111 results on '"Meurs, J.B.J. (Joyce) van"'
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2. Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits
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Maas, S.C.E., Mens, M.M.J., Kuhnel, B. (Brigitte), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Peters, A. (Annette), Prokisch, H. (Holger), Herder, C. (Christian), Grallert, H. (Harald), Kunze, S., Waldenberger, M. (Melanie), Kavousi, M. (Maryam), Kayser, M.H. (Manfred), Ghanbari, M. (Mohsen), Maas, S.C.E., Mens, M.M.J., Kuhnel, B. (Brigitte), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Peters, A. (Annette), Prokisch, H. (Holger), Herder, C. (Christian), Grallert, H. (Harald), Kunze, S., Waldenberger, M. (Melanie), Kavousi, M. (Maryam), Kayser, M.H. (Manfred), and Ghanbari, M. (Mohsen)
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Background: Tobacco smoking is a well-known modifable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifcations, which could afect 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 fndings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identifed both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifcally, 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 identifed 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 efect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. Conclusions: Our study indicates that smoking
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- 2020
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3. Serum fatty acid chain length associates with prevalent symptomatic end-stage osteoarthritis, independent of BMI
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Meessen, J.M.T.A., Saberi-Hosnijeh, F., Bomer, N. (Nils), den Hollander, W, Bom, J.G., van Hilten, J.A., Spil, W.E. (Willem) van, So-Osman, C. (Cynthia), Uitterlinden, A.G. (André), Kloppenburg, M. (Margreet), Nelissen, R.G.H.H. (Rob), Duijn, C.M., Slagboom, PE, Meurs, J.B.J. (Joyce) van, Meulenbelt, I. (Ingrid), Meessen, J.M.T.A., Saberi-Hosnijeh, F., Bomer, N. (Nils), den Hollander, W, Bom, J.G., van Hilten, J.A., Spil, W.E. (Willem) van, So-Osman, C. (Cynthia), Uitterlinden, A.G. (André), Kloppenburg, M. (Margreet), Nelissen, R.G.H.H. (Rob), Duijn, C.M., Slagboom, PE, Meurs, J.B.J. (Joyce) van, and Meulenbelt, I. (Ingrid)
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- 2020
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4. Reply to P-A Dugué et al
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Mandaviya, P.R. (Pooja), Meurs, J.B.J. (Joyce) van, Heil, S.G. (Sandra), Mandaviya, P.R. (Pooja), Meurs, J.B.J. (Joyce) van, and Heil, S.G. (Sandra)
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- 2020
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5. The tissue-specific aspect of genome-wide DNA methylation in newborn and placental tissues: Implications for epigenetic epidemiologic studies
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Herzog, E.M. (Emilie), Eggink, A.J. (Alex), Willemsen, S.P. (Sten), Slieker, R. (Roderick), Felix, J.F. (Janine), Stubbs, A.P. (Andrew), Spek, P.J. (Peter) van der, Meurs, J.B.J. (Joyce) van, Heijmans, B.T. (Bastiaan T.), Steegers-Theunissen, R.P.M. (Régine P. M.), Herzog, E.M. (Emilie), Eggink, A.J. (Alex), Willemsen, S.P. (Sten), Slieker, R. (Roderick), Felix, J.F. (Janine), Stubbs, A.P. (Andrew), Spek, P.J. (Peter) van der, Meurs, J.B.J. (Joyce) van, Heijmans, B.T. (Bastiaan T.), and Steegers-Theunissen, R.P.M. (Régine P. M.)
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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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- 2020
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6. Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference
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Hop, P.J. (Paul J.), Luijk, R. (René), Daxinger, L. (Lucia), Iterson, M. (Maarten) van, Dekkers, K.F. (Koen F.), Jansen, R. (Rick), Meurs, J.B.J. (Joyce) van, 't Hoen, P.A.C. (Peter A C), Ikram, M.A. (Arfan), van Greevenbroek, M.M.J. (Marleen M J), Boomsma, D.I. (Dorret), Slagboom, P.E. (Eline), Veldink, J.H. (Jan), Zwet, E.W. (Erik) van, Heijmans, B.T. (Bastiaan T.), Hop, P.J. (Paul J.), Luijk, R. (René), Daxinger, L. (Lucia), Iterson, M. (Maarten) van, Dekkers, K.F. (Koen F.), Jansen, R. (Rick), Meurs, J.B.J. (Joyce) van, 't Hoen, P.A.C. (Peter A C), Ikram, M.A. (Arfan), van Greevenbroek, M.M.J. (Marleen M J), Boomsma, D.I. (Dorret), Slagboom, P.E. (Eline), Veldink, J.H. (Jan), Zwet, E.W. (Erik) van, and Heijmans, B.T. (Bastiaan T.)
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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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- 2020
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7. Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency
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Suratannon, N. (Narissara), van Wijck, R.T.A. (Rogier T. A.), Broer, L. (Linda), Xue, L. (Laixi), Meurs, J.B.J. (Joyce) van, Barendregt, B.H. (Barbara), Burg, M. (Mirjam) van der, Dik, W.A. (Willem), Chatchatee, P. (Pantipa), Langerak, A.W. (Anton), Swagemakers, S.M.A. (Sigrid), Goos, J.A.C. (Jacqueline), Mathijssen, I.M.J. (Irene M. J.), Dalm, V.A.S.H. (Virgil), Suphapeetiporn, K. (Kanya), Heezen, K. (Kim), Drabwell, J. (Jose), Uitterlinden, A.G. (André), Spek, P.J. (Peter) van der, van Hagen, P.M. (P. Martin), Suratannon, N. (Narissara), van Wijck, R.T.A. (Rogier T. A.), Broer, L. (Linda), Xue, L. (Laixi), Meurs, J.B.J. (Joyce) van, Barendregt, B.H. (Barbara), Burg, M. (Mirjam) van der, Dik, W.A. (Willem), Chatchatee, P. (Pantipa), Langerak, A.W. (Anton), Swagemakers, S.M.A. (Sigrid), Goos, J.A.C. (Jacqueline), Mathijssen, I.M.J. (Irene M. J.), Dalm, V.A.S.H. (Virgil), Suphapeetiporn, K. (Kanya), Heezen, K. (Kim), Drabwell, J. (Jose), Uitterlinden, A.G. (André), Spek, P.J. (Peter) van der, and van Hagen, P.M. (P. Martin)
- Abstract
Background: 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. Methods: 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), we
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- 2020
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8. Intestinal microbiome composition and its relation to joint pain and inflammation
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Boer, C.G. (Cindy), Radjabzadeh, D. (Djawad), Medina-Gomez, M.C. (Carolina), Garmaeva, S. (Sanzhima), Schiphof, D. (Dieuwke), Arp, P.P. (Pascal), Koet, T. (Thomas), Kurilshikov, A. (Alexander), Fu, J. (Jingyuan), Ikram, M.A. (Arfan), Bierma-Zeinstra, S.M. (Sita), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Zhernakova, A. (Alexandra), Meurs, J.B.J. (Joyce) van, Boer, C.G. (Cindy), Radjabzadeh, D. (Djawad), Medina-Gomez, M.C. (Carolina), Garmaeva, S. (Sanzhima), Schiphof, D. (Dieuwke), Arp, P.P. (Pascal), Koet, T. (Thomas), Kurilshikov, A. (Alexander), Fu, J. (Jingyuan), Ikram, M.A. (Arfan), Bierma-Zeinstra, S.M. (Sita), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Zhernakova, A. (Alexandra), and Meurs, J.B.J. (Joyce) van
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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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- 2019
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9. Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy
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Ince-Askan, H. (Hilal), Mandaviya, P.R. (Pooja), Felix, J.F. (Janine), Duijts, L. (Liesbeth), Meurs, J.B.J. (Joyce) van, Hazes, J.M.W. (Mieke), Dolhain, R.J.E.M. (Radboud), Ince-Askan, H. (Hilal), Mandaviya, P.R. (Pooja), Felix, J.F. (Janine), Duijts, L. (Liesbeth), Meurs, J.B.J. (Joyce) van, Hazes, J.M.W. (Mieke), and Dolhain, R.J.E.M. (Radboud)
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Objectives The main objective of this study was to determine whether the DNA methylation profile of children born to mothers with rheumatoid arthritis (RA) is different from that of children born to mothers from the general population. In addition, we aimed to determine whether any differences in methylation are associated with maternal RA disease activity or medication use during pregnancy. Methods For this study, genome-wide DNA methylation was measured at cytosine-phosphateguanine (CpG) sites, using the Infinium Illumina HumanMethylation 450K BeadChip, in 80 blood samples from children (mean age=6.8 years) born to mothers with RA. As controls, blood samples from 354 children (mean age=6.0 years) from the population-based Generation R Study were used. Linear mixed models were performed to investigate differential methylation between the groups, corrected for relevant confounders. Results A total of 147 CpGs were differentially methylated between blood samples of children born to mothers with RA and the control blood samples. The five most significantly associated CpGs were cg06642177, cg08867893, cg06778273, cg07786668 and cg20116574. The differences in methylation were not associated with maternal RA disease activity or medication use during pregnancy. Conclusions DNA methylation at 147 CpGs differed between children born to mothers with RA and children born to mothers from the general population. It remains unknown whether the identified associations are causal, and if so whether they are caused by the disease or treatment. More research, including replication of these results, is necessary in order to strengthen the relevance of our findings for the later-life health of children born to mothers with RA
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- 2019
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10. Evaluation of commonly used analysis strategies for epigenome- and transcriptome-wide association studies through replication of large-scale population studies
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van Rooij, J. (Jeroen), Mandaviya, P.R. (Pooja), Claringbould, A. (Annique), Felix, J.F. (Janine), Dongen, J. (Jenny) van, Jansen, R. (Rick), Franke, L. (Lude), 't Hoen, P.A.C. (Peter A C), Heijmans, B. (Bas), Meurs, J.B.J. (Joyce) van, van Rooij, J. (Jeroen), Mandaviya, P.R. (Pooja), Claringbould, A. (Annique), Felix, J.F. (Janine), Dongen, J. (Jenny) van, Jansen, R. (Rick), Franke, L. (Lude), 't Hoen, P.A.C. (Peter A C), Heijmans, B. (Bas), and Meurs, J.B.J. (Joyce) van
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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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- 2019
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11. Validated inference of smoking habits from blood with a finite DNA methylation marker set
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Maas, S.C.E. (Silvana C. E.), Vidaki, A. (Athina), Wilson, R. (Rory), Teumer, A. (Alexander), Liu, F. (Fan), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Boomsma, D.I. (Dorret), Geus, E.J.C. (Eco) de, Willemsen, G.A.H.M. (Gonneke), Dongen, J. (Jenny) van, Kallen, C.J. van der, Slagboom, P.E. (Eline), Beekman, M. (Marian), Heemst, D. (Diana) van, Berg, L.H. (Leonard) van den, Duijts, L. (Liesbeth), Jaddoe, V.W.V. (Vincent), Ladwig, K.-H. (Karl-Heinz), Kunze, S. (Sonja), Peters, A. (Annette), Ikram, M.A. (Arfan), Grabe, H.J. (Hans Jörgen), Felix, J.F. (Janine), Waldenberger, M. (Melanie), Franco, O.H. (Oscar), Ghanbari, M. (Mohsen), Kayser, M.H. (Manfred), Maas, S.C.E. (Silvana C. E.), Vidaki, A. (Athina), Wilson, R. (Rory), Teumer, A. (Alexander), Liu, F. (Fan), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Boomsma, D.I. (Dorret), Geus, E.J.C. (Eco) de, Willemsen, G.A.H.M. (Gonneke), Dongen, J. (Jenny) van, Kallen, C.J. van der, Slagboom, P.E. (Eline), Beekman, M. (Marian), Heemst, D. (Diana) van, Berg, L.H. (Leonard) van den, Duijts, L. (Liesbeth), Jaddoe, V.W.V. (Vincent), Ladwig, K.-H. (Karl-Heinz), Kunze, S. (Sonja), Peters, A. (Annette), Ikram, M.A. (Arfan), Grabe, H.J. (Hans Jörgen), Felix, J.F. (Janine), Waldenberger, M. (Melanie), Franco, O.H. (Oscar), Ghanbari, M. (Mohsen), and Kayser, M.H. (Manfred)
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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
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- 2019
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12. An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis
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Liu, J. (Jun), Carnero-Montoro, E. (Elena), Dongen, J. (Jenny) van, Lent, S. (Samantha), Prokić, I. (Ivana), Ligthart, S. (Symen), Tsai, P.-C. (Pei-Chien), Martin, T.C. (Tiphaine C.), Mandaviya, P.R. (Pooja), Jansen, R. (Rick), Peters, M.A.D. (Marjolein), Duijts, L. (Liesbeth), Jaddoe, V.W.V. (Vincent), Tiemeier, H.W. (Henning), Felix, J.F. (Janine), Willemsen, G.A.H.M. (Gonneke), Geus, E.J.C. (Eco) de, Chu, A.Y. (Audrey), Levy, D. (Daniel), Hwang, S.-J. (Shih-Jen), Bressler, J. (Jan), Gondalia, R. (Rahul), Salfati, E. (Elias), Herder, C. (Christian), Hidalgo, B. (Bertha), Tanaka, T. (Toshiko), Moore, A.Z. (Ann Zenobia), Lemaitre, R.N. (Rozenn N.), Jhun, M.A. (Min A.), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Bandinelli, S. (Stefania), Ferrucci, L. (Luigi), Arnett, D.K. (Donna), Grallert, H. (Harald), Assimes, T.L. (Themistocles L.), Hou, L. (Lifang), Baccarelli, A.A. (Andrea), Whitsel, E.A. (Eric), van Dijk, K.W. (Ko Willems), Amin, N. (Najaf), Uitterlinden, A.G. (André), Sijbrands, E.J.G. (Eric), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Spector, T.D. (Timothy), Hivert, M.-F. (Marie-France), Rotter, J.I. (Jerome I.), Meigs, J.B. (James), Palmer, C.N.A. (Colin), Meurs, J.B.J. (Joyce) van, Isaacs, A.J. (Aaron), Boomsma, D.I. (Dorret I.), Bell, J.T. (Jordana T.), Demirkan, A. (Ayşe), Duijn, C.M. (Cornelia) van, Liu, J. (Jun), Carnero-Montoro, E. (Elena), Dongen, J. (Jenny) van, Lent, S. (Samantha), Prokić, I. (Ivana), Ligthart, S. (Symen), Tsai, P.-C. (Pei-Chien), Martin, T.C. (Tiphaine C.), Mandaviya, P.R. (Pooja), Jansen, R. (Rick), Peters, M.A.D. (Marjolein), Duijts, L. (Liesbeth), Jaddoe, V.W.V. (Vincent), Tiemeier, H.W. (Henning), Felix, J.F. (Janine), Willemsen, G.A.H.M. (Gonneke), Geus, E.J.C. (Eco) de, Chu, A.Y. (Audrey), Levy, D. (Daniel), Hwang, S.-J. (Shih-Jen), Bressler, J. (Jan), Gondalia, R. (Rahul), Salfati, E. (Elias), Herder, C. (Christian), Hidalgo, B. (Bertha), Tanaka, T. (Toshiko), Moore, A.Z. (Ann Zenobia), Lemaitre, R.N. (Rozenn N.), Jhun, M.A. (Min A.), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Bandinelli, S. (Stefania), Ferrucci, L. (Luigi), Arnett, D.K. (Donna), Grallert, H. (Harald), Assimes, T.L. (Themistocles L.), Hou, L. (Lifang), Baccarelli, A.A. (Andrea), Whitsel, E.A. (Eric), van Dijk, K.W. (Ko Willems), Amin, N. (Najaf), Uitterlinden, A.G. (André), Sijbrands, E.J.G. (Eric), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Spector, T.D. (Timothy), Hivert, M.-F. (Marie-France), Rotter, J.I. (Jerome I.), Meigs, J.B. (James), Palmer, C.N.A. (Colin), Meurs, J.B.J. (Joyce) van, Isaacs, A.J. (Aaron), Boomsma, D.I. (Dorret I.), Bell, J.T. (Jordana T.), Demirkan, A. (Ayşe), and Duijn, C.M. (Cornelia) van
- Abstract
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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- 2019
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13. RNA-Seq in 296 phased trios provides a high-resolution map of genomic imprinting
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Jadhav, B. (Bharati), Monajemi, R. (Ramin), Gagalova, K.K. (Kristina K.), Ho, D. (Daniel), Draisma, G. (Gerrit), Wiel, M.A. (Mark) van de, Franke, L. (Lude), Heijmans, B.T. (Bastiaan T.), Meurs, J.B.J. (Joyce) van, Jansen, R. (Rick), T'Hoen, P.A.C. (Peter A. C.), Sharp, A.J. (Andrew), Kielbasa, S.M. (Szymon M.), Jadhav, B. (Bharati), Monajemi, R. (Ramin), Gagalova, K.K. (Kristina K.), Ho, D. (Daniel), Draisma, G. (Gerrit), Wiel, M.A. (Mark) van de, Franke, L. (Lude), Heijmans, B.T. (Bastiaan T.), Meurs, J.B.J. (Joyce) van, Jansen, R. (Rick), T'Hoen, P.A.C. (Peter A. C.), Sharp, A.J. (Andrew), and Kielbasa, S.M. (Szymon M.)
