ORCID Profile
0000-0003-0585-6206
Current Organisation
Leiden University Medical Center
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Publisher: Impact Journals, LLC
Date: 04-12-2015
Publisher: Research Square Platform LLC
Date: 10-08-2021
DOI: 10.21203/RS.3.RS-688986/V1
Abstract: We performed a trans-ethnic Epigenome Wide Association study on 22,774 in iduals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We found 1,511 independent differentially methylated loci associated with CRP. These CpG sites showed correlation structures across chromosomes, and were primarily situated in euchromatin, depleted in CpG islands and enriched in transcription factor binding sites and genomic enhancer regions. Mendelian randomisation analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis revealed obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we found that a fully activated CpG signature, meaning that if all novel discovered CpGs would either be fully methylated or unmethylated depending on their CRP associated direction of effect, the risk of myocardial infarction would be increased by 20.3%, risk of T2D by 11.3% and the risk of COPD by 5.6%.
Publisher: Wiley
Date: 19-11-2013
DOI: 10.1111/ACEL.12160
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
Publisher: Public Library of Science (PLoS)
Date: 31-01-2013
Publisher: Springer Science and Business Media LLC
Date: 03-05-2022
DOI: 10.1038/S41467-022-29792-6
Abstract: We performed a multi-ethnic Epigenome Wide Association study on 22,774 in iduals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.
Publisher: Springer Science and Business Media LLC
Date: 12-06-2015
DOI: 10.1038/NCOMMS8208
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-01-2019
DOI: 10.1212/WNL.0000000000006851
Abstract: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10 −8 and LINC00539/ZDHHC20, p = 5.82 × 10 −9 . Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up s le or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( p value for BI, p [BI] = 9.38 × 10 −25 p [SSBI] = 5.23 × 10 −14 for hypertension), smoking ( p [BI] = 4.4 × 10 −10 p [SSBI] = 1.2 × 10 −4 ), diabetes ( p [BI] = 1.7 × 10 −8 p [SSBI] = 2.8 × 10 −3 ), previous cardiovascular disease ( p [BI] = 1.0 × 10 −18 p [SSBI] = 2.3 × 10 −7 ), stroke ( p [BI] = 3.9 × 10 −69 p [SSBI] = 3.2 × 10 −24 ), and MRI-defined white matter hyperintensity burden ( p [BI] = 1.43 × 10 −157 p [SSBI] = 3.16 × 10 −106 ), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( p ≤ 0.0022), without indication of directional pleiotropy. In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
Publisher: Public Library of Science (PLoS)
Date: 07-2015
Publisher: Springer Science and Business Media LLC
Date: 22-10-2003
Publisher: Public Library of Science (PLoS)
Date: 08-03-2011
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Impact Journals, LLC
Date: 10-01-2017
Publisher: Oxford University Press (OUP)
Date: 30-01-2021
DOI: 10.1093/HMG/DDAB023
Abstract: Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) in iduals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all s les. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Publisher: Springer Science and Business Media LLC
Date: 11-11-2015
Publisher: CMA Joule Inc.
Date: 05-11-2012
DOI: 10.1503/CMAJ.120233
Publisher: Elsevier BV
Date: 07-2015
Publisher: Springer Science and Business Media LLC
Date: 16-01-2013
Publisher: Springer Science and Business Media LLC
Date: 12-08-2019
DOI: 10.1038/S41598-019-47282-6
Abstract: Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 in iduals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological s les from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10 −6 ), methionine ( p-value = 9.2 × 10 −5 ), tyrosine ( p-value = 2.1 × 10 −4 ), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10 −4 ), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10 −4 ), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10 −4 ). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.
Publisher: Cambridge University Press (CUP)
Date: 08-2003
Publisher: Springer Science and Business Media LLC
Date: 26-10-2018
DOI: 10.1038/S41467-018-06356-1
Abstract: Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 in iduals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2020
DOI: 10.1007/S00401-019-02107-8
Abstract: The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
Publisher: Cambridge University Press (CUP)
Date: 04-2002
Publisher: Wiley
Date: 23-11-2012
DOI: 10.1111/ACEL.12015
Abstract: mTOR signalling is implicated in the development of disease and in lifespan extension in model organisms. This pathway has been associated with human diseases such as diabetes and cancer, but has not been investigated for its impact on longevity per se. Here, we investigated whether transcriptional variation within the mTOR pathway is associated with human longevity using whole-blood s les from the Leiden Longevity Study. This is a unique cohort of Dutch families with extended survival across generations, decreased morbidity and beneficial metabolic profiles in middle-age. By comparing mRNA levels of nonagenarians and middle-aged controls, the mTOR signalling gene set was found to associate with old age (P = 4.6 × 10(-7)). Single gene analysis showed that seven of 40 mTOR pathway genes had a significant differential expression of at least 5%. Of these, the RPTOR (Raptor) gene was found to be differentially expressed also when the offspring of nonagenarians was compared with their spouses, indicating association with familial longevity in middle-age. This association was not explained by variation between the groups in the prevalence of type 2 diabetes and cancer or glucose levels. Thus, the mTOR pathway not only plays a role in the regulation of disease and aging in animal models, but also in human health and longevity.
