fracture risk, in spite of systemically higher BMD. © 2013 Elsevier Inc.

Kerkhof H.J.M.,Erasmus Medical Center | Kerkhof H.J.M.,The Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging NGI NCHA | Meulenbelt I.,The Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging NGI NCHA | Meulenbelt I.,Leiden University | And 22 more authors.
BMC Medical Genetics | Year: 2010

Background: The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis.Methods: In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls.Results: The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05).Conclusion: This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase. © 2010 Kerkhof et al; licensee BioMed Central Ltd.

Meyer T.E.,University of Texas Health Science Center at Houston | Meyer T.E.,U.S. National Cancer Institute | Verwoert G.C.,Erasmus University Rotterdam | Verwoert G.C.,The Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging NGI NCHA | And 51 more authors.
PLoS Genetics | Year: 2010

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ~2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5×10-8) or suggestive associations (p<4×10-7) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4×10-7. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

Ligthart S.,Erasmus Medical Center | Steenaard R.V.,Erasmus Medical Center | Peters M.J.,Erasmus Medical Center | Peters M.J.,The Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging NGI NCHA | And 10 more authors.
Diabetologia | Year: 2016

Aims/hypothesis: Tobacco smoking, a risk factor for diabetes, is an established modifier of DNA methylation. We hypothesised that tobacco smoking modifies DNA methylation of genes previously identified for diabetes. Methods: We annotated CpG sites available on the Illumina Human Methylation 450K array to diabetes genes previously identified by genome-wide association studies (GWAS), and investigated them for an association with smoking by comparing current to never smokers. The discovery study consisted of 630 individuals (Bonferroni-corrected p = 1.4 × 10−5), and we sought replication in an independent sample of 674 individuals. The replicated sites were tested for association with nearby genetic variants and gene expression and fasting glucose and insulin levels. Results: We annotated 3,620 CpG sites to the genes identified in the GWAS on type 2 diabetes. Comparing current smokers to never smokers, we found 12 differentially methylated CpG sites, of which five replicated: cg23161492 within ANPEP (p = 1.3 × 10−12); cg26963277 (p = 1.2 × 10−9), cg01744331 (p = 8.0 × 10−6) and cg16556677 (p = 1.2 × 10−5) within KCNQ1 and cg03450842 (p = 3.1 × 10−8) within ZMIZ1. The effect of smoking on DNA methylation at the replicated CpG sites attenuated after smoking cessation. Increased DNA methylation at cg23161492 was associated with decreased gene expression levels of ANPEP (p = 8.9 × 10−5). rs231356-T, which was associated with hypomethylation of cg26963277 (KCNQ1), was associated with a higher odds of diabetes (OR 1.06, p = 1.3 × 10−5). Additionally, hypomethylation of cg26963277 was associated with lower fasting insulin levels (p = 0.04). Conclusions/interpretation: Tobacco smoking is associated with differential DNA methylation of the diabetes risk genes ANPEP, KCNQ1 and ZMIZ1. Our study highlights potential biological mechanisms connecting tobacco smoking to excess risk of type 2 diabetes. © 2016, The Author(s).

Westra H.-J.,University of Groningen | Arends D.,University of Groningen | Esko T.,University of Tartu | Esko T.,Boston Childrens Hospital | And 78 more authors.
PLoS Genetics | Year: 2015

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus. © 2015, Public Library of Science. All rights reserved.

Steenaard R.V.,Erasmus University Rotterdam | Ligthart S.,Erasmus University Rotterdam | Stolk L.,Erasmus University Rotterdam | Peters M.J.,Erasmus University Rotterdam | And 7 more authors.
Clinical Epigenetics | Year: 2015

Background: Tobacco smoking, a risk factor for coronary artery disease (CAD), is known to modify DNA methylation. We hypothesized that tobacco smoking modifies methylation of the genes identified for CAD by genome-wide association study (GWAS). Results: We selected genomic regions based on 150 single-nucleotide polymorphisms (SNPs) identified in the largest GWAS on CAD. We investigated the association between current smoking and the CpG sites within and near these CAD-related genes. Methylation was measured with the Illumina Human Methylation 450K array in whole blood of 724 Caucasian subjects from the Rotterdam Study, a Dutch population based cohort study. A total of 3669 CpG sites within 169 CAD-related genes were studied for association with current compared to never smoking. Fifteen CpG sites were significantly associated after correction for multiple testing (Bonferroni-corrected p value <1.4 × 10−5). These sites were located in the genes TERT, SARS, GNGT2, SMG6, SKI, TOM1L2, SIPA1, MRAS, CDKN1A, LRRC2, FES and RPH3A. In 12 sites, current smoking was associated with a 1.2 to 2.4 % lower methylation compared to never smoking; and in three sites, it was associated with a 1.2 to 1.8 % higher methylation. The effect estimates were lower in 10 of the 15 CpG sites when comparing current to former smoking. One CpG site, cg05603985 (SKI), was found to be associated with expression of nearby CAD-related gene PRKCZ. Conclusions: Our study suggests an effect of tobacco smoking on DNA methylation of CAD-related genes and thus provides novel insights in the pathways that link tobacco smoking to risk of CAD. © 2015 Steenaard et al.

