Publications by authors named "Joyce B J van Meurs"

148 Publications

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

Genome Biol 2021 Jun 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

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.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

A comparison of genotyping arrays.

Eur J Hum Genet 2021 Jun 18. Epub 2021 Jun 18.

Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Array technology to genotype single-nucleotide variants (SNVs) is widely used in genome-wide association studies (GWAS), clinical diagnostics, and linkage studies. Arrays have undergone a tremendous growth in both number and content over recent years making a comprehensive comparison all the more important. We have compared 28 genotyping arrays on their overall content, genome-wide coverage, imputation quality, presence of known GWAS loci, mtDNA variants and clinically relevant genes (i.e., American College of Medical Genetics (ACMG) actionable genes, pharmacogenetic genes, human leukocyte antigen (HLA) genes and SNV density). Our comparison shows that genome-wide coverage is highly correlated with the number of SNVs on the array but does not correlate with imputation quality, which is the main determinant of GWAS usability. Average imputation quality for all tested arrays was similar for European and African populations, indicating that this is not a good criterion for choosing a genotyping array. Rather, the additional content on the array, such as pharmacogenetics or HLA variants, should be the deciding factor. As the research question of a study will in large part determine which class of genes are of interest, there is not just one perfect array for all different research questions. This study can thus help as a guideline to determine which array best suits a study's requirements.
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http://dx.doi.org/10.1038/s41431-021-00917-7DOI Listing
June 2021

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption.

Nat Commun 2021 05 14;12(1):2830. Epub 2021 May 14.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.
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http://dx.doi.org/10.1038/s41467-021-22752-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121846PMC
May 2021

Towards sex-specific osteoarthritis risk models: evaluation of risk factors for knee osteoarthritis in males and females.

Rheumatology (Oxford) 2021 Apr 24. Epub 2021 Apr 24.

Department of Orthopedics, Erasmus MC, University Medical Center Rotterdam, The Netherlands; e-mail:

Objectives: The aim of this study was to identify sex-specific prevalence and strength of risk factors for the incidence of radiographic knee osteoarthritis (incRKOA).

Methods: Our study population consisted of 10,958 Rotterdam Study participants free of knee OA in one/both knees at baseline. 1064 participants developed RKOA after a median follow-up time of 9.6 years. We estimated the association between each available risk factor and incRKOA using sex stratified multivariate regression models with generalized estimating equations. Subsequently, we statistically tested sex differences between risk estimates and calculated the population attributable fractions (PAFs) for modifiable risk factors.

Results: The prevalence of the investigated risk factors was, in general, higher in women compared to men, except alcohol intake and smoking was higher in men and high BMI showed equal prevalence. We found significantly different risk estimates between men and women: high level of PA (RR 1.76, 95% CI 1.29-2.40) or a KL-score 1 at baseline (RR 5.48, 95% CI 4.51-6.65) was higher in men. Among borderline significantly different risk estimates was BMI ≥27, associated with higher risk for incRKOA in women (RR 2.00, 95% CI 1.74-2.31). The PAF for higher BMI was 25.6% in women and 19.3% in men.

Conclusion: We found sex-specific differences in both presence and relative risks of several risk factors for incRKOA. Especially BMI, a modifiable risk factor, impacts women more strongly than men. These risk factors can be used in the development of personalized prevention strategies and in building sex-specific prediction tools to identify high-risk profile patients.
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http://dx.doi.org/10.1093/rheumatology/keab378DOI Listing
April 2021

DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts.

Clin Epigenetics 2021 02 23;13(1):40. Epub 2021 Feb 23.

MRC Integrative Epidemiology, Bristol Medical School, Bristol, BS8 2BN, UK.

Background: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones.

Results: We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R = 10.6%).

Conclusions: This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.
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http://dx.doi.org/10.1186/s13148-021-01027-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903628PMC
February 2021

Genome-wide transcriptome study using deep RNA sequencing for myocardial infarction and coronary artery calcification.

BMC Med Genomics 2021 02 10;14(1):45. Epub 2021 Feb 10.

Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA.