Publisher: BMJ
Date: 27-10-2012
DOI: 10.1136/ANNRHEUMDIS-2012-202013
Abstract: In idual metabolic characteristics and age-related changes may affect osteoarthritis (OA) risk as well as levels of potential OA biomarkers such as serum cartilage oligomeric protein (sCOMP) and urinary cross-linked C-telopeptide of type 2 collagen (uCTX2). We investigated hand OA and these putative OA biomarker characteristics at different ages in in iduals with a propensity for healthy ageing, in controls, and in patients with OA. We investigated hand radiological OA (ROA) and levels of sCOMP and uCTX2 in the Leiden Longevity Study, which consisted of the middle-aged offspring of long-lived sibling pairs as metabolically healthy agers and their partners as controls, and for ROA we compared patients with OA at multiple joint sites from the Genetics, osteoARthritis and Progression Study with the healthy agers and controls. Hand ROA mean scores were lower in the healthy agers than in controls. Lower hand ROA scores at higher ages were observed in healthy agers with low glucose levels. Furthermore, in healthy agers, a higher mean sCOMP level was observed than in controls. All study groups had higher sCOMP levels at higher chronological age. Likewise, uCTX2 levels were higher at higher chronological age in the controls and patients with OA, which was not observed in the healthy agers. Metabolic health in middle age is associated with less ROA and influences putative OA marker profiles, independently of chronological age. When used as OA biomarkers, it is relevant that independently of hand ROA status, uCTX2 is influenced by healthy metabolism and sCOMP is higher at higher chronological age.
Publisher: Springer Science and Business Media LLC
Date: 03-2004
Publisher: The Royal Society
Date: 12-01-2011
Abstract: In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: Elsevier BV
Date: 04-2016
Publisher: Springer Science and Business Media LLC
Date: 18-04-2017
DOI: 10.1038/TP.2017.73
Abstract: The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts ( N =17 052 mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST ( β =0.051 per s.d.-increase of TL 95% confidence interval (CI): 0.024, 0.077 P =0.0002), and MMSE ( β =0.025 95% CI: 0.002, 0.047 P =0.03), and faster STROOP ( β =−0.053 95% CI: −0.087, −0.018 P =0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers ( β =0.081 95% CI: 0.045, 0.117 P =1.0 × 10 −5 ), whereas carriers performed better in STROOP ( β =−0.074 95% CI: −0.140, −0.009 P =0.03). Causal associations were found for STROOP only ( β =−0.598 per s.d.-increase of TL 95% CI: −1.125, −0.072 P =0.026), with a larger effect in ɛ4-carriers ( β =−0.699 95% CI: −1.330, −0.069 P =0.03). Two-s le replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2011
Publisher: Public Library of Science (PLoS)
Date: 07-02-2013
Publisher: Springer Science and Business Media LLC
Date: 13-07-2005
Abstract: Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four s les with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the s le-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1 cM of major candidate genes, namely APOB (LOD=2.1), LDLR (LOD=1.9) and APOE (LOD=1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2018
Publisher: Impact Journals, LLC
Date: 07-07-2017
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NCOMMS10494
Abstract: Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin ( LEP ) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 in iduals and followed up loci reaching P −6 in 19,979 additional in iduals. We identify five loci robustly associated ( P × 10 −8 ) with leptin levels in/near LEP , SLC32A1 , GCKR , CCNL1 and FTO . Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin , a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2018
DOI: 10.1038/S41467-017-02662-2
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci ( GC, NADSYN1/DHCR7, CYP2R1, CYP24A1 ). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery s le size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants ( P = 4.7×10 −9 at rs8018720 in SEC23A , and P = 1.9×10 −14 at rs10745742 in AMDHD1 ). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2015
DOI: 10.1038/NG.3300
Publisher: Springer Science and Business Media LLC
Date: 08-06-2014
DOI: 10.1038/NG.3004
Publisher: EMBO
Date: 21-10-2019
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: Springer Science and Business Media LLC
Date: 08-12-2020
DOI: 10.1038/S41467-020-19111-2
Abstract: White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older in iduals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk in iduals and for genetically-informed prioritization of drug targets for prevention trials.
No related grants have been discovered for Marian Beekman.