- Abstract
Background: Identification of imprinted genes, demonstrating a consistent preference towards the paternal or maternal allelic expression, is important for the understanding of gene expression regulation during embryonic development and of the molecular basis of developmental disorders with a parent-of-origin effect. Combining allelic analysis of RNA-Seq data with phased genotypes in family trios provides a powerful method to detect parent-of-origin biases in gene expression. Results: We report findings in 296 family trios from two large studies: 165 lymphoblastoid cell lines from the 1000 Genomes Project and 131 blood samples from the Genome of the Netherlands (GoNL) participants. Based on parental haplotypes, we identified > 2.8 million transcribed heterozygous SNVs phased for parental origin and developed a robust statistical framework for measuring allelic expression. We identified a total of 45 imprinted genes and one imprinted unannotated transcript, including multiple imprinted transcripts showing incomplete parental expression bias that was located adjacent to strongly imprinted genes. For example, PXDC1, a gene which lies adjacent to the paternally expressed gene FAM50B, shows a 2:1 paternal expression bias. Other imprinted genes had promoter regions that coincide with sites of parentally biased DNA methylation identified in the blood from uniparental disomy (UPD) samples, thus providing independent validation of our results. Using the stranded nature of the RNA-Seq data in lymphoblastoid cell lines, we identified multiple loci with overlapping sense/antisense transcripts, of which one is expressed paternally and the other maternally. Using a sliding window approach, we searched for imprinted expression across the entire genome, identifying a novel imprinted putative lncRNA in 13q21.2. Overall, we identified 7 transcripts showing parental bias in gene expression which were not reported in 4 other recent RNA-Seq studies of imprinting. Conclusions: Our methods
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- 2019
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14. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
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Porcu, E. (Eleonora), Rüeger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Heijmans, B.T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G.W. (Grant), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Slagboom, P.E. (Eline), Stehouwer, C.D. (Coen), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), ‘t Hoen, P.A.C. (Peter A. C.), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), van Dongen, J. (Jenny), Iterson, M. (Maarten) van, Meurs, J. (J.) van, Veldink, J.H. (Jan), Verlouw, J.A.M. (Joost), Visscher, P.M. (Peter M.), Völker, U. (Uwe), Võsa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D.I. (Dorret), Bot, J.J. (Jan), Deelen, J. (Joris), Hofman, B.A. (Bert A.), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Bonder, M.J. (Marc), Jhamai, P.M. (Mila), Kielbasa, S.M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (René), Mei, H. (Hailiang), Moed, H. (Heleen), Nooren, I. (Irene), Pool, R. (Reńe), Schalkwijk, C.G. (Casper), Stehouwer, C.D.A. (Coen D. A.), Suchiman, H.E.D. (H. Eka D.), Swertz, M.A. (Morris A.), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Berg, L.H. (Leonard) van den, Breggen, R. (Ruud) van der, Kallen, C.J. van der, Dijk, F. (Freerk) van, Dongen, J. (Jenny) van, Duijn, C.M. (Cornelia) van, Van Galen, M. (Michiel), van Greevenbroek, M.M.J. (Marleen M. J.), Heemst, D. (Diana) van, Meurs, J.B.J. (Joyce) van, van Rooij, J. (Jeroen), van’t Hof, P. (Peter), Zwet, E.W. (Erik) van, Vermaat, M. (Martijn), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Zhernakova, D.V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F.A. (Federico A.), Reymond, A. (Alexandre), Kutalik, Z. (Zoltán), Porcu, E. (Eleonora), Rüeger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Heijmans, B.T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G.W. (Grant), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Slagboom, P.E. (Eline), Stehouwer, C.D. (Coen), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), ‘t Hoen, P.A.C. (Peter A. C.), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), van Dongen, J. (Jenny), Iterson, M. (Maarten) van, Meurs, J. (J.) van, Veldink, J.H. (Jan), Verlouw, J.A.M. (Joost), Visscher, P.M. (Peter M.), Völker, U. (Uwe), Võsa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D.I. (Dorret), Bot, J.J. (Jan), Deelen, J. (Joris), Hofman, B.A. (Bert A.), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Bonder, M.J. (Marc), Jhamai, P.M. (Mila), Kielbasa, S.M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (René), Mei, H. (Hailiang), Moed, H. (Heleen), Nooren, I. (Irene), Pool, R. (Reńe), Schalkwijk, C.G. (Casper), Stehouwer, C.D.A. (Coen D. A.), Suchiman, H.E.D. (H. Eka D.), Swertz, M.A. (Morris A.), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Berg, L.H. (Leonard) van den, Breggen, R. (Ruud) van der, Kallen, C.J. van der, Dijk, F. (Freerk) van, Dongen, J. (Jenny) van, Duijn, C.M. (Cornelia) van, Van Galen, M. (Michiel), van Greevenbroek, M.M.J. (Marleen M. J.), Heemst, D. (Diana) van, Meurs, J.B.J. (Joyce) van, van Rooij, J. (Jeroen), van’t Hof, P. (Peter), Zwet, E.W. (Erik) van, Vermaat, M. (Martijn), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Zhernakova, D.V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F.A. (Federico A.), Reymond, A. (Alexandre), and Kutalik, Z. (Zoltán)
- Abstract
Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majo
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- 2019
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15. Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults
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Parmar, P. (Priyanka), Lowry, E. (Estelle), Cugliari, G. (Giovanni), Suderman, M.J. (Matthew J.), Wilson, R. (Rory), Karhunen, V. (Ville), Andrew, T. (Toby), Wiklund, P. (Petri), Wielscher, M. (Matthias), Guarrera, S. (Simonetta), Teumer, A. (Alexander), Lehne, B. (Benjamin), Milani, L. (Lili), de Klein, N. (Niek), Mishra, P.P. (Pashupati P.), Melton, P.E. (Phillip E.), Mandaviya, P.R. (Pooja), Kasela, S. (Silva), Nano, J. (Jana), Zhang, W. (Weihua), Zhang, Y. (Yan), Uitterlinden, A.G. (André), Peters, A. (Annette), Schöttker, B. (Ben), Gieger, C. (Christian), Anderson, D. (Denise), Boomsma, D.I. (Dorret I.), Grabe, H.J. (Hans Jörgen), Panico, S. (Salvatore), Veldink, J.H. (Jan), Meurs, J.B.J. (Joyce) van, Berg, L.H. (Leonard) van den, Beilin, L.J. (Lawrence), Franke, L. (Lude), Loh, M. (Marie), Greevenbroek, M.M. van, Nauck, M. (Matthias), Kähönen, M. (Mika), Hurme, M. (Mikko), Raitakari, O. (Olli), Franco, O.H. (Oscar), Slagboom, P.E. (Eline), van der Harst, P. (Pim), Kunze, S. (Sonja), Felix, S.B. (Stephan), Zhang, T. (Tao), Chen, W. (Wei), Mori, T.A. (Trevor A.), Bonnefond, A. (Amélie), Heijmans, B.T. (Bastiaan T.), Muka, T. (Taulant), Kooner, J.S. (Jaspal S.), Fischer, K. (Krista), Waldenberger, M. (Melanie), Froguel, P. (Philippe), Huang, R.-C. (Rae-Chi), Lehtimäki, T. (Terho), Rathmann, W. (Wolfgang), Relton, C.L. (Caroline), Matullo, G., Brenner, H. (Hermann), Verweij, N. (Niek), Li, S. (Shengxu), Chambers, J.C. (John C.), Järvelin, M.-R. (Marjo-Riitta), Sebert, S. (Sylvain), Parmar, P. (Priyanka), Lowry, E. (Estelle), Cugliari, G. (Giovanni), Suderman, M.J. (Matthew J.), Wilson, R. (Rory), Karhunen, V. (Ville), Andrew, T. (Toby), Wiklund, P. (Petri), Wielscher, M. (Matthias), Guarrera, S. (Simonetta), Teumer, A. (Alexander), Lehne, B. (Benjamin), Milani, L. (Lili), de Klein, N. (Niek), Mishra, P.P. (Pashupati P.), Melton, P.E. (Phillip E.), Mandaviya, P.R. (Pooja), Kasela, S. (Silva), Nano, J. (Jana), Zhang, W. (Weihua), Zhang, Y. (Yan), Uitterlinden, A.G. (André), Peters, A. (Annette), Schöttker, B. (Ben), Gieger, C. (Christian), Anderson, D. (Denise), Boomsma, D.I. (Dorret I.), Grabe, H.J. (Hans Jörgen), Panico, S. (Salvatore), Veldink, J.H. (Jan), Meurs, J.B.J. (Joyce) van, Berg, L.H. (Leonard) van den, Beilin, L.J. (Lawrence), Franke, L. (Lude), Loh, M. (Marie), Greevenbroek, M.M. van, Nauck, M. (Matthias), Kähönen, M. (Mika), Hurme, M. (Mikko), Raitakari, O. (Olli), Franco, O.H. (Oscar), Slagboom, P.E. (Eline), van der Harst, P. (Pim), Kunze, S. (Sonja), Felix, S.B. (Stephan), Zhang, T. (Tao), Chen, W. (Wei), Mori, T.A. (Trevor A.), Bonnefond, A. (Amélie), Heijmans, B.T. (Bastiaan T.), Muka, T. (Taulant), Kooner, J.S. (Jaspal S.), Fischer, K. (Krista), Waldenberger, M. (Melanie), Froguel, P. (Philippe), Huang, R.-C. (Rae-Chi), Lehtimäki, T. (Terho), Rathmann, W. (Wolfgang), Relton, C.L. (Caroline), Matullo, G., Brenner, H. (Hermann), Verweij, N. (Niek), Li, S. (Shengxu), Chambers, J.C. (John C.), Järvelin, M.-R. (Marjo-Riitta), and Sebert, S. (Sylvain)
- Abstract
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 × 10−7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10−8 < 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
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- 2018
- Full Text
- View/download PDF
16. Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults
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Parmar, P. (Priyanka), Lowry, E. (Estelle), Cugliari, G. (Giovanni), Suderman, M.J. (Matthew J.), Wilson, R. (Rory), Karhunen, V. (Ville), Andrew, T. (Toby), Wiklund, P. (Petri), Wielscher, M. (Matthias), Guarrera, S. (Simonetta), Teumer, A. (Alexander), Lehne, B. (Benjamin), Milani, L. (Lili), de Klein, N. (Niek), Mishra, P.P. (Pashupati P.), Melton, P.E. (Phillip E.), Mandaviya, P.R. (Pooja), Kasela, S. (Silva), Nano, J. (Jana), Zhang, W. (Weihua), Zhang, Y. (Yan), Uitterlinden, A.G. (André), Peters, A. (Annette), Schöttker, B. (Ben), Gieger, C. (Christian), Anderson, D. (Denise), Boomsma, D.I. (Dorret I.), Grabe, H.J. (Hans Jörgen), Panico, S. (Salvatore), Veldink, J.H. (Jan), Meurs, J.B.J. (Joyce) van, Berg, L.H. (Leonard) van den, Beilin, L.J. (Lawrence), Franke, L. (Lude), Loh, M. (Marie), Greevenbroek, M.M. van, Nauck, M. (Matthias), Kähönen, M. (Mika), Hurme, M. (Mikko), Raitakari, O. (Olli), Franco, O.H. (Oscar), Slagboom, P.E. (Eline), van der Harst, P. (Pim), Kunze, S. (Sonja), Felix, S.B. (Stephan), Zhang, T. (Tao), Chen, W. (Wei), Mori, T.A. (Trevor A.), Bonnefond, A. (Amélie), Heijmans, B.T. (Bastiaan T.), Muka, T. (Taulant), Kooner, J.S. (Jaspal S.), Fischer, K. (Krista), Waldenberger, M. (Melanie), Froguel, P. (Philippe), Huang, R.-C. (Rae-Chi), Lehtimäki, T. (Terho), Rathmann, W. (Wolfgang), Relton, C.L. (Caroline), Matullo, G., Brenner, H. (Hermann), Verweij, N. (Niek), Li, S. (Shengxu), Chambers, J.C. (John C.), Järvelin, M.-R. (Marjo-Riitta), Sebert, S. (Sylvain), Parmar, P. (Priyanka), Lowry, E. (Estelle), Cugliari, G. (Giovanni), Suderman, M.J. (Matthew J.), Wilson, R. (Rory), Karhunen, V. (Ville), Andrew, T. (Toby), Wiklund, P. (Petri), Wielscher, M. (Matthias), Guarrera, S. (Simonetta), Teumer, A. (Alexander), Lehne, B. (Benjamin), Milani, L. (Lili), de Klein, N. (Niek), Mishra, P.P. (Pashupati P.), Melton, P.E. (Phillip E.), Mandaviya, P.R. (Pooja), Kasela, S. (Silva), Nano, J. (Jana), Zhang, W. (Weihua), Zhang, Y. (Yan), Uitterlinden, A.G. (André), Peters, A. (Annette), Schöttker, B. (Ben), Gieger, C. (Christian), Anderson, D. (Denise), Boomsma, D.I. (Dorret I.), Grabe, H.J. (Hans Jörgen), Panico, S. (Salvatore), Veldink, J.H. (Jan), Meurs, J.B.J. (Joyce) van, Berg, L.H. (Leonard) van den, Beilin, L.J. (Lawrence), Franke, L. (Lude), Loh, M. (Marie), Greevenbroek, M.M. van, Nauck, M. (Matthias), Kähönen, M. (Mika), Hurme, M. (Mikko), Raitakari, O. (Olli), Franco, O.H. (Oscar), Slagboom, P.E. (Eline), van der Harst, P. (Pim), Kunze, S. (Sonja), Felix, S.B. (Stephan), Zhang, T. (Tao), Chen, W. (Wei), Mori, T.A. (Trevor A.), Bonnefond, A. (Amélie), Heijmans, B.T. (Bastiaan T.), Muka, T. (Taulant), Kooner, J.S. (Jaspal S.), Fischer, K. (Krista), Waldenberger, M. (Melanie), Froguel, P. (Philippe), Huang, R.-C. (Rae-Chi), Lehtimäki, T. (Terho), Rathmann, W. (Wolfgang), Relton, C.L. (Caroline), Matullo, G., Brenner, H. (Hermann), Verweij, N. (Niek), Li, S. (Shengxu), Chambers, J.C. (John C.), Järvelin, M.-R. (Marjo-Riitta), and Sebert, S. (Sylvain)