Pilling L.C.,University of Exeter | Joehanes R.,Lung And Blood Institutes Framingham Heart Study | Joehanes R.,U.S. National Institutes of Health | Kacprowski T.,University of Greifswald | And 39 more authors.
Physiological Genomics | Year: 2016

Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20–104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength. © 2016 the American Physiological Society.

Ghanbari M.,Erasmus Medical Center | Ghanbari M.,Mashhad University of Medical Sciences | de Vries P.S.,Erasmus Medical Center | de Looper H.,Erasmus University Rotterdam | And 15 more authors.
Human Mutation | Year: 2014

MicroRNAs (miRNA) play a crucial role in the regulation of diverse biological processes by post-transcriptional modulation of gene expression. Genetic polymorphisms in miRNA-related genes can potentially contribute to a wide range of phenotypes. The effect of such variants on cardiometabolic diseases has not yet been defined. We systematically investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes, using the thus far largest genome-wide association studies on 17 cardiometabolic traits/diseases. We found that rs2168518:G>A, a seed region variant of miR-4513, associates with fasting glucose, low-density lipoprotein-cholesterol, total cholesterol, systolic and diastolic blood pressure, and risk of coronary artery disease. We experimentally showed that miR-4513 expression is significantly reduced in the presence of the rs2168518 mutant allele. We sought to identify miR-4513 target genes that may mediate these associations and revealed five genes (PCSK1, BNC2, MTMR3, ANK3, and GOSR2) through which these effects might be taking place. Using luciferase reporter assays, we validated GOSR2 as a target of miR-4513 and further demonstrated that the miRNA-mediated regulation of this gene is changed by rs2168518. Our findings indicate a pleiotropic effect of miR-4513 on cardiometabolic phenotypes and may improve our understanding of the pathophysiology of cardiometabolic diseases. In this study, we found that rs2168518 in the seed region of miR-4513 associates with fasting glucose, LDL-cholesterol and total cholesterol, blood pressure and risk of coronary artery disease. We identified five miR-4513 target genes, GOSR2, ANK3, PCSK1, BNC2, and MTMR3, as potential mediators of these associations. We showed two mechanisms through which the SNP affects miR-4513 function: the mutant allele firstly decreases miR-4513 expression (Fig. 1) and secondly reduces the ability of miR-4513 to repress the target genes expression (Fig. 2). © 2014 WILEY PERIODICALS, INC.

Williams F.M.K.,King's College London | Bansal A.T.,Acclarogen Ltd. | Van Meurs J.B.,Erasmus University Rotterdam | Van Meurs J.B.,The Netherlands Genomics Initiative Sponsored Netherlands Consortium for Healthy Aging NGI NCHA | And 17 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective: Lumbar disc degeneration (LDD) is an important cause of low back pain, which is a common and costly problem. LDD is characterised by disc space narrowing and osteophyte growth at the circumference of the disc. To date, the agnostic search of the genome by genome-wide association (GWA) to identify common variants associated with LDD has not been fruitful. This study is the first GWA meta-analysis of LDD. Methods: We have developed a continuous trait based on disc space narrowing and osteophytes growth which is measurable on all forms of imaging ( plain radiograph, CT scan and MRI) and performed a meta-analysis of five cohorts of Northern European extraction each having GWA data imputed to HapMap V.2. Results: This study of 4600 individuals identified four single nucleotide polymorphisms with p<5×10-8, the threshold set for genome-wide significance. We identified a variant in the PARK2 gene (p=2.8×10-8) associated with LDD. Differential methylation at one CpG island of the PARK2 promoter was observed in a small subset of subjects (β=8.74×10-4, p=0.006). Conclusions LDD accounts for a considerable proportion of low back pain and the pathogenesis of LDD is poorly understood. This work provides evidence of association of the PARK2 gene and suggests that methylation of the PARK2 promoter may influence degeneration of the intervertebral disc. This gene has not previously been considered a candidate in LDD and further functional work is needed on this hitherto unsuspected pathway.

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