Background: Coronary artery calcification (CAC) is a noninvasive measure of coronary atherosclerosis, the proximal pathophysiology underlying most cases of myocardial infarction (MI). We sought to identify expression signatures of early MI and subclinical atherosclerosis in the Framingham Heart Study (FHS). In this study, we conducted paired-end RNA sequencing on whole blood collected from 198 FHS participants (55 with a history of early MI, 72 with high CAC without prior MI, and 71 controls free of elevated CAC levels or history of MI). We applied DESeq2 to identify coding-genes and long intergenic noncoding RNAs (lincRNAs) differentially expressed in MI and high CAC, respectively, compared with the control.

Results: On average, 150 million paired-end reads were obtained for each sample. At the false discovery rate (FDR) < 0.1, we found 68 coding genes and 2 lincRNAs that were differentially expressed in early MI versus controls. Among them, 60 coding genes were detectable and thus tested in an independent RNA-Seq data of 807 individuals from the Rotterdam Study, and 8 genes were supported by p value and direction of the effect. Immune response, lipid metabolic process, and interferon regulatory factor were enriched in these 68 genes. By contrast, only 3 coding genes and 1 lincRNA were differentially expressed in high CAC versus controls. APOD, encoding a component of high-density lipoprotein, was significantly downregulated in both early MI (FDR = 0.007) and high CAC (FDR = 0.01) compared with controls.

Conclusions: We identified transcriptomic signatures of early MI that include differentially expressed protein-coding genes and lincRNAs, suggesting important roles for protein-coding genes and lincRNAs in the pathogenesis of MI.
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http://dx.doi.org/10.1186/s12920-020-00838-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874462PMC
February 2021

Mendelian randomization study on vitamin D levels and osteoarthritis risk: a concise report.

Rheumatology (Oxford) 2021 Jul;60(7):3409-3412

Department of Internal Medicine.

Objective: The role of vitamin D in OA is unclear and previous epidemiological studies have provided inconsistent results. We conducted a two-sample Mendelian randomization (MR) study to investigate the causal relationship between genetically determined serum vitamin D levels and hip/knee OA.

Methods: Six single-nucleotide polymorphisms (SNPs) associated with vitamin D levels in the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits Consortium were selected as instrumental variables. Summary statistics of the SNPs effects on OA were derived from the Iceland and UK Biobank, comprising 23 877 knee OA cases, 17 151 hip OA cases and >562 000 controls. The control samples match the OA cases in age, sex and county of origin.

Results: The MR analyses showed no causal association between genetically determined vitamin D levels and knee OA [odds ratio (OR) 1.03 (95% CI 0.84, 1.26)] or hip OA [OR 1.06 (95% CI 0.83, 1.35)].

Conclusion: Genetic variations associated with low vitamin D serum levels are not associated with increased risk of hip or knee OA in community-dwelling older adults, suggesting that vitamin D levels are not causally linked to OA. It is therefore unlikely that vitamin D supplementation protects against hip or knee OA.
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http://dx.doi.org/10.1093/rheumatology/keaa697DOI Listing
July 2021

The interrelatedness of chronic cough and chronic pain.

Eur Respir J 2021 05 6;57(5). Epub 2021 May 6.

Dept of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.

Since chronic cough has common neurobiological mechanisms and pathophysiology with chronic pain, both clinical disorders might be interrelated. Hence, we examined the association between chronic cough and chronic pain in adult subjects in the Rotterdam Study, a large prospective population-based cohort study.Using a standardised questionnaire, chronic pain was defined as pain lasting up to 6 months and grouped into a frequency of weekly/monthly or daily pain. Chronic cough was described as daily coughing for at least 3 months duration. The longitudinal and cross-sectional associations were investigated bi-directionally.Of 7141 subjects in the study, 54% (n=3888) reported chronic pain at baseline. The co-prevalence of daily chronic pain and chronic cough was 4.4%. Chronic cough was more prevalent in subjects with daily and weekly/monthly chronic pain compared with those without chronic pain (13.8% and 10.3% 8.2%; p<0.001). After adjustment for potential confounders, prevalent chronic pain was significantly associated with incident chronic cough (OR 1.47, 95% CI 1.08-1.99). The association remained significant in subjects with daily chronic pain (OR 1.49, 95% CI 1.06-2.11) with a similar effect estimate, albeit non-significant in those with weekly/monthly chronic pain (OR 1.43, 95% CI 0.98-2.10). After adjustment for covariables, subjects with chronic cough had a significant risk of developing chronic pain (OR 1.63, 95% CI 1.02-2.62) compared with those without chronic cough.Chronic cough and chronic pain confer risk on each other among adult subjects, indicating that both conditions might share common risk factors and/or pathophysiologic mechanisms.
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http://dx.doi.org/10.1183/13993003.02651-2020DOI Listing
May 2021

Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits.