- Abstract
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 × 10−7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10−8 < 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
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- 2018
- Full Text
- View/download PDF
17. Development of a prediction model for future risk of radiographic hip osteoarthritis
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Saberi Hosnijeh, F. (Fatemeh), Kavousi, M. (Maryam), Boer, C.G. (C. G.), Uitterlinden, A.G. (André), Hofman, A. (Albert), Reijman, M. (Max), Oei, E.H.G. (Edwin), Bierma-Zeinstra, S.M. (Sita), Meurs, J.B.J. (Joyce) van, Saberi Hosnijeh, F. (Fatemeh), Kavousi, M. (Maryam), Boer, C.G. (C. G.), Uitterlinden, A.G. (André), Hofman, A. (Albert), Reijman, M. (Max), Oei, E.H.G. (Edwin), Bierma-Zeinstra, S.M. (Sita), and Meurs, J.B.J. (Joyce) van
- Abstract
Objective: To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors. Design: We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n = 1435) and the Cohort Hip and Cohort Knee (CHECK) study (n = 786). Results: From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC) = 0.67) or genetic markers (AUC = 0.55) or urinary C-terminal cross-linked telopeptide of type II collagen (uCTX-II) levels (AUC = 0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC = 0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC = 0.78) compared with uCTX-II (AUC = 0.74) or genetic markers (AUC = 0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort. Conclusions: The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA.
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- 2018
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18. Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain
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Suri, P. (Pradeep), Palmer, M.R. (Melody R.), Tsepilov, Y.A. (Yakov), Freidin, M.B. (Maxim B.), Boer, C.G. (Cindy), Yau, M.S. (Michelle S.), Evans, D.S. (Daniel), Gelemanovic, A. (Andrea), Bartz, T.M. (Traci M.), Nethander, M. (Maria), Arbeeva, L. (Liubov), Karssen, L.C. (Lennart), Neogi, T. (Tuhina), Campbell, A. (Archie), Mellström, D. (Dan), Ohlsson, C. (Claes), Marshall, L.M. (Lynn M.), Orwoll, E. (Eric), Uitterlinden, A. (Andre), Rotter, J.I. (Jerome I.), Lauc, G. (Gordan), Psaty, B.M. (Bruce M.), Karlsson, M. (Magnus), Lane, N.E., Jarvik, G.P. (Gail), Polasek, O. (Ozren), Hochberg, M.C. (Marc), Jordan, J.M. (Joanne), Meurs, J.B.J. (Joyce) van, Jackson, R.D. (Rebecca), Nielson, C. (Carrie), Mitchell, B.D. (Braxton), Smith, B.H. (Blair), Hayward, C. (Caroline), Smith, N.L. (Nicholas L.), Aulchenko, Y.S. (Yurii S.), Williams, F.M. (Frances), Suri, P. (Pradeep), Palmer, M.R. (Melody R.), Tsepilov, Y.A. (Yakov), Freidin, M.B. (Maxim B.), Boer, C.G. (Cindy), Yau, M.S. (Michelle S.), Evans, D.S. (Daniel), Gelemanovic, A. (Andrea), Bartz, T.M. (Traci M.), Nethander, M. (Maria), Arbeeva, L. (Liubov), Karssen, L.C. (Lennart), Neogi, T. (Tuhina), Campbell, A. (Archie), Mellström, D. (Dan), Ohlsson, C. (Claes), Marshall, L.M. (Lynn M.), Orwoll, E. (Eric), Uitterlinden, A. (Andre), Rotter, J.I. (Jerome I.), Lauc, G. (Gordan), Psaty, B.M. (Bruce M.), Karlsson, M. (Magnus), Lane, N.E., Jarvik, G.P. (Gail), Polasek, O. (Ozren), Hochberg, M.C. (Marc), Jordan, J.M. (Joanne), Meurs, J.B.J. (Joyce) van, Jackson, R.D. (Rebecca), Nielson, C. (Carrie), Mitchell, B.D. (Braxton), Smith, B.H. (Blair), Hayward, C. (Caroline), Smith, N.L. (Nicholas L.), Aulchenko, Y.S. (Yurii S.), and Williams, F.M. (Frances)
- Abstract
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 chr
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- 2018
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19. Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation
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Luijk, R. (René), Wu, H. (Haoyu), Ward-Caviness, C.K. (Cavin K.), Hannon, E. (Eilis), Carnero-Montoro, E. (Elena), Min, J. (Josine), Mandaviya, P.R. (Pooja), Müller-Nurasyid, M. (Martina), Mei, H. (Hailiang), Maarel, S.M. (Silvre) van der, Beekman, M. (Marian), der Breggen, R. (Ruud van), Deelen, J. (Joris), Lakenberg, N. (Nico), Moed, H. (Heleen), Suchiman, H.E.D. (Eka), Arindrarto, W. (Wibowo), van’t Hof, P. (Peter), Jan Bonder, M. (Marc), Deelen, P. (Patrick), Tigchelaar, E.F. (Ettje F.), Zhernakova, A. (Alexandra), Zhernakova, D.V. (Dasha V.), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Pool, R. (Reńe), Isaacs, A. (Aaron), Hofman, B.A. (Bert A.), Jhamai, M. (Mila), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Berg, L.H. (Leonard) van den, Van Galen, M. (Michiel), Vermaat, M. (Martijn), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Kielbasa, P.S.M. (P. Szymon M.), Bot, J.J. (Jan), Nooren, I. (Irene), Dijk, F. (Freerk) van, Swertz, M.A. (Morris A.), Heemst, D. (Diana) van, Relton, C.L. (Caroline), Mill, J. (Jonathan), Waldenberger, M. (Melanie), Bell, J.T. (Jordana T.), Jansen, R. (Rick), Franke, L. (Lude), ‘t Hoen, P.A.C. (Peter A. C.), Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Meurs, J.B.J. (Joyce) van, Daxinger, L. (Lucia), Slagboom, P.E. (Eline), Zwet, E.W. (Erik) van, Heijmans, B.T. (Bastiaan T.), Luijk, R. (René), Wu, H. (Haoyu), Ward-Caviness, C.K. (Cavin K.), Hannon, E. (Eilis), Carnero-Montoro, E. (Elena), Min, J. (Josine), Mandaviya, P.R. (Pooja), Müller-Nurasyid, M. (Martina), Mei, H. (Hailiang), Maarel, S.M. (Silvre) van der, Beekman, M. (Marian), der Breggen, R. (Ruud van), Deelen, J. (Joris), Lakenberg, N. (Nico), Moed, H. (Heleen), Suchiman, H.E.D. (Eka), Arindrarto, W. (Wibowo), van’t Hof, P. (Peter), Jan Bonder, M. (Marc), Deelen, P. (Patrick), Tigchelaar, E.F. (Ettje F.), Zhernakova, A. (Alexandra), Zhernakova, D.V. (Dasha V.), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Pool, R. (Reńe), Isaacs, A. (Aaron), Hofman, B.A. (Bert A.), Jhamai, M. (Mila), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Berg, L.H. (Leonard) van den, Van Galen, M. (Michiel), Vermaat, M. (Martijn), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Kielbasa, P.S.M. (P. Szymon M.), Bot, J.J. (Jan), Nooren, I. (Irene), Dijk, F. (Freerk) van, Swertz, M.A. (Morris A.), Heemst, D. (Diana) van, Relton, C.L. (Caroline), Mill, J. (Jonathan), Waldenberger, M. (Melanie), Bell, J.T. (Jordana T.), Jansen, R. (Rick), Franke, L. (Lude), ‘t Hoen, P.A.C. (Peter A. C.), Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Meurs, J.B.J. (Joyce) van, Daxinger, L. (Lucia), Slagboom, P.E. (Eline), Zwet, E.W. (Erik) van, and Heijmans, B.T. (Bastiaan T.)
- Abstract
X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.
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- 2018
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20. Skewed X-inactivation is common in the general female population
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Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), Wijmenga, C. (C.), Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), and Wijmenga, C. (C.)
- Abstract
X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.
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- 2018
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21. Differentially methylated regions in T cells identify kidney transplant patients at risk for de novo skin cancer
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Peters, F.S. (Fleur), Peeters, A.M.A. (Annemiek), Mandaviya, P.R. (Pooja), Meurs, J.B.J. (Joyce) van, Hofland, L.J. (Leo), Wetering, J. (Jacqueline) van de, Betjes, M.G.H. (Michiel), Baan, C.C. (Carla), Boer, K. (Karin), Peters, F.S. (Fleur), Peeters, A.M.A. (Annemiek), Mandaviya, P.R. (Pooja), Meurs, J.B.J. (Joyce) van, Hofland, L.J. (Leo), Wetering, J. (Jacqueline) van de, Betjes, M.G.H. (Michiel), Baan, C.C. (Carla), and Boer, K. (Karin)
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- 2018
- Full Text
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22. A DNA methylation biomarker of alcohol consumption
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Liu, C. (C.), Marioni, R.E. (Riccardo), Hedman, A.K. (Asa), Pfeiffer, L. (L.), Tsai, P.-C. (P. C.), Reynolds, L.M. (Lindsay), Just, A.C. (A. C.), Duan, Q. (Qing), Boer, C.G. (Cindy), Tanaka, T. (T.), Elks, C.E. (Cathy), Aslibekyan, S. (S.), Brody, J.A. (Jennifer A.), Kuhnel, B. (Brigitte), Herder, C. (Christian), Almli, L.M. (L. M.), Zhi, D. (D.), Wang, Y. (Y.), Huan, T. (T.), Yao, C. (C.), Mendelson, M.M. (M. M.), Joehanes, R. (Roby), Liang, L. (Liming), Love, S.-A. (S. A.), Guan, W. (Weihua), Shah, S. (S.), McRae, A.F. (A. F.), Kretschmer, A. (A.), Prokisch, H. (Holger), Strauch, K. (K.), Peters, A. (Annette), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Guo, X. (Xiuqing), Wiggins, K.L. (Kerri), Smith, A.K. (A. K.), Binder, E.B. (Elisabeth), Ressler, K.J. (Kerry), Irvin, M.R. (M. R.), Absher, D.M. (D. M.), Hernandez, D.G. (Dena), Ferrucci, L. (Luigi), Bandinelli, S. (Stefania), Lohman, K. (K.), Ding, J. (J.), Trevisi, L. (L.), Gustafsson, S. (Stefan), Sandling, J.K. (Johanna), Stolk, L. (Lisette), Uitterlinden, A.G. (André), Yet, I. (Idil), Castillo-Fernandez, J.E. (J. E.), Spector, T.D. (Timothy), Schwartz, J.D. (J. D.), Vokonas, P. (P.), Kao, W.H.L. (Wen), Li, Y. (Y.), Fornage, M. (Myriam), Arnett, D.K. (Donna), Wareham, N.J. (Nick), Sotoodehnia, N. (Nona), Ong, K.K. (Ken), Meurs, J.B.J. (Joyce) van, Conneely, K.N. (Karen N.), Baccarelli, A.A. (A. A.), Deary, I.J. (Ian), Bell, J.T. (J. T.), North, K.E. (Kari), Liu, Y. (YongMei), Waldenberger, M. (M.), London, S.J. (S. J.), Ingelsson, E. (Erik), Levy, D. (D.), Liu, C. (C.), Marioni, R.E. (Riccardo), Hedman, A.K. (Asa), Pfeiffer, L. (L.), Tsai, P.-C. (P. C.), Reynolds, L.M. (Lindsay), Just, A.C. (A. C.), Duan, Q. (Qing), Boer, C.G. (Cindy), Tanaka, T. (T.), Elks, C.E. (Cathy), Aslibekyan, S. (S.), Brody, J.A. (Jennifer A.), Kuhnel, B. (Brigitte), Herder, C. (Christian), Almli, L.M. (L. M.), Zhi, D. (D.), Wang, Y. (Y.), Huan, T. (T.), Yao, C. (C.), Mendelson, M.M. (M. M.), Joehanes, R. (Roby), Liang, L. (Liming), Love, S.-A. (S. A.), Guan, W. (Weihua), Shah, S. (S.), McRae, A.F. (A. F.), Kretschmer, A. (A.), Prokisch, H. (Holger), Strauch, K. (K.), Peters, A. (Annette), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Guo, X. (Xiuqing), Wiggins, K.L. (Kerri), Smith, A.K. (A. K.), Binder, E.B. (Elisabeth), Ressler, K.J. (Kerry), Irvin, M.R. (M. R.), Absher, D.M. (D. M.), Hernandez, D.G. (Dena), Ferrucci, L. (Luigi), Bandinelli, S. (Stefania), Lohman, K. (K.), Ding, J. (J.), Trevisi, L. (L.), Gustafsson, S. (Stefan), Sandling, J.K. (Johanna), Stolk, L. (Lisette), Uitterlinden, A.G. (André), Yet, I. (Idil), Castillo-Fernandez, J.E. (J. E.), Spector, T.D. (Timothy), Schwartz, J.D. (J. D.), Vokonas, P. (P.), Kao, W.H.L. (Wen), Li, Y. (Y.), Fornage, M. (Myriam), Arnett, D.K. (Donna), Wareham, N.J. (Nick), Sotoodehnia, N. (Nona), Ong, K.K. (Ken), Meurs, J.B.J. (Joyce) van, Conneely, K.N. (Karen N.), Baccarelli, A.A. (A. A.), Deary, I.J. (Ian), Bell, J.T. (J. T.), North, K.E. (Kari), Liu, Y. (YongMei), Waldenberger, M. (M.), London, S.J. (S. J.), Ingelsson, E. (Erik), and Levy, D. (D.)
- Abstract
The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal = 13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n = 6926) and identified 144 CpGs that provided substantial discrimination (area under the curve = 0.90-0.99) for current heavy alcohol intake (≥42 g per day in men and ≥28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1×10-7. Analysis of the monocyte-derived DNA (n = 1251) identified 62 alcohol-related CpGs at P<1×10-7. In whole-blood samples of people of European ancestry, we detected differen
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- 2018
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23. Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero
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Warrington, N.M. (Nicole M.), Shevroja, E. (Enisa), Hemani, G., Hysi, P.G. (Pirro), Jiang, Y. (Yunxuan), Auton, A. (Adam), Boer, C.G. (Cindy), Mangino, M. (Massimo), Wang, C.A. (Carol A.), Kemp, J.P. (John), Mcmahon, G. (George), Medina-Gomez, M.C. (Carolina), Hickey, M. (Martha), Trajanoska, K. (Katerina), Wolke, D. (Dieter), Ikram, M.A. (Arfan), Montgomery, G.W. (Grant W.), Felix, J.F. (Janine F.), Wright, M.J. (Margaret J.), Mackey, D.A. (David), Jaddoe, V.W.V. (Vincent), Martin, N.G. (Nicholas), Tung, J.Y. (Joyce Y.), Smith, G.D. (George Davey), Pennell, C.E. (Craig), Spector, T.D. (Timothy), Meurs, J.B.J. (Joyce) van, Rivadeneira, F. (Fernando), Medland, S.E. (Sarah), Evans, D.M. (David M.), The 23and Me Research Team, (), Warrington, N.M. (Nicole M.), Shevroja, E. (Enisa), Hemani, G., Hysi, P.G. (Pirro), Jiang, Y. (Yunxuan), Auton, A. (Adam), Boer, C.G. (Cindy), Mangino, M. (Massimo), Wang, C.A. (Carol A.), Kemp, J.P. (John), Mcmahon, G. (George), Medina-Gomez, M.C. (Carolina), Hickey, M. (Martha), Trajanoska, K. (Katerina), Wolke, D. (Dieter), Ikram, M.A. (Arfan), Montgomery, G.W. (Grant W.), Felix, J.F. (Janine F.), Wright, M.J. (Margaret J.), Mackey, D.A. (David), Jaddoe, V.W.V. (Vincent), Martin, N.G. (Nicholas), Tung, J.Y. (Joyce Y.), Smith, G.D. (George Davey), Pennell, C.E. (Craig), Spector, T.D. (Timothy), Meurs, J.B.J. (Joyce) van, Rivadeneira, F. (Fernando), Medland, S.E. (Sarah), Evans, D.M. (David M.), and The 23and Me Research Team, ()
- Abstract
The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sexspecific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N=15 661, with replication N=75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (b=0.06; P=0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.
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- 2018
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24. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes
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Xue, A. (Angli), Wu, Y. (Yang), Zhu, Z. (Zhihong), Zhang, F. (Futao), Kemper, K.E. (Kathryn E.), Zheng, Z. (Zhili), Yengo, L. (Loic), Lloyd-Jones, L.R. (Luke R.), Sidorenko, J. (Julia), Wu, Y. (Yeda), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M.J. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), McRae, A.F. (Allan F.), Visscher, P.M. (Peter), Zeng, J. (Jian), Yang, J. (Jian), Xue, A. (Angli), Wu, Y. (Yang), Zhu, Z. (Zhihong), Zhang, F. (Futao), Kemper, K.E. (Kathryn E.), Zheng, Z. (Zhili), Yengo, L. (Loic), Lloyd-Jones, L.R. (Luke R.), Sidorenko, J. (Julia), Wu, Y. (Yeda), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M.J. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), McRae, A.F. (Allan F.), Visscher, P.M. (Peter), Zeng, J. (Jian), and Yang, J. (Jian)
- Abstract
Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.
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- 2018
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25. Genome-wide identification of directed gene networks using large-scale population genomics data
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Luijk, R. (René), Dekkers, K.F. (Koen F.), Iterson, M. (Maarten) van, Arindrarto, W. (Wibowo), Claringbould, A. (Annique), Hop, P. (Paul), Beekman, M. (Marian), Breggen, R. (Ruud) van der, Deelen, J. (Joris), Lakenberg, N. (Nico), Moed, H. (Heleen), Suchiman, H.E.D. (Eka), van ’t Hof, P. (Peter), Bonder, M.J. (Marc), Deelen, P. (Patrick), Tigchelaar, E.F. (Ettje F.), Zhernakova, A. (Alexandra), Zhernakova, D.V. (Dasha V.), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Pool, R. (Reńe), Isaacs, A. (Aaron), Hofman, B.A. (Bert A.), Jhamai, M. (Mila), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Berg, L.H. (Leonard) van den, Van Galen, M. (Michiel), Vermaat, M. (Martijn), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Kielbasa, P.S.M. (P. Szymon M.), Bot, J.J. (Jan), Nooren, I. (Irene), Dijk, F. (Freerk) van, Swertz, M.A. (Morris A.), Heemst, D. (Diana) van, Boomsma, D.I. (Dorret I.), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Franke, L. (Lude), ’t Hoen, P.A.C. (Peter A. C.), Jansen, R. (Rick), Meurs, J.B.J. (Joyce) van, Mei, H. (Hailiang), Slagboom, P.E. (Eline), Heijmans, B.T. (Bastiaan T.), Zwet, E.W. (Erik) van, Luijk, R. (René), Dekkers, K.F. (Koen F.), Iterson, M. (Maarten) van, Arindrarto, W. (Wibowo), Claringbould, A. (Annique), Hop, P. (Paul), Beekman, M. (Marian), Breggen, R. (Ruud) van der, Deelen, J. (Joris), Lakenberg, N. (Nico), Moed, H. (Heleen), Suchiman, H.E.D. (Eka), van ’t Hof, P. (Peter), Bonder, M.J. (Marc), Deelen, P. (Patrick), Tigchelaar, E.F. (Ettje F.), Zhernakova, A. (Alexandra), Zhernakova, D.V. (Dasha V.), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Pool, R. (Reńe), Isaacs, A. (Aaron), Hofman, B.A. (Bert A.), Jhamai, M. (Mila), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Berg, L.H. (Leonard) van den, Van Galen, M. (Michiel), Vermaat, M. (Martijn), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Kielbasa, P.S.M. (P. Szymon M.), Bot, J.J. (Jan), Nooren, I. (Irene), Dijk, F. (Freerk) van, Swertz, M.A. (Morris A.), Heemst, D. (Diana) van, Boomsma, D.I. (Dorret I.), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Franke, L. (Lude), ’t Hoen, P.A.C. (Peter A. C.), Jansen, R. (Rick), Meurs, J.B.J. (Joyce) van, Mei, H. (Hailiang), Slagboom, P.E. (Eline), Heijmans, B.T. (Bastiaan T.), and Zwet, E.W. (Erik) van
- Abstract
Identification of causal drivers behind regulatory gene networks is crucial in understanding gene function. Here, we develop a method for the large-scale inference of gene–gene interactions in observational population genomics data that are both directed (using local genetic instruments as causal anchors, akin to Mendelian Randomization) and specific (by controlling for linkage disequilibrium and pleiotropy). Analysis of genotype and whole-blood RNA-sequencing data from 3072 individuals identified 49 genes as drivers of downstream transcriptional changes (Wald P < 7 × 10−10), among which transcription factors were overrepresented (Fisher’s P = 3.3 × 10−7). Our analysis suggests new gene functions and targets, including for SENP7 (zinc-finger genes involved in retroviral repression) and BCL2A1 (target genes possibly involved in auditory dysfunction). Our work highlights the utility of population genomics data in deriving directed gene expression networks. A resource of trans-effects for all 6600 genes with a genetic instrument can be explored individually using a web-based browser.
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- 2018
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26. COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression
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Prokić, I. (Ivana), Lahousse, L. (Lies), Carnero-Montoro, E. (Elena), Faiz, A. (Alen), Vonk, J.M. (Judith), Jong, K. (Kim) de, van der Plaat, D.A. (Diana A.), Diemen, C.C. (Cleo) van, Van Den Berge, M. (Maarten), Obeidat, M. (Ma'en), Bossé, Y. (Yohan), Nickle, D.C. (David C.), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Postma, D.S. (Dirkje S.), Boezen, H.M. (Marike), Duijn, C.M. (Cornelia) van, Amin, N. (Najaf), Prokić, I. (Ivana), Lahousse, L. (Lies), Carnero-Montoro, E. (Elena), Faiz, A. (Alen), Vonk, J.M. (Judith), Jong, K. (Kim) de, van der Plaat, D.A. (Diana A.), Diemen, C.C. (Cleo) van, Van Den Berge, M. (Maarten), Obeidat, M. (Ma'en), Bossé, Y. (Yohan), Nickle, D.C. (David C.), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Postma, D.S. (Dirkje S.), Boezen, H.M. (Marike), Duijn, C.M. (Cornelia) van, and Amin, N. (Najaf)
- Abstract
Chronic obstructive pulmonary disease (COPD) is among the major health burdens in adults. While cigarette smoking is the leading risk factor, a growing number of genetic variations have been discovered to influence disease susceptibility. Epigenetic modifications may mediate the response of the genome to smoking and regulate gene expression. Chromosome 19q13.2 region is associated with both smoking and COPD, yet its functional role is unclear. Our study aimed to determine whether rs7937 (RAB4B, EGLN2), a top genetic variant in 19q13.2 region identified in genome-wide association studies of COPD, is associated with differential DNA methylation in blood (N=1490) and gene expression in blood (N=721) and lungs (N=1087). We combined genetic and epigenetic data from the Rotterdam Study (RS) to perform the epigenome-wide association analysis of rs7937. Further, we used genetic and transcriptomic data from blood (RS) and from lung tissue (Lung expression quantitative trait loci mapping study), to perform the transcriptome-wide association study of rs7937. Rs7937 was significantly (FDR < 0.05) and consistently associated with differential DNA methylation in blood at 4 CpG sites in cis, independent of smoking. One methylation site (cg11298343-EGLN2) was also associated with COPD (P=0.001). Additionally, rs7937 was associated with gene expression levels in blood in cis (EGLN2), 42% mediated through cg11298343, and in lung tissue, in cis and trans (NUMBL, EGLN2, DNMT3A, LOC101929709 and PAK2). Our results suggest that changes of DNA methylation and gene expression may be intermediate steps between genetic variants and COPD, but further causal studies in lung tissue should confirm this hypothesis.
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- 2018
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27. Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood
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Qi, T. (Ting), Wu, Y. (Yang), Zeng, J. (Jian), Zhang, F. (Futao), Xue, A. (Angli), Jiang, L. (Longda), Zhu, Z. (Zhihong), Kemper, K. (Kathryn), Yengo, L. (Loic), Zheng, Z. (Zhili), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D.I. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), Marioni, R.E. (Riccardo), Montgomery, G.W. (Grant W.), Deary, I.J. (Ian), Wray, N.R. (Naomi R.), Visscher, P.M. (Peter), McRae, A.F. (Allan F.), Yang, J. (Jian), Qi, T. (Ting), Wu, Y. (Yang), Zeng, J. (Jian), Zhang, F. (Futao), Xue, A. (Angli), Jiang, L. (Longda), Zhu, Z. (Zhihong), Kemper, K. (Kathryn), Yengo, L. (Loic), Zheng, Z. (Zhili), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D.I. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), Marioni, R.E. (Riccardo), Montgomery, G.W. (Grant W.), Deary, I.J. (Ian), Wray, N.R. (Naomi R.), Visscher, P.M. (Peter), McRae, A.F. (Allan F.), and Yang, J. (Jian)
- Abstract
Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r b ). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples (r b = 0.70 for cis-eQTLs and r ^ b = 0.78 for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.