Clin Epigenetics 2020 10 22;12(1):157. Epub 2020 Oct 22.

Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, 3015 GB, Rotterdam, The Netherlands.

Background: Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits.

Results: We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression.

Conclusions: Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.
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http://dx.doi.org/10.1186/s13148-020-00951-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579899PMC
October 2020

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference.

Genome Biol 2020 08 28;21(1):220. Epub 2020 Aug 28.

Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands.

Background: DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data.

Results: By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation.

Conclusion: We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.
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http://dx.doi.org/10.1186/s13059-020-02114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453518PMC
August 2020

Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency.

Front Immunol 2020 15;11:614. Epub 2020 Apr 15.

Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands.

Genetic tests for primary immunodeficiency disorders (PIDs) are expensive, time-consuming, and not easily accessible in developing countries. Therefore, we studied the feasibility of a customized single nucleotide variant (SNV) microarray that we developed to detect disease-causing variants and copy number variation (CNV) in patients with PIDs for only 40 Euros. Probes were custom-designed to genotype 9,415 variants of 277 PID-related genes, and were added to the genome-wide Illumina Global Screening Array (GSA). Data analysis of GSA was performed using Illumina GenomeStudio 2.0, Biodiscovery Nexus 10.0, and R-3.4.4 software. Validation of genotype calling was performed by comparing the GSA with whole-genome sequencing (WGS) data of 56 non-PID controls. DNA samples of 95 clinically diagnosed PID patients, of which 60 patients (63%) had a genetically established diagnosis (by Next-Generation Sequencing (NGS) PID panels or Sanger sequencing), were analyzed to test the performance of the GSA. The additional SNVs detected by GSA were validated by Sanger sequencing. Genotype calling of the customized array had an accuracy rate of 99.7%. The sensitivity for detecting rare PID variants was high (87%). The single sample replication in two runs was high (94.9%). The customized GSA was able to generate a genetic diagnosis in 37 out of 95 patients (39%). These 37 patients included 29 patients in whom the genetic variants were confirmed by conventional methods (26 patients by SNV and 3 by CNV analysis), while in 8 patients a new genetic diagnosis was established (6 patients by SNV and 2 patients suspected for leukemia by CNV analysis). Twenty-eight patients could not be detected due to the limited coverage of the custom probes. However, the diagnostic yield can potentially be increased when newly updated variants are added. Our robust customized GSA seems to be a promising first-line rapid screening tool for PIDs at an affordable price, which opens opportunities for low-cost genetic testing in developing countries. The technique is scalable, allows numerous new genetic variants to be added, and offers the potential for genetic testing not only in PIDs, but also in many other genetic diseases.
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http://dx.doi.org/10.3389/fimmu.2020.00614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179678PMC
March 2021

The tissue-specific aspect of genome-wide DNA methylation in newborn and placental tissues: implications for epigenetic epidemiologic studies.

J Dev Orig Health Dis 2021 02 24;12(1):113-123. Epub 2020 Apr 24.

Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre Rotterdam, Postbus 2040, 3000 CARotterdam, The Netherlands.

Epigenetic programming is essential for lineage differentiation, embryogenesis and placentation in early pregnancy. In epigenetic association studies, DNA methylation is often examined in DNA derived from white blood cells, although its validity to other tissues of interest remains questionable. Therefore, we investigated the tissue specificity of epigenome-wide DNA methylation in newborn and placental tissues. Umbilical cord white blood cells (UC-WBC, n = 25), umbilical cord blood mononuclear cells (UC-MNC, n = 10), human umbilical vein endothelial cells (HUVEC, n = 25) and placental tissue (n = 25) were obtained from 36 uncomplicated pregnancies. Genome-wide DNA methylation was measured by the Illumina HumanMethylation450K BeadChip. Using UC-WBC as a reference tissue, we identified 3595 HUVEC tissue-specific differentially methylated regions (tDMRs) and 11,938 placental tDMRs. Functional enrichment analysis showed that HUVEC and placental tDMRs were involved in embryogenesis, vascular development and regulation of gene expression. No tDMRs were identified in UC-MNC. In conclusion, the extensive amount of genome-wide HUVEC and placental tDMRs underlines the relevance of tissue-specific approaches in future epigenetic association studies, or the use of validated representative tissues for a certain disease of interest, if available. To this purpose, we herewith provide a relevant dataset of paired, tissue-specific, genome-wide methylation measurements in newborn tissues.
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http://dx.doi.org/10.1017/S2040174420000136DOI Listing
February 2021

Multi-Omics Analysis Reveals MicroRNAs Associated With Cardiometabolic Traits.

Front Genet 2020 27;11:110. Epub 2020 Feb 27.

Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands.

MicroRNAs (miRNAs) are non-coding RNA molecules that regulate gene expression. Extensive research has explored the role of miRNAs in the risk for type 2 diabetes (T2D) and coronary heart disease (CHD) using single-omics data, but much less by leveraging population-based omics data. Here we aimed to conduct a multi-omics analysis to identify miRNAs associated with cardiometabolic risk factors and diseases. First, we used publicly available summary statistics from large-scale genome-wide association studies to find genetic variants in miRNA-related sequences associated with various cardiometabolic traits, including lipid and obesity-related traits, glycemic indices, blood pressure, and disease prevalence of T2D and CHD. Then, we used DNA methylation and miRNA expression data from participants of the Rotterdam Study to further investigate the link between associated miRNAs and cardiometabolic traits. After correcting for multiple testing, 180 genetic variants annotated to 67 independent miRNAs were associated with the studied traits. Alterations in DNA methylation levels of CpG sites annotated to 38 of these miRNAs were associated with the same trait(s). Moreover, we found that plasma expression levels of 8 of the 67 identified miRNAs were also associated with the same trait. Integrating the results of different omics data showed miR-10b-5p, miR-148a-3p, miR-125b-5p, and miR-100-5p to be strongly linked to lipid traits. Collectively, our multi-omics analysis revealed multiple miRNAs that could be considered as potential biomarkers for early diagnosis and progression of cardiometabolic diseases.
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http://dx.doi.org/10.3389/fgene.2020.00110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056871PMC
February 2020

Epigenetic Link Between Statin Therapy and Type 2 Diabetes.

Diabetes Care 2020 04 7;43(4):875-884. Epub 2020 Feb 7.

Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.

Objective: To investigate the role of epigenetics in statins' diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood.

Research Design And Methods: Five cohort studies' participants ( = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated.

Results: Discovery ( = 6,820) and replication ( = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 × 10 []), cg10177197 (3.94 × 10 []), cg06500161 (2.67 × 10 []), cg27243685 (6.01 × 10 []), and cg05119988 (7.26 × 10 []). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and methylation were associated with downregulation, suggesting epigenetic regulation of expression. Further, outcomes insulin and HOMA-IR were significantly associated with expression.

Conclusions: This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins' effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to epigenetic regulation.
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http://dx.doi.org/10.2337/dc19-1828DOI Listing
April 2020

Diversity, compositional and functional differences between gut microbiota of children and adults.

Sci Rep 2020 01 23;10(1):1040. Epub 2020 Jan 23.

Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

The gut microbiota has been shown to play diverse roles in human health and disease although the underlying mechanisms have not yet been fully elucidated. Large cohort studies can provide further understanding into inter-individual differences, with more precise characterization of the pathways by which the gut microbiota influences human physiology and disease processes. Here, we aimed to profile the stool microbiome of children and adults from two population-based cohort studies, comprising 2,111 children in the age-range of 9 to 12 years (the Generation R Study) and 1,427 adult individuals in the range of 46 to 88 years of age (the Rotterdam Study). For the two cohorts, 16S rRNA gene profile datasets derived from the Dutch population were generated. The comparison of the two cohorts showed that children had significantly lower gut microbiome diversity. Furthermore, we observed higher relative abundances of genus Bacteroides in children and higher relative abundances of genus Blautia in adults. Predicted functional metagenome analysis showed an overrepresentation of the glycan degradation pathways, riboflavin (vitamin B2), pyridoxine (vitamin B6) and folate (vitamin B9) biosynthesis pathways in children. In contrast, the gut microbiome of adults showed higher abundances of carbohydrate metabolism pathways, beta-lactam resistance, thiamine (vitamin B1) and pantothenic (vitamin B5) biosynthesis pathways. A predominance of catabolic pathways in children (valine, leucine and isoleucine degradation) as compared to biosynthetic pathways in adults (valine, leucine and isoleucine biosynthesis) suggests a functional microbiome switch to the latter in adult individuals. Overall, we identified compositional and functional differences in gut microbiome between children and adults in a population-based setting. These microbiome profiles can serve as reference for future studies on specific human disease susceptibility in childhood, adulthood and specific diseased populations.
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http://dx.doi.org/10.1038/s41598-020-57734-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978381PMC
January 2020