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- 2018
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28. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
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Wahl, S. (Simone), Drong, A. (Alexander), Lehne, B. (Benjamin), Loh, M. (Marie), Scott, W.R. (William R.), Kunze, S. (Sonja), Tsai, P.-C. (Pei-Chien), Ried, J.S. (Janina S.), Zhang, W. (Weihua), Yang, Y. (Youwen), Tan, S. (Sili), Fiorito, G. (Giovanni), Franke, L. (Lude), Guarrera, S. (Simonetta), Kasela, S. (Silva), Kriebel, J. (Jennifer), Richmond, R.C. (Rebecca C.), Adamo, M. (Marco), Afzal, U. (Uzma), Ala-Korpela, M. (Mika), Albetti, B. (Benedetta), Ammerpohl, O. (Ole), Apperley, J. (Jane), Beekman, M. (Marian), Bertazzi, P.A. (Pier Alberto), Black, S.L. (S. Lucas), Blancher, C. (Christine), Bonder, M.J. (Marc), Brosch, M. (Mario), Carstensen-Kirberg, M. (Maren), Craen, A.J. (Anton) de, Lusignan, S. (Simon) de, Dehghan, A. (Abbas), Elkalaawy, M. (Mohamed), Fischer, K. (Krista), Franco, O.H. (Oscar), Gaunt, T.R. (Tom), Hampe, J. (Jochen), Hashemi, M. (Majid), Isaacs, A.J. (Aaron), Jenkinson, A. (Andrew), Jha, S. (Sujeet), Kato, N. (Norihiro), Krogh, V. (Vittorio), Laffan, M. (Michael), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mok, Z.Y. (Zuan Yu), Motta, V. (Valeria), Ng, H.K. (Hong Kiat), Nikolakopoulou, Z. (Zacharoula), Nteliopoulos, G. (Georgios), Panico, S. (Salvatore), Pervjakova, N. (Natalia), Prokisch, H. (Holger), Rathmann, W. (Wolfgang), Roden, M. (Michael), Rota, F. (Federica), Rozario, M.A. (Michelle Ann), Sandling, J.K. (Johanna), Schafmayer, C. (Clemens), Schramm, K. (Katharina), Siebert, R. (Reiner), Slagboom, P.E. (Eline), Soininen, P. (Pasi), Stolk, L. (Lisette), Strauch, K. (Konstantin), Tai, E.S. (Shyong), Tarantini, L. (Letizia), Thorand, B. (Barbara), Tigchelaar, E.F. (Ettje F.), Tumino, R. (Rosario), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Meurs, J.B.J. (Joyce) van, Vineis, P. (Paolo), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Yang, T.-P. (Tsun-Po), Yuan, W. (Wei), Zhernakova, A. (Alexandra), Batterham, R.L., Smith, A.V. (Davey), Deloukas, P. (Panos), Heijmans, B.T. (Bastiaan T.), Herder, C. (Christian), Hofman, A. (Albert), Lindgren, C.M. (Cecilia M.), Milani, L. (Lili), Harst, P. (Pim) van der, Peters, A. (Annette), Illig, T. (Thomas), Relton, C.L. (Caroline), Waldenberger, M. (Melanie), Jarvelin, M.-R. (Marjo-Riitta), Bollati, V. (Valentina), Soong, R. (Richie), Spector, T.D. (Timothy), Scott, J. (James), McCarthy, M.I. (Mark), Elliott, P. (Paul), Bell, J.T. (Jordana T.), Matullo, G., Gieger, C. (Christian), Kooner, J.S. (Jaspal S.), Grallert, H. (Harald), Chambers, J.C. (John C.), Wahl, S. (Simone), Drong, A. (Alexander), Lehne, B. (Benjamin), Loh, M. (Marie), Scott, W.R. (William R.), Kunze, S. (Sonja), Tsai, P.-C. (Pei-Chien), Ried, J.S. (Janina S.), Zhang, W. (Weihua), Yang, Y. (Youwen), Tan, S. (Sili), Fiorito, G. (Giovanni), Franke, L. (Lude), Guarrera, S. (Simonetta), Kasela, S. (Silva), Kriebel, J. (Jennifer), Richmond, R.C. (Rebecca C.), Adamo, M. (Marco), Afzal, U. (Uzma), Ala-Korpela, M. (Mika), Albetti, B. (Benedetta), Ammerpohl, O. (Ole), Apperley, J. (Jane), Beekman, M. (Marian), Bertazzi, P.A. (Pier Alberto), Black, S.L. (S. Lucas), Blancher, C. (Christine), Bonder, M.J. (Marc), Brosch, M. (Mario), Carstensen-Kirberg, M. (Maren), Craen, A.J. (Anton) de, Lusignan, S. (Simon) de, Dehghan, A. (Abbas), Elkalaawy, M. (Mohamed), Fischer, K. (Krista), Franco, O.H. (Oscar), Gaunt, T.R. (Tom), Hampe, J. (Jochen), Hashemi, M. (Majid), Isaacs, A.J. (Aaron), Jenkinson, A. (Andrew), Jha, S. (Sujeet), Kato, N. (Norihiro), Krogh, V. (Vittorio), Laffan, M. (Michael), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mok, Z.Y. (Zuan Yu), Motta, V. (Valeria), Ng, H.K. (Hong Kiat), Nikolakopoulou, Z. (Zacharoula), Nteliopoulos, G. (Georgios), Panico, S. (Salvatore), Pervjakova, N. (Natalia), Prokisch, H. (Holger), Rathmann, W. (Wolfgang), Roden, M. (Michael), Rota, F. (Federica), Rozario, M.A. (Michelle Ann), Sandling, J.K. (Johanna), Schafmayer, C. (Clemens), Schramm, K. (Katharina), Siebert, R. (Reiner), Slagboom, P.E. (Eline), Soininen, P. (Pasi), Stolk, L. (Lisette), Strauch, K. (Konstantin), Tai, E.S. (Shyong), Tarantini, L. (Letizia), Thorand, B. (Barbara), Tigchelaar, E.F. (Ettje F.), Tumino, R. (Rosario), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Meurs, J.B.J. (Joyce) van, Vineis, P. (Paolo), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Yang, T.-P. (Tsun-Po), Yuan, W. (Wei), Zhernakova, A. (Alexandra), Batterham, R.L., Smith, A.V. (Davey), Deloukas, P. (Panos), Heijmans, B.T. (Bastiaan T.), Herder, C. (Christian), Hofman, A. (Albert), Lindgren, C.M. (Cecilia M.), Milani, L. (Lili), Harst, P. (Pim) van der, Peters, A. (Annette), Illig, T. (Thomas), Relton, C.L. (Caroline), Waldenberger, M. (Melanie), Jarvelin, M.-R. (Marjo-Riitta), Bollati, V. (Valentina), Soong, R. (Richie), Spector, T.D. (Timothy), Scott, J. (James), McCarthy, M.I. (Mark), Elliott, P. (Paul), Bell, J.T. (Jordana T.), Matullo, G., Gieger, C. (Christian), Kooner, J.S. (Jaspal S.), Grallert, H. (Harald), and Chambers, J.C. (John C.)
- Abstract
Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10 -7, range P = 9.2 × 10 -8 to 6.0 × 10 -46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10 -6, range P = 5.5 × 10 -6 to 6.1 × 10 -35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10 -54). Our results provide new insights into the biologic pathways influenc
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- 2017
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29. Genome-wide association scan of neuropathic pain symptoms post total joint replacement highlights a variant in the protein-kinase C gene
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Warner, S.C. (Sophie C.), Meurs, J.B.J. (Joyce) van, Schiphof, D. (Dieuwke), Bierma-Zeinstra, S.M. (Sita), Hofman, A. (Albert), Uitterlinden, A.G. (André), Richardson, H. (Helen), Jenkins, W. (Wendy), Doherty, M. (Michael), Valdes, A.M. (Ana Maria), Warner, S.C. (Sophie C.), Meurs, J.B.J. (Joyce) van, Schiphof, D. (Dieuwke), Bierma-Zeinstra, S.M. (Sita), Hofman, A. (Albert), Uitterlinden, A.G. (André), Richardson, H. (Helen), Jenkins, W. (Wendy), Doherty, M. (Michael), and Valdes, A.M. (Ana Maria)
- Abstract
Neuropathic pain-like joint symptoms (NP) are seen in a proportion of individuals diagnosed with osteoarthritis (OA) and post total joint replacement (TJR). In this study, we performed a genome-wide association study (GWAS) using NP as defined by the painDETECT questionnaire (score >12 indicating possible NP) in 613 post-TJR participants recruited from Nottinghamshire (UK). The prevalence of possible NP was 17.8%. The top four hits from the GWAS and two other biologically relevant single-nucleotide polymorphisms (SNPs) were replicated in individuals with OA and post TJR from an independent study in the same area (N=908) and in individuals from the Rotterdam Study (N=212). Three of these SNPs showed effect sizes in the same direction as in the GWAS results in both replication cohorts. The strongest association upon meta-analysis of a recessive model was for the variant allele in rs88
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- 2017
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30. Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity
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Sutphin, G.L. (George L.), Backer, G. (Grant), Sheehan, S. (Susan), Bean, S. (Shannon), Corban, C. (Caroline), Liu, T. (Teresa), Peters, M.A.D. (Marjolein), Meurs, J.B.J. (Joyce) van, Murabito, J. (Joanne), Johnson, A.D. (Andrew D.), Korstanje, R. (Ron), Sutphin, G.L. (George L.), Backer, G. (Grant), Sheehan, S. (Susan), Bean, S. (Shannon), Corban, C. (Caroline), Liu, T. (Teresa), Peters, M.A.D. (Marjolein), Meurs, J.B.J. (Joyce) van, Murabito, J. (Joanne), Johnson, A.D. (Andrew D.), and Korstanje, R. (Ron)
- Abstract
We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity-correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. kynu-1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age-associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow-up.
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- 2017
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31. Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index
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Hinney, A. (Anke), Kesselmeier, M. (M.), Jall, S. (S.), Volckmar, A.-L. (A. L.), Föcker, M. (M.), Antel, J. (J.), Heid, I.M. (Iris), Winkler, T.W. (Thomas W.), Grant, S.F.A. (S. F.A.), Guo, Y. (Yongli), Bergen, A.W. (Andrew), Grant, S.F.A. (Struan), Berrettini, W. (Wade), Hakonarson, H. (Hakon), Herpertz-Dahlmann, B. (B.), De Zwaan, M. (M.), Herzog, W. (W.), Ehrlich, S.M. (Stefan), Zipfel, S. (S.), Egberts, K. (Karin), Adan, R. (R.), Brandys, M. (M.), Elburg, A.A. (Annemarie) van, Boraska Perica, V. (V.), Müller, T.D., Tschöp, M.H. (M. H.), Zeggini, E. (Eleftheria), Bulik, C.M. (C. M.), Collier, D.A. (David), Scherag, A. (A.), Hebebrand, J. (J.), Tschop, M. (Matthias), Floyd, J. (Jamie), Thornton, L.M. (Laura), Huckins, L.M. (Laura M), Southam, L. (Lorraine), Rayner, N.W. (Nigel William), Tachmazidou, I. (Ioanna), Klump, K.L. (K. L.), Treasure, J. (Janet), Lewis, C.M. (Cathryn), Schmidt, U. (Ulrike), Tozzi, F. (Federica), Iezebrink, K. (Kirsty), Gorwood, P. (Philip), Kas, M.J.H. (Martien), Favaro, A. (Angela), Santonastaso, P. (Paolo), Fernández-Aranda, F. (Fernando), Gratacos, M. (Monica), Rybakowski, F. (Filip), Dmitrzak-Weglarz, M. (Monika), Kaprio, J. (Jaakko), Keski-Rahkonen, A. (Anna), Raevuori-Helkamaa, A. (Anu), Furth, E.F. (Eric) van, Slof-Op’t Landt, M.C.T. (Margarita C. T.), Hudson, J.I. (James I), Knudsen, G.P.S. (Gun Peggy S.), Monteleone, P. (Palmiero), Kaplan, A.S. (Allan S), Karwautz, A. (Andreas), Li, D. (Dong), Komaki, G. (Gen), Ando, T. (Tetsuya), Inoko, H. (Hidetoshi), Esko, T. (T.), Fischer, K. (Krista), Männik, K. (Katrin), Metspalu, A. (Andres), Baker, J.H. (Jessica H), Cone, R.D. (Roger D), Esko, T. (Tõnu), DeSocio, J.E. (Janiece E), Hilliard, C.E. (Christopher E), O’Toole, J.K. (Julie K), Pantel, J. (Jacques), Szatkiewicz, J.P. (Jin P), Taico, C. (Chrysecolla), Zerwas, S. (Stephanie), Trace, S.E. (Sara E), Davis, O.S.P. (Oliver S.), Helder, S. (Sietske), Bühren, K. (Katharina), Burghardt, R. (Roland), Imgart, H. (Hartmut), Scherag, A. (Andre), Boni, C. (Claudette), Ramoz, N. (Nicolas), Versini, A. (Audrey), Danner, U.N. (Unna N), de Kove, C. (Carolien), Hendriks, J. (Judith), Koeleman, B.P.C. (Bobby P. C.), Ophoff, R.A. (Roel), Strengman, E. (Eric), Bruson, A. (Alice), Clementi, M. (Maurizio), Degortes, D. (Daniela), Forzan, M. (Monica), Tenconi, E. (Elena), Docampo, E. (Elisa), Jiménez-Murcia, G.E.S. (Geòrgia Escaramí Susana), Lissowska, J. (Jolanta), Rajewski, A. (Andrzej), Szeszenia-Dabrowska, N. (Neonila), Slopien, A. (Agnieszka), Hauser, J. (J.), Karhunen, L. (Leila), Meulenbelt, I. (Ingrid), Slagboom, P.E. (Eline), Tortorella, A. (Alfonso), Maj, M. (Mario), Dedoussis, G.V. (George), Dedoussis, G.V. (G. V.), Koeleman, B.P.C. (Bobby), Gonidakis, F. (Fragiskos), Tziouvas, K. (Konstantinos), Tsitsika, A. (Artemis), Papezova, H. (Hana), Slachtova, L. (Lenka), Martaskova, D. (Debora), Kennedy, J.L., Levitan, R.D. (Robert D), Yilmaz, Z. (Zeynep), Huemer, J. (Julia), Koubek, D. (Doris), Merl, E. (Elisabeth), Wagner, G. (Gudrun), Lichtenstein, P. (Paul), Breen, G. (Gerome), Cohen-Woods, S. (Sarah), Farmer, A.E. (Anne E), Mcguffin, P. (Peter), Cichon, S. (Sven), Giegling, I. (Ina), Herms, S. (Stefan), Rujescu, D. (Dan), Schreiber, S. (Stefan), Wichmann, H.E. (Heinz Erich), Sladek, R. (Rob), Gambaro, G. (Giovanni), Soranzo, N. (Nicole), Julia, A. (Antonio), Marsal, S. (Sara), Rabionet, R. (Raquel), Gaborieau, V. (Valerie), Dick, D.M. (Danielle), Palotie, A. (A.), Ripatti, S. (Samuli), Widen, E., Espeseth, T. (Thomas), Lundervold, A.J. (Astri), Reinvang, I. (Ivar), Steen, V.M. (Vidar), Le Hellard, S. (Stephanie), Mattingsdal, M. (Morten), Ntalla, I. (Ioanna), Bencko, V. (Vladimir), Foretova, L. (Lenka), Janout, V. (Vladimir), Navratilova, M. (Marie), Pinto, D. (Dalila), Scherer, S.W. (Stephen W), Carlberg, L. (Laura), Schosser, A. (Alexandra), Alfredsson, L. (Lars), Pinto, D. (Duane), Scherer, S.W. (Stephen), Padyukov, L. (Leonid), Finan, C. (Chris), Kalsi, G. (Gursharan), Roberts, M. (Marion), Logan, D.W. (Darren W), Peltonen, L. (Leena Johanna), Ritchie, G.R.S. (Graham R.S.), Barrett, J.C. (Jeffrey), Estivill, X. (Xavier), Sullivan, P.F. (Patrick), Anderson, C.A. (Carl A), McGinnis, R. (Ralph), Sambrook, J. (Jennifer), Stephens, J. (Jonathan), Ouwehand, W.H. (Willem), McArdle, P.F. (P. F.), Ring, S.M. (Susan), Strachan, D.P. (David), Alexander, G. (Graeme), Conlon, P.J. (Peter J), Dominiczak, A. (Anna), Duncanson, A. (Audrey), Padyukov, L. (L.), Langford, C. (Cordelia), Lord, G. (Graham), Conlon, P. (Peter), Sandford, R. (Richard), Sheerin, N. (Neil), Vannberg, F.O. (Frederik O), Blackburn, H. (Hannah), Maxwell, A.P. (A.), Edkins, T. (Ted), Gillman, M.W. (Matthew W.), Gray, E. (Emma), Hunt, S.E. (Sarah E), Nengut, S.-G. (Suna-Gumuscu), Potter, S.C. (Simon), Rich, S.S. (Stephen), Simpkin, D. (Douglas), Whittaker, P. (Pamela), Ang, W.Q. (Wei), Atalay, M. (Mustafa), Beijsterveldt, C.E.M. (Toos) van, Bergen, N. (N.), Benke, K. (K.), Berry, D. (Diane), Boomsma, D.I. (Dorret), Bradfield, J.P. (Jonathan), Charoen, P. (Pimphen), Coin, L. (Lachlan), Cooper, C. (C.), Cousminer, D.L. (Diana), Das, S. (Shikta), Elliott, P. (P.), Evans, D.M. (D. M.), Feenstra, B. (B.), Flexeder, C. (Claudia), Frayling, T.M. (Timothy), Freathy, R.M. (Rachel), Gaillard, R. (R.), Geller, F. (Frank), Groen-Blokhuis, M. (Maria), Goh, L.K. (L. K.), Guxens Junyent, M. (Mònica), Hattersley, A.T. (Andrew), Haworth, C.M.A. (Claire M.), Hadley, D. (D.), Heinrich, J. (J.), Hirschhorn, J.N. (Joel), Hocher, B. (Berthold), Holloway, J.W. (J. W.), Holst, J.J., Hottenga, J.J. (Jouke Jan), Horikoshi, M. (Momoko), Huikari, V. (Ville), Hypponen, E. (E.), Iñiguez, C. (C.), Jaddoe, V.W. (V. W.), Jarvelin, M.R. (M. R.), Kaakinen, M. (M.), Kilpeläinen, T.O. (Tuomas), Hypponen, E. (Elina), Kowgier, M. (Matthew), Lakka, T.A. (Timo), Cooper, C. (Charles), Lange, L.A. (Leslie), Lawlor, D.A. (D. A.), Lehtimäki, T. (Terho), Lewin, A. (Alex), Elliott, P. (Paul), Lindi, V. (Virpi), Maggi, R. (Reedik), Feenstra, B. (Bjarke), McCarthy, M.I. (M. I.), Melbye, M. (Mads), Middeldorp, C.M. (Christel), Millwood, I.Y. (Iona), Mohlke, K.L. (Karen), Mook-Kanamori, D.O. (D. O.), Murray, J.C. (Jeffrey), Nivard, M. (Michel), Nohr, C. (Christian), Oken, E. (Emily), Ong, K.K. (K. K.), O'Reilly, P.F. (P. F.), Palmer, C. (Cameron), Panoutsopoulou, K. (K.), Pararajasingham, J. (Jennifer), Pearson, E.R. (E. R.), Pennell, C.E. (Craig), Power, C. (Christopher), Price, T.S. (Thomas), Prokopenko, I. (Inga), Raitakari, O.T. (O. T.), Rodriguez, A. (A.), Salem, R.M. (Rany), Saw, S.M. (S. M.), Sebert, S. (S.), Siitonen, N. (Niina), Jaddoe, V.W.V. (Vincent), Sørensen, T.I.A. (Thorkild), Sovio, U. (Ulla), Lawlor, D.A. (Debbie), Sunyer, J. (J.), Taal, H.R. (Rob), Teo, Y.Y. (Y. Y.), Thiering, E. (Elisabeth), Tiesler, C. (C.), Timpson, N.J. (Nicholas), Uitterlinden, A.G. (André), Valcárcel, B. (Beatriz), Teo, Y.Y. (Yik Ying), White, S.J. (Stefan), Willemsen, G.A.H.M. (Gonneke), Wilson, J.F. (J. F.), Yaghootkar, H. (H.), Elks, C.E. (Cathy), Perry, J.R. (J. R.), Sulem, P. (Patrick), Chasman, D.I. (Daniel), Franceschini, N. (Nora), He, C. (C.), Lunetta, K.L. (Kathryn), Visser, J.A. (Jenny), Byrne, E.M. (E. M.), Gudbjartsson, D.F. (Daniel), Koller, D.L. (Daniel), Kutalik, Z. (Zoltán), Lin, P. (P.), Mangino, M. (Massimo), Byrne, E.M. (Enda), Smith, A.V. (Albert), Stolk, L. (Lisette), Wingerden, S. (Sophie) van, Zhao, J.H. (J. H.), Albrecht, E. (Eva), Corre, T. (Tanguy), Ingelsson, E. (Erik), Hayward, C. (Caroline), Magnusson, P.K. (Patrik), Smith, A.V. (Davey), Chanock, S.J. (Stephen), Warrington, M. (M.), Zgaga, L. (L.), Alavere, H. (Helene), Amin, N. (Najaf), Aspelund, T. (T.), Ulivi, S. (Shelia), Sunyer, J. (Jordi), Berenson, G. (Gerald), Bergmann, S.M. (Sven), Boerwinkle, E. (E.), Buring, J.E. (Julie), Busonero, F. (F.), Barroso, I.E. (Inês), Chanock, S.J. (S. J.), Warrington, N.M. (Nicole), Couper, D.J. (David), Coviello, A.D. (Andrea), Busonero, F., Faire, U. (Ulf) de, de Geus, E.J. (E. J.), Deloukas, P. (Panagiotis), Döring, A. (Angela), Davey Smith, G. (G.), Adamo, P. (Pio) d', Eiriksdottir, G. (Gudny), Geus, E.J.C. (Eco) de, Hagen, K. (Knut), Ferrucci, L. (L.), Folsom, A.R. (A. R.), Foroud, T. (T.), Garcia, M.E. (M.), Gasparini, P. (P.), Gieger, C. (Christian), Gudnason, V. (V.), Folsom, A.R. (Aaron), Hankinson, S.E. (S. E.), Ferreli, L. (Liana), Gasparini, P. (Paolo), Hernandez, D.G. (Dena), Hofman, A. (Albert), Hu, F.B. (F. B.), Illig, T. (T.), Jarvelin, M.-R. (Marjo-Riitta), Johnson, A.D. (Andrew), Karasik, D. (David), Khaw, K.T. (K. T.), Kiel, D.P. (Douglas P.), Kolcic, I. (Ivana), Kraft, P. (Peter), Launer, L.J. (Lenore), Laven, J.S. (J. S.), Li, S. (S.), Liu, J. (J.), Levy, D. (D.), Martin, N.G. (N. G.), Aspelund, T. (Thor), Nalls, M.A. (Michael), Navarro, P. (Pau), Nelis, M. (M.), Ness, A.R. (A. R.), Boerwinkle, E.A. (Eric), Oostra, B.A. (Ben), Peacock, M. (M.), Pare, G. (Guillame), Parker, A.N. (Alex), Pedersen, N.L. (Nancy), Cornelis, M. (Marilyn), Polasek, O. (Ozren), Plump, A.S. (A. S.), Peacock, M. (Munro), Porcu, E. (Eleonora), Rafnar, T. (Thorunn), Rice, J.P. (John), Rivadeneira, F. (F.), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sanna, S. (Serena), Schlessinger, D. (D.), Scuteri, A. (A.), Segrè, A.V. (Ayellet), Foroud, T. (Tatiana), Srinivasan, S.R. (Sathanur), Tammesoo, M.L. (M. L.), Tikkanen, E. (Emmi), Toniolo, D. (Daniela), Scuteri, A. (Angelo), Tryggvadottir, L. (Laufey), Tyrer, J. (J.), Uda, M. (M.), van Dam, R.M. (R. M.), Meurs, J.B.J. (Joyce) van, Vollenweider, P. (Peter), Waeber, G. (Gérard), Wareham, N.J. (Nick), Waterworth, D. (Dawn), Weedon, M.N. (Michael), Wright, A.F. (Alan), Young, L. (L.), Zhai, G. (G.), Zhuang, W.V. (W. V.), Bierut, L.J. (L. J.), Boyd, H.A. (H. A.), Crisponi, L. (Laura), Demerath, E.W. (E. W.), Duijn, C.M. (Cornelia) van, Econs, M.J. (M. J.), Harris, T.B. (Tamara), Bierut, L.J. (Laura), Loos, R.J.F. (Ruth), Ridker, P.M. (Paul), Demerath, E.W. (Ellen), Streeten, E.A. (Elizabeth), Econs, M.J. (Michael), Thorsteinsdottir, U. (Unnur), Widen, E. (E.), Murabito, J. (Joanne), Ness, A.R. (Andrew), Spector, T.D. (Timothy), Crawford, S. (Steve), Crow, S. (Scott), Fichter, M.M. (M. M.), Halmi, K.A. (K. A.), Palotie, A. (Aarno), La Via, M. (Maria), Mitchell, J. (James), Strober, M. (Michael), Rotondo, A. (Alessandro), Woodside, D.B. (D Blake), Keel, P. (Pamela), Lilenfeld, L. (Lisa), Rivadeneira Ramirez, F. (Fernando), Magistretti, P. (Pierre), Montgomery, G.W. (G. W.), Hinney, A. (Anke), Kesselmeier, M. (M.), Jall, S. (S.), Volckmar, A.-L. (A. L.), Föcker, M. (M.), Antel, J. (J.), Heid, I.M. (Iris), Winkler, T.W. (Thomas W.), Grant, S.F.A. (S. F.A.), Guo, Y. (Yongli), Bergen, A.W. (Andrew), Grant, S.F.A. (Struan), Berrettini, W. (Wade), Hakonarson, H. (Hakon), Herpertz-Dahlmann, B. (B.), De Zwaan, M. (M.), Herzog, W. (W.), Ehrlich, S.M. (Stefan), Zipfel, S. (S.), Egberts, K. (Karin), Adan, R. (R.), Brandys, M. (M.), Elburg, A.A. (Annemarie) van, Boraska Perica, V. (V.), Müller, T.D., Tschöp, M.H. (M. H.), Zeggini, E. (Eleftheria), Bulik, C.M. (C. M.), Collier, D.A. (David), Scherag, A. (A.), Hebebrand, J. (J.), Tschop, M. (Matthias), Floyd, J. (Jamie), Thornton, L.M. (Laura), Huckins, L.M. (Laura M), Southam, L. (Lorraine), Rayner, N.W. (Nigel William), Tachmazidou, I. (Ioanna), Klump, K.L. (K. L.), Treasure, J. (Janet), Lewis, C.M. (Cathryn), Schmidt, U. (Ulrike), Tozzi, F. (Federica), Iezebrink, K. (Kirsty), Gorwood, P. (Philip), Kas, M.J.H. (Martien), Favaro, A. (Angela), Santonastaso, P. (Paolo), Fernández-Aranda, F. (Fernando), Gratacos, M. (Monica), Rybakowski, F. (Filip), Dmitrzak-Weglarz, M. (Monika), Kaprio, J. (Jaakko), Keski-Rahkonen, A. (Anna), Raevuori-Helkamaa, A. (Anu), Furth, E.F. (Eric) van, Slof-Op’t Landt, M.C.T. (Margarita C. T.), Hudson, J.I. (James I), Knudsen, G.P.S. (Gun Peggy S.), Monteleone, P. (Palmiero), Kaplan, A.S. (Allan S), Karwautz, A. (Andreas), Li, D. (Dong), Komaki, G. (Gen), Ando, T. (Tetsuya), Inoko, H. (Hidetoshi), Esko, T. (T.), Fischer, K. (Krista), Männik, K. (Katrin), Metspalu, A. (Andres), Baker, J.H. (Jessica H), Cone, R.D. (Roger D), Esko, T. (Tõnu), DeSocio, J.E. (Janiece E), Hilliard, C.E. (Christopher E), O’Toole, J.K. (Julie K), Pantel, J. (Jacques), Szatkiewicz, J.P. (Jin P), Taico, C. (Chrysecolla), Zerwas, S. (Stephanie), Trace, S.E. (Sara E), Davis, O.S.P. (Oliver S.), Helder, S. (Sietske), Bühren, K. (Katharina), Burghardt, R. (Roland), Imgart, H. (Hartmut), Scherag, A. (Andre), Boni, C. (Claudette), Ramoz, N. (Nicolas), Versini, A. (Audrey), Danner, U.N. (Unna N), de Kove, C. (Carolien), Hendriks, J. (Judith), Koeleman, B.P.C. (Bobby P. C.), Ophoff, R.A. (Roel), Strengman, E. (Eric), Bruson, A. (Alice), Clementi, M. (Maurizio), Degortes, D. (Daniela), Forzan, M. (Monica), Tenconi, E. (Elena), Docampo, E. (Elisa), Jiménez-Murcia, G.E.S. (Geòrgia Escaramí Susana), Lissowska, J. (Jolanta), Rajewski, A. (Andrzej), Szeszenia-Dabrowska, N. (Neonila), Slopien, A. (Agnieszka), Hauser, J. (J.), Karhunen, L. (Leila), Meulenbelt, I. (Ingrid), Slagboom, P.E. (Eline), Tortorella, A. (Alfonso), Maj, M. (Mario), Dedoussis, G.V. (George), Dedoussis, G.V. (G. V.), Koeleman, B.P.C. (Bobby), Gonidakis, F. (Fragiskos), Tziouvas, K. (Konstantinos), Tsitsika, A. (Artemis), Papezova, H. (Hana), Slachtova, L. (Lenka), Martaskova, D. (Debora), Kennedy, J.L., Levitan, R.D. (Robert D), Yilmaz, Z. (Zeynep), Huemer, J. (Julia), Koubek, D. (Doris), Merl, E. (Elisabeth), Wagner, G. (Gudrun), Lichtenstein, P. (Paul), Breen, G. (Gerome), Cohen-Woods, S. (Sarah), Farmer, A.E. (Anne E), Mcguffin, P. (Peter), Cichon, S. (Sven), Giegling, I. (Ina), Herms, S. (Stefan), Rujescu, D. (Dan), Schreiber, S. (Stefan), Wichmann, H.E. (Heinz Erich), Sladek, R. (Rob), Gambaro, G. (Giovanni), Soranzo, N. (Nicole), Julia, A. (Antonio), Marsal, S. (Sara), Rabionet, R. (Raquel), Gaborieau, V. (Valerie), Dick, D.M. (Danielle), Palotie, A. (A.), Ripatti, S. (Samuli), Widen, E., Espeseth, T. (Thomas), Lundervold, A.J. (Astri), Reinvang, I. (Ivar), Steen, V.M. (Vidar), Le Hellard, S. (Stephanie), Mattingsdal, M. (Morten), Ntalla, I. (Ioanna), Bencko, V. (Vladimir), Foretova, L. (Lenka), Janout, V. (Vladimir), Navratilova, M. (Marie), Pinto, D. (Dalila), Scherer, S.W. (Stephen W), Carlberg, L. (Laura), Schosser, A. (Alexandra), Alfredsson, L. (Lars), Pinto, D. (Duane), Scherer, S.W. (Stephen), Padyukov, L. (Leonid), Finan, C. (Chris), Kalsi, G. (Gursharan), Roberts, M. (Marion), Logan, D.W. (Darren W), Peltonen, L. (Leena Johanna), Ritchie, G.R.S. (Graham R.S.), Barrett, J.C. (Jeffrey), Estivill, X. (Xavier), Sullivan, P.F. (Patrick), Anderson, C.A. (Carl A), McGinnis, R. (Ralph), Sambrook, J. (Jennifer), Stephens, J. (Jonathan), Ouwehand, W.H. (Willem), McArdle, P.F. (P. F.), Ring, S.M. (Susan), Strachan, D.P. (David), Alexander, G. (Graeme), Conlon, P.J. (Peter J), Dominiczak, A. (Anna), Duncanson, A. (Audrey), Padyukov, L. (L.), Langford, C. (Cordelia), Lord, G. (Graham), Conlon, P. (Peter), Sandford, R. (Richard), Sheerin, N. (Neil), Vannberg, F.O. (Frederik O), Blackburn, H. (Hannah), Maxwell, A.P. (A.), Edkins, T. (Ted), Gillman, M.W. (Matthew W.), Gray, E. (Emma), Hunt, S.E. (Sarah E), Nengut, S.-G. (Suna-Gumuscu), Potter, S.C. (Simon), Rich, S.S. (Stephen), Simpkin, D. (Douglas), Whittaker, P. (Pamela), Ang, W.Q. (Wei), Atalay, M. (Mustafa), Beijsterveldt, C.E.M. (Toos) van, Bergen, N. (N.), Benke, K. (K.), Berry, D. (Diane), Boomsma, D.I. (Dorret), Bradfield, J.P. (Jonathan), Charoen, P. (Pimphen), Coin, L. (Lachlan), Cooper, C. (C.), Cousminer, D.L. (Diana), Das, S. (Shikta), Elliott, P. (P.), Evans, D.M. (D. M.), Feenstra, B. (B.), Flexeder, C. (Claudia), Frayling, T.M. (Timothy), Freathy, R.M. (Rachel), Gaillard, R. (R.), Geller, F. (Frank), Groen-Blokhuis, M. (Maria), Goh, L.K. (L. K.), Guxens Junyent, M. (Mònica), Hattersley, A.T. (Andrew), Haworth, C.M.A. (Claire M.), Hadley, D. (D.), Heinrich, J. (J.), Hirschhorn, J.N. (Joel), Hocher, B. (Berthold), Holloway, J.W. (J. W.), Holst, J.J., Hottenga, J.J. (Jouke Jan), Horikoshi, M. (Momoko), Huikari, V. (Ville), Hypponen, E. (E.), Iñiguez, C. (C.), Jaddoe, V.W. (V. W.), Jarvelin, M.R. (M. R.), Kaakinen, M. (M.), Kilpeläinen, T.O. (Tuomas), Hypponen, E. (Elina), Kowgier, M. (Matthew), Lakka, T.A. (Timo), Cooper, C. (Charles), Lange, L.A. (Leslie), Lawlor, D.A. (D. A.), Lehtimäki, T. (Terho), Lewin, A. (Alex), Elliott, P. (Paul), Lindi, V. (Virpi), Maggi, R. (Reedik), Feenstra, B. (Bjarke), McCarthy, M.I. (M. I.), Melbye, M. (Mads), Middeldorp, C.M. (Christel), Millwood, I.Y. (Iona), Mohlke, K.L. (Karen), Mook-Kanamori, D.O. (D. O.), Murray, J.C. (Jeffrey), Nivard, M. (Michel), Nohr, C. (Christian), Oken, E. (Emily), Ong, K.K. (K. K.), O'Reilly, P.F. (P. F.), Palmer, C. (Cameron), Panoutsopoulou, K. (K.), Pararajasingham, J. (Jennifer), Pearson, E.R. (E. R.), Pennell, C.E. (Craig), Power, C. (Christopher), Price, T.S. (Thomas), Prokopenko, I. (Inga), Raitakari, O.T. (O. T.), Rodriguez, A. (A.), Salem, R.M. (Rany), Saw, S.M. (S. M.), Sebert, S. (S.), Siitonen, N. (Niina), Jaddoe, V.W.V. (Vincent), Sørensen, T.I.A. (Thorkild), Sovio, U. (Ulla), Lawlor, D.A. (Debbie), Sunyer, J. (J.), Taal, H.R. (Rob), Teo, Y.Y. (Y. Y.), Thiering, E. (Elisabeth), Tiesler, C. (C.), Timpson, N.J. (Nicholas), Uitterlinden, A.G. (André), Valcárcel, B. (Beatriz), Teo, Y.Y. (Yik Ying), White, S.J. (Stefan), Willemsen, G.A.H.M. (Gonneke), Wilson, J.F. (J. F.), Yaghootkar, H. (H.), Elks, C.E. (Cathy), Perry, J.R. (J. R.), Sulem, P. (Patrick), Chasman, D.I. (Daniel), Franceschini, N. (Nora), He, C. (C.), Lunetta, K.L. (Kathryn), Visser, J.A. (Jenny), Byrne, E.M. (E. M.), Gudbjartsson, D.F. (Daniel), Koller, D.L. (Daniel), Kutalik, Z. (Zoltán), Lin, P. (P.), Mangino, M. (Massimo), Byrne, E.M. (Enda), Smith, A.V. (Albert), Stolk, L. (Lisette), Wingerden, S. (Sophie) van, Zhao, J.H. (J. H.), Albrecht, E. (Eva), Corre, T. (Tanguy), Ingelsson, E. (Erik), Hayward, C. (Caroline), Magnusson, P.K. (Patrik), Smith, A.V. (Davey), Chanock, S.J. (Stephen), Warrington, M. (M.), Zgaga, L. (L.), Alavere, H. (Helene), Amin, N. (Najaf), Aspelund, T. (T.), Ulivi, S. (Shelia), Sunyer, J. (Jordi), Berenson, G. (Gerald), Bergmann, S.M. (Sven), Boerwinkle, E. (E.), Buring, J.E. (Julie), Busonero, F. (F.), Barroso, I.E. (Inês), Chanock, S.J. (S. J.), Warrington, N.M. (Nicole), Couper, D.J. (David), Coviello, A.D. (Andrea), Busonero, F., Faire, U. (Ulf) de, de Geus, E.J. (E. J.), Deloukas, P. (Panagiotis), Döring, A. (Angela), Davey Smith, G. (G.), Adamo, P. (Pio) d', Eiriksdottir, G. (Gudny), Geus, E.J.C. (Eco) de, Hagen, K. (Knut), Ferrucci, L. (L.), Folsom, A.R. (A. R.), Foroud, T. (T.), Garcia, M.E. (M.), Gasparini, P. (P.), Gieger, C. (Christian), Gudnason, V. (V.), Folsom, A.R. (Aaron), Hankinson, S.E. (S. E.), Ferreli, L. (Liana), Gasparini, P. (Paolo), Hernandez, D.G. (Dena), Hofman, A. (Albert), Hu, F.B. (F. B.), Illig, T. (T.), Jarvelin, M.-R. (Marjo-Riitta), Johnson, A.D. (Andrew), Karasik, D. (David), Khaw, K.T. (K. T.), Kiel, D.P. (Douglas P.), Kolcic, I. (Ivana), Kraft, P. (Peter), Launer, L.J. (Lenore), Laven, J.S. (J. S.), Li, S. (S.), Liu, J. (J.), Levy, D. (D.), Martin, N.G. (N. G.), Aspelund, T. (Thor), Nalls, M.A. (Michael), Navarro, P. (Pau), Nelis, M. (M.), Ness, A.R. (A. R.), Boerwinkle, E.A. (Eric), Oostra, B.A. (Ben), Peacock, M. (M.), Pare, G. (Guillame), Parker, A.N. (Alex), Pedersen, N.L. (Nancy), Cornelis, M. (Marilyn), Polasek, O. (Ozren), Plump, A.S. (A. S.), Peacock, M. (Munro), Porcu, E. (Eleonora), Rafnar, T. (Thorunn), Rice, J.P. (John), Rivadeneira, F. (F.), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sanna, S. (Serena), Schlessinger, D. (D.), Scuteri, A. (A.), Segrè, A.V. (Ayellet), Foroud, T. (Tatiana), Srinivasan, S.R. (Sathanur), Tammesoo, M.L. (M. L.), Tikkanen, E. (Emmi), Toniolo, D. (Daniela), Scuteri, A. (Angelo), Tryggvadottir, L. (Laufey), Tyrer, J. (J.), Uda, M. (M.), van Dam, R.M. (R. M.), Meurs, J.B.J. (Joyce) van, Vollenweider, P. (Peter), Waeber, G. (Gérard), Wareham, N.J. (Nick), Waterworth, D. (Dawn), Weedon, M.N. (Michael), Wright, A.F. (Alan), Young, L. (L.), Zhai, G. (G.), Zhuang, W.V. (W. V.), Bierut, L.J. (L. J.), Boyd, H.A. (H. A.), Crisponi, L. (Laura), Demerath, E.W. (E. W.), Duijn, C.M. (Cornelia) van, Econs, M.J. (M. J.), Harris, T.B. (Tamara), Bierut, L.J. (Laura), Loos, R.J.F. (Ruth), Ridker, P.M. (Paul), Demerath, E.W. (Ellen), Streeten, E.A. (Elizabeth), Econs, M.J. (Michael), Thorsteinsdottir, U. (Unnur), Widen, E. (E.), Murabito, J. (Joanne), Ness, A.R. (Andrew), Spector, T.D. (Timothy), Crawford, S. (Steve), Crow, S. (Scott), Fichter, M.M. (M. M.), Halmi, K.A. (K. A.), Palotie, A. (Aarno), La Via, M. (Maria), Mitchell, J. (James), Strober, M. (Michael), Rotondo, A. (Alessandro), Woodside, D.B. (D Blake), Keel, P. (Pamela), Lilenfeld, L. (Lisa), Rivadeneira Ramirez, F. (Fernando), Magistretti, P. (Pierre), and Montgomery, G.W. (G. W.)
- Abstract
The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the associa
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- 2017
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32. Epigenome-Wide Association Study Identifies Methylation Sites Associated With Liver Enzymes and Hepatic Steatosis
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Nano, J. (Jana), Ghanbari, M. (Mohsen), Wang, W. (Wenshi), Vries, P.S. (Paul) de, Dhana, K. (Klodian), Muka, T. (Taulant), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Hofman, A. (Albert), Franco, O.H. (Oscar), Pan, Q. (Qiuwei), Darwish Murad, S. (Sarwa), Dehghan, A. (Abbas), Nano, J. (Jana), Ghanbari, M. (Mohsen), Wang, W. (Wenshi), Vries, P.S. (Paul) de, Dhana, K. (Klodian), Muka, T. (Taulant), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Hofman, A. (Albert), Franco, O.H. (Oscar), Pan, Q. (Qiuwei), Darwish Murad, S. (Sarwa), and Dehghan, A. (Abbas)
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_BACKGROUND & AIMS:_ Epigenetic mechanisms might be involved in the regulation of liver enzyme level. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of liver enzymes and hepatic steatosis. _METHODS:_ We conducted an epigenome-wide association study in whole blood for liver enzyme levels, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), among a discovery set of 731 participants of the Rotterdam Study and sought replication in a non-overlapping sample of 719 individuals. Significant DNA methylation changes were further analyzed to evaluate their relation with hepatic steatosis. Expression levels of the top identified gene were measured in 9 human liver cell lines and compared with expression profiles of its potential targets associated with lipid traits. The candidate gene was subsequently knocked down in human hepatoma cells using lentiviral vectors expressing small hairpin RNAs. _RESULTS:_ Eight probes annotated to SLC7A11, SLC1A5, SLC43A1, PHGDH, PSORS1C1, SREBF1, ANKS3 were associated with GGT and 1 probe annotated to SLC7A11 was associated with ALT after Bonferroni correction (1.0 × 10-7). No probe was identified for AST levels. Four probes for GGT levels including cg06690548 (SLC7A11), cg11376147 (SLC43A1), cg22304262 (SLC1A5), and cg14476101 (PHGDH), and 1 for ALT cg06690548 (SLC7A11) were replicated. DNA methylation at SLC7A11 was associated with reduced risk of hepatic steatosis in participants (odds ratio, 0.69; 95% CI= 0.55-0.93; P value: 2.7 × 10-3). In functional experiments, SLC7A11 was highly expressed in human liver cells; its expression is positively correlated with expression of a panel of lipid-associated genes, indicating a role of SLC7A11 in lipid metabolism. _CONCLUSIONS:_ Our results provide new insights into epigenetic mechanisms associated with markers of liver function and hepatic steatosis, laying the groundwork for future diagno
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- 2017
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33. Homocysteine levels associate with subtle changes in leukocyte DNA methylation: An epigenome-wide analysis
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Mandaviya, P.R. (Pooja), Aïssi, D. (Dylan), Dekkers, K.F. (Koen F), Joehanes, R. (Roby), Kasela, S. (Silva), Truong, V. (Vinh), Stolk, L. (Lisette), Heemst, D.V. (Diana Van), Ikram, M.K. (Kamran), Lindemans, J. (Jan), Slagboom, P.E. (Eline), Tregouet, D.-A. (David-Alexandre), Uitterlinden, A.G. (André), Wei, C. (Chen), Wells, P. (Phil), Gagnon, F. (France), Greevenbroek, M.M. van, Heijmans, B.T. (Bastiaan T), Milani, L. (Lili), Morange, P.-E. (P.), Meurs, J.B.J. (Joyce) van, Heil, S.G. (Sandra), Mandaviya, P.R. (Pooja), Aïssi, D. (Dylan), Dekkers, K.F. (Koen F), Joehanes, R. (Roby), Kasela, S. (Silva), Truong, V. (Vinh), Stolk, L. (Lisette), Heemst, D.V. (Diana Van), Ikram, M.K. (Kamran), Lindemans, J. (Jan), Slagboom, P.E. (Eline), Tregouet, D.-A. (David-Alexandre), Uitterlinden, A.G. (André), Wei, C. (Chen), Wells, P. (Phil), Gagnon, F. (France), Greevenbroek, M.M. van, Heijmans, B.T. (Bastiaan T), Milani, L. (Lili), Morange, P.-E. (P.), Meurs, J.B.J. (Joyce) van, and Heil, S.G. (Sandra)
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Aim: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes. Methods: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis. Results: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6. Conclusion: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.
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- 2017
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34. Epigenome-wide association study (EWAS) on lipids: the Rotterdam Study
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Braun, K.V.E. (Kim), Dhana, K. (Klodian), Vries, P.S. (Paul) de, Voortman, R.G. (Trudy), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Hu, F.B. (Frank B.), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Braun, K.V.E. (Kim), Dhana, K. (Klodian), Vries, P.S. (Paul) de, Voortman, R.G. (Trudy), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Hu, F.B. (Frank B.), Franco, O.H. (Oscar), and Dehghan, A. (Abbas)
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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.
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- 2017
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35. Cam Deformity and Acetabular Dysplasia as Risk Factors for Hip Osteoarthritis
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Saberi Hosnijeh, F. (Fatemeh), Zuiderwijk, M.E. (Maria E.), Versteeg, M. (Mathijs), Smeele, H.T.W. (Hieronymus T.W.), Hofman, A. (Albert), Uitterlinden, A.G. (André), Agricola, R. (Rintje), Oei, E.H.G. (Edwin), Waarsing, J.H. (Jan), Bierma-Zeinstra, S.M. (Sita), Meurs, J.B.J. (Joyce) van, Saberi Hosnijeh, F. (Fatemeh), Zuiderwijk, M.E. (Maria E.), Versteeg, M. (Mathijs), Smeele, H.T.W. (Hieronymus T.W.), Hofman, A. (Albert), Uitterlinden, A.G. (André), Agricola, R. (Rintje), Oei, E.H.G. (Edwin), Waarsing, J.H. (Jan), Bierma-Zeinstra, S.M. (Sita), and Meurs, J.B.J. (Joyce) van
- Abstract
Objective: Cam deformity and acetabular dysplasia have been recognized as relevant risk factors for hip osteoarthritis (OA) in a few prospective studies with limited sample sizes. To date, however, no evidence is available from prospective studies regarding whether the magnitude of these associations differs according to sex, body mass index (B
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- 2017
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36. Blood lipids influence DNA methylation in circulating cells
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Dekkers, K.F. (Koen F.), Iterson, M. (Maarten) van, Slieker, R. (Roderick), Moed, H. (Heleen), Bonder, M.J. (Marc), Van Galen, M. (Michiel), Mei, S. (Shan), Zhernakova, A. (Alexandra), Berg, L.H. (Leonard) van den, Deelen, J. (Joris), Dongen, J. (Jenny) van, Heemst, D. (Diana) van, Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Franke, L. (Lude), 't Hoen, P.A.C. (Peter A.C.), Jansen, R., Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Zwet, E.W. (Erik) van, Slagboom, P.E. (Eline), Jukema, J.W. (Jan Wouter), Heijmans, B.T. (Bastiaan), Dekkers, K.F. (Koen F.), Iterson, M. (Maarten) van, Slieker, R. (Roderick), Moed, H. (Heleen), Bonder, M.J. (Marc), Van Galen, M. (Michiel), Mei, S. (Shan), Zhernakova, A. (Alexandra), Berg, L.H. (Leonard) van den, Deelen, J. (Joris), Dongen, J. (Jenny) van, Heemst, D. (Diana) van, Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Franke, L. (Lude), 't Hoen, P.A.C. (Peter A.C.), Jansen, R., Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Zwet, E.W. (Erik) van, Slagboom, P.E. (Eline), Jukema, J.W. (Jan Wouter), and Heijmans, B.T. (Bastiaan)
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Background: Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals. Results: This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and A
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- 2016
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37. Peripheral blood transcriptomic signatures of fasting glucose and insulin concentrations
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Chen, B.H. (Brian), Hivert, M.-F. (Marie-France), Peters, M.J. (Marjolein), Pilling, L.C. (Luke), Hogan, J.D. (John D.), Pham, L.M. (Lisa M.), Harries, L.W. (Lorna), Fox, C.S. (Caroline), Bandinelli, S. (Stefania), Dehghan, A. (Abbas), Hernandez, D.G. (Dena), Hofman, A. (Albert), Hong, J. (Jaeyoung), Joehanes, R. (Roby), Johnson, A.D. (Andrew), Munson, P.J. (Peter), Rybin, D. (Denis), Singleton, A. (Andrew), Uitterlinden, A.G. (André), Ying, S.-X. (Sai-Xia), Melzer, D. (David), Levy, D. (Daniel), Meurs, J.B.J. (Joyce) van, Ferrucci, L. (Luigi), Florez, J.C. (Jose), Dupuis, J. (Josée), Meigs, J.B. (James), Kolaczyk, E.D. (Eric D.), Chen, B.H. (Brian), Hivert, M.-F. (Marie-France), Peters, M.J. (Marjolein), Pilling, L.C. (Luke), Hogan, J.D. (John D.), Pham, L.M. (Lisa M.), Harries, L.W. (Lorna), Fox, C.S. (Caroline), Bandinelli, S. (Stefania), Dehghan, A. (Abbas), Hernandez, D.G. (Dena), Hofman, A. (Albert), Hong, J. (Jaeyoung), Joehanes, R. (Roby), Johnson, A.D. (Andrew), Munson, P.J. (Peter), Rybin, D. (Denis), Singleton, A. (Andrew), Uitterlinden, A.G. (André), Ying, S.-X. (Sai-Xia), Melzer, D. (David), Levy, D. (Daniel), Meurs, J.B.J. (Joyce) van, Ferrucci, L. (Luigi), Florez, J.C. (Jose), Dupuis, J. (Josée), Meigs, J.B. (James), and Kolaczyk, E.D. (Eric D.)
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Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes-imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-Associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-Analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis.
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- 2016
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38. Epigenetic Signatures of Cigarette Smoking
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Joehanes, R. (Roby), Just, A.C. (Allan C.), Marioni, R.E. (Riccardo), Pilling, L.C. (Luke), Reynolds, L.M. (Lindsay), Mandaviya, P.R. (Pooja R.), Guan, W. (Weihua), Xu, T. (Tao), Elks, C.E. (Cathy), Aslibekyan, S. (Stella), Moreno-Macías, H. (Hortensia), Smith, J.A. (Jennifer A), Brody, J.A. (Jennifer A.), Dhingra, R. (Radhika), Yousefi, P. (Paul), Pankow, J.S. (James), Kunze, S. (Sonja), Shah, S.H. (Sonia H.), McRae, A.F. (Allan F.), Lohman, K. (Kurt), Sha, J. (Jin), Absher, D. (Devin), Ferrucci, L. (Luigi), Zhao, W. (Wei), Demerath, E.W. (Ellen), Bressler, J. (Jan), Grove, M.L. (Megan), Huan, T. (Tianxiao), Liu, C. (Chunyu), Mendelson, M.M. (Michael M.), Yao, C. (Chen), Kiel, D.P. (Douglas P.), Peters, A. (Annette), Wang-Sattler, R. (Rui), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Starr, J.M. (John), Ding, J. (Jingzhong), Rodriguez, C.J. (Carlos J.), Wareham, N.J. (Nick), Irvin, M.R. (Marguerite R.), Zhi, D. (Degui), Barrdahl, M. (Myrto), Vineis, P. (Paolo), Ambatipudi, S. (Srikant), Uitterlinden, A.G. (André), Hofman, A. (Albert), Schwartz, J. (Joel), Colicino, E. (Elena), Hou, L. (Lifang), Vokonas, P.S. (Pantel S.), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Bandinelli, S. (Stefania), Turner, S.T. (Stephen), Ware, E.B. (Erin B.), Smith, A.K. (Alicia K.), Klengel, T. (Torsten), Binder, E.B. (Elisabeth B.), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Gharib, S.A. (Sina), Swenson, B.R. (Brenton R.), Liang, L. (Liming), Demeo, D.L. (Dawn), O'Connor, G.T. (George), Herceg, Z. (Zdenko), Ressler, K.J. (Kerry J.), Conneely, K.N. (Karen N.), Sotoodehnia, N. (Nona), Kardia, S.L.R. (Sharon L. R.), Melzer, D. (David), Baccarelli, A.A. (Andrea), Meurs, J.B.J. (Joyce) van, Romieu, I. (Isabelle), Arnett, D.K. (Donna), Ong, K.K. (Ken K.), Liu, Y. (YongMei), Waldenberger, M. (Melanie), Deary, I.J. (Ian), Fornage, M. (Myriam), Levy, D. (Daniel), London, S.J. (Stephanie J.), Joehanes, R. (Roby), Just, A.C. (Allan C.), Marioni, R.E. (Riccardo), Pilling, L.C. (Luke), Reynolds, L.M. (Lindsay), Mandaviya, P.R. (Pooja R.), Guan, W. (Weihua), Xu, T. (Tao), Elks, C.E. (Cathy), Aslibekyan, S. (Stella), Moreno-Macías, H. (Hortensia), Smith, J.A. (Jennifer A), Brody, J.A. (Jennifer A.), Dhingra, R. (Radhika), Yousefi, P. (Paul), Pankow, J.S. (James), Kunze, S. (Sonja), Shah, S.H. (Sonia H.), McRae, A.F. (Allan F.), Lohman, K. (Kurt), Sha, J. (Jin), Absher, D. (Devin), Ferrucci, L. (Luigi), Zhao, W. (Wei), Demerath, E.W. (Ellen), Bressler, J. (Jan), Grove, M.L. (Megan), Huan, T. (Tianxiao), Liu, C. (Chunyu), Mendelson, M.M. (Michael M.), Yao, C. (Chen), Kiel, D.P. (Douglas P.), Peters, A. (Annette), Wang-Sattler, R. (Rui), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Starr, J.M. (John), Ding, J. (Jingzhong), Rodriguez, C.J. (Carlos J.), Wareham, N.J. (Nick), Irvin, M.R. (Marguerite R.), Zhi, D. (Degui), Barrdahl, M. (Myrto), Vineis, P. (Paolo), Ambatipudi, S. (Srikant), Uitterlinden, A.G. (André), Hofman, A. (Albert), Schwartz, J. (Joel), Colicino, E. (Elena), Hou, L. (Lifang), Vokonas, P.S. (Pantel S.), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Bandinelli, S. (Stefania), Turner, S.T. (Stephen), Ware, E.B. (Erin B.), Smith, A.K. (Alicia K.), Klengel, T. (Torsten), Binder, E.B. (Elisabeth B.