Reply to P-A Dugué et al.

Am J Clin Nutr 2020 01;111(1):230-231

From the Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, Netherlands.

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http://dx.doi.org/10.1093/ajcn/nqz254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171229PMC
January 2020

Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study.

J Alzheimers Dis 2020 ;73(2):707-714

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped association between telomere length and risk of Alzheimer's disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13-2.23) for the lowest tertile and 1.47 (1.03-2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer's disease in the general population.
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http://dx.doi.org/10.3233/JAD-190759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029372PMC
November 2020

Evaluation of commonly used analysis strategies for epigenome- and transcriptome-wide association studies through replication of large-scale population studies.

Genome Biol 2019 11 14;20(1):235. Epub 2019 Nov 14.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

Background: A large number of analysis strategies are available for DNA methylation (DNAm) array and RNA-seq datasets, but it is unclear which strategies are best to use. We compare commonly used strategies and report how they influence results in large cohort studies.

Results: We tested the associations of DNAm and RNA expression with age, BMI, and smoking in four different cohorts (n = ~ 2900). By comparing strategies against the base model on the number and percentage of replicated CpGs for DNAm analyses or genes for RNA-seq analyses in a leave-one-out cohort replication approach, we find the choice of the normalization method and statistical test does not strongly influence the results for DNAm array data. However, adjusting for cell counts or hidden confounders substantially decreases the number of replicated CpGs for age and increases the number of replicated CpGs for BMI and smoking. For RNA-seq data, the choice of the normalization method, gene expression inclusion threshold, and statistical test does not strongly influence the results. Including five principal components or excluding correction of technical covariates or cell counts decreases the number of replicated genes.

Conclusions: Results were not influenced by the normalization method or statistical test. However, the correction method for cell counts, technical covariates, principal components, and/or hidden confounders does influence the results.
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http://dx.doi.org/10.1186/s13059-019-1878-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857161PMC
November 2019

Intestinal microbiome composition and its relation to joint pain and inflammation.

Nat Commun 2019 10 25;10(1):4881. Epub 2019 Oct 25.

Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Macrophage-mediated inflammation is thought to have a causal role in osteoarthritis-related pain and severity, and has been suggested to be triggered by endotoxins produced by the gastrointestinal microbiome. Here we investigate the relationship between joint pain and the gastrointestinal microbiome composition, and osteoarthritis-related knee pain in the Rotterdam Study; a large population based cohort study. We show that abundance of Streptococcus species is associated with increased knee pain, which we validate by absolute quantification of Streptococcus species. In addition, we replicate these results in 867 Caucasian adults of the Lifelines-DEEP study. Finally we show evidence that this association is driven by local inflammation in the knee joint. Our results indicate the microbiome is a possible therapeutic target for osteoarthritis-related knee pain.
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http://dx.doi.org/10.1038/s41467-019-12873-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814863PMC
October 2019

Validated inference of smoking habits from blood with a finite DNA methylation marker set.

Eur J Epidemiol 2019 Nov 7;34(11):1055-1074. Epub 2019 Sep 7.

Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUC 0.925 ± 0.021, AUC0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.
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http://dx.doi.org/10.1007/s10654-019-00555-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861351PMC
November 2019

An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis.

Nat Commun 2019 06 13;10(1):2581. Epub 2019 Jun 13.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.
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http://dx.doi.org/10.1038/s41467-019-10487-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565679PMC
June 2019

Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals.

Am J Clin Nutr 2019 08;110(2):437-450

Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.

Background: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans.

Objective: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes.

Methods: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes.

Results: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs.

Conclusions: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.
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http://dx.doi.org/10.1093/ajcn/nqz031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669135PMC
August 2019

A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease.

Diabetes 2019 05 1;68(5):1073-1083. Epub 2019 Apr 1.

Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding = 6.9 × 10) with replication at Bonferroni-corrected < 8.6 × 10 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 () with NAFLD ( = 2.5 × 10). Hypomethylation of the same CpG was also associated with risk for new-onset T2D ( = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.
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http://dx.doi.org/10.2337/DB18-1193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477898PMC
May 2019

Dissecting the association of autophagy-related genes with cardiovascular diseases and intermediate vascular traits: A population-based approach.

PLoS One 2019 25;14(3):e0214137. Epub 2019 Mar 25.

Department of Epidemiology and Biostatistics, Imperial College London, London, England.

Autophagy is involved in cellular homeostasis and maintenance and may play a role in cardiometabolic health. We aimed to elucidate the role of autophagy in cardiometabolic traits by investigating genetic variants and DNA methylation in autophagy-related genes in relation to cardiovascular diseases and related traits. To address this research question, we implemented a multidirectional approach using several molecular epidemiology tools, including genetic association analysis with genome wide association studies data and exome sequencing data and differential DNA methylation analysis. We investigated the 21 autophagy-related genes in relation to coronary artery disease and a number of cardiometabolic traits (blood lipids, blood pressure, glycemic traits, type 2 diabetes). We used data from the largest genome wide association studies as well as DNA methylation and exome sequencing data from the Rotterdam Study. Single-nucleotide polymorphism rs110389913 in AMBRA1 (p-value = 4.9×10-18) was associated with blood proinsulin levels, whereas rs6587988 in ATG4C and rs10439163 in ATG4D with lipid traits (ATG4C: p-value = 2.5×10-15 for total cholesterol and p-value = 3.1×10-18 for triglycerides, ATG4D: p-value = 9.9×10-12 for LDL and p-value = 1.3×10-10 for total cholesterol). Moreover, rs7635838 in ATG7 was associated with HDL (p-value = 1.9×10-9). Rs2447607 located in ATG7 showed association with systolic blood pressure and pulse pressure. Rs2424994 in MAP1LC3A was associated with coronary artery disease (p-value = 5.8×10-6). Furthermore, we identified association of an exonic variant located in ATG3 with diastolic blood pressure (p-value = 6.75×10-6). Using DNA methylation data, two CpGs located in ULK1 (p-values = 4.5×10-7 and 1×10-6) and two located in ATG4B (2×10-13 and 1.48×10-7) were significantly associated with both systolic and diastolic blood pressure. In addition one CpG in ATG4D was associated with HDL (p-value = 3.21×10-5). Our findings provide support for the role of autophagy in glucose and lipid metabolism, as well as blood pressure regulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214137PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433264PMC
December 2019

DNA methylation signatures of educational attainment.

NPJ Sci Learn 2018 23;3. Epub 2018 Mar 23.

1Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Educational attainment is a key behavioural measure in studies of cognitive and physical health, and socioeconomic status. We measured DNA methylation at 410,746 CpGs ( = 4152) and identified 58 CpGs associated with educational attainment at loci characterized by pleiotropic functions shared with neuronal, immune and developmental processes. Associations overlapped with those for smoking behaviour, but remained after accounting for smoking at many CpGs: Effect sizes were on average 28% smaller and genome-wide significant at 11 CpGs after adjusting for smoking and were 62% smaller in never smokers. We examined sources and biological implications of education-related methylation differences, demonstrating correlations with maternal prenatal folate, smoking and air pollution signatures, and associations with gene expression in cis, dynamic methylation in foetal brain, and correlations between blood and brain. Our findings show that the methylome of lower-educated people resembles that of smokers beyond effects of their own smoking behaviour and shows traces of various other exposures.
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http://dx.doi.org/10.1038/s41539-018-0020-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220239PMC
March 2018

Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults.

EBioMedicine 2018 Dec 13;38:206-216. Epub 2018 Nov 13.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health.

Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP).

Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels.

Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. FUND: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.
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http://dx.doi.org/10.1016/j.ebiom.2018.10.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306313PMC
December 2018

Are Bone Mineral Density and Fractures Related to the Incidence and Progression of Radiographic Osteoarthritis of the Knee, Hip, and Hand in Elderly Men and Women? The Rotterdam Study.

Arthritis Rheumatol 2019 03 9;71(3):361-369. Epub 2019 Feb 9.

Erasmus Medical Center, Rotterdam, The Netherlands.

Objective: To examine the longitudinal relationship between bone mineral density (BMD) and the incidence and progression of knee, hip, and hand osteoarthritis (OA), and to examine the relationship between prevalent vertebral and nonvertebral fractures and the incidence and progression of OA in elderly men and women in the Rotterdam Study.

Methods: Age- and sex-specific quartiles of baseline femoral neck BMD data were constructed for 4,154 subjects. Radiographs were scored for incidence and progression of knee and hip OA, and for incidence of hand OA. Prevalent vertebral fractures were scored using the McCloskey/Kanis method, and prevalent nonvertebral fractures were reported by baseline interview.

Results: Subjects in the highest quartile of femoral neck BMD had an increased risk of incident radiographic knee OA (ROA) (odds ratio [OR] 1.58 [95% confidence interval (95% CI) 1.14-2.18]), and an increased risk of incident hip ROA (OR 1.57 [95% CI 1.06-2.32]), compared to the lowest quartile. No significant relationship was found between high femoral neck BMD and progression of knee or hip ROA or the incidence of hand ROA. Prevalent vertebral and nonvertebral fractures were not related to an increase in the incidence or progression of knee or hip ROA. However, vertebral fractures were associated with incident hand ROA (OR 1.74 [95% CI 1.02-2.98]).

Conclusion: Results from the present study confirm earlier findings and thus provide strong evidence that high femoral neck BMD is a prognostic risk factor for the development of knee and hip ROA. Vertebral fractures were found to be a risk factor for incident hand ROA.
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http://dx.doi.org/10.1002/art.40735DOI Listing
March 2019

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

PLoS Genet 2018 09 27;14(9):e1007601. Epub 2018 Sep 27.

Department of Medicine, The Ohio State University, Columbus, Ohio, United States of America.

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).
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http://dx.doi.org/10.1371/journal.pgen.1007601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159857PMC
September 2018

DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis.

Blood 2018 10 24;132(17):1842-1850. Epub 2018 Jul 24.

Cardiovascular Health Research Unit, University of Washington, Seattle, WA.

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; = 6.6 10) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene () and the 3 fibrinogen subunit-encoding genes (, , and ) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.
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http://dx.doi.org/10.1182/blood-2018-02-831347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202911PMC
October 2018

Whole Blood Gene Expression Associated With Clinical Biological Age.

J Gerontol A Biol Sci Med Sci 2019 01;74(1):81-88

National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Massachusetts.

Background: Biologic age may better reflect an individual's rate of aging than chronologic age.

Methods: We conducted a transcriptome-wide association study with biologic age estimated with clinical biomarkers, which included: systolic blood pressure, forced expiratory volume at 1 second (FEV1), total cholesterol, fasting glucose, C-reactive protein, and serum creatinine. We assessed the association between the difference between biologic age and chronologic age (∆age) and gene expression in whole blood measured using the Affymetrix Human Exon 1.0st Array.

Results: Our discovery sample included 2,163 participants from the Framingham Offspring cohort (mean age 67 ± 9 years, 55% women). A total of 481 genes were significantly associated with ∆age (p < 2.8 × 10-6). Among them, 415 genes were validated (p < .05/481 = 1.0 × 10-4) in 2,946 participants from the Framingham Third Generation cohort (mean age 46 ± 9 years, 53% women). Many of the significant genes were involved in the ubiquitin-mediated proteolysis pathway. The replication in 414 Rotterdam Study participants (mean age 59 ± 8, 52% women) found 104 of 415 validated genes reached nominal significance (p < .05).

Conclusion: We identified and validated 415 genes associated with ∆age in a community-based cohort. Future functional characterization of the biologic age-related gene network may identify targets to test for interventions to delay aging in older adults.
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http://dx.doi.org/10.1093/gerona/gly164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298179PMC
January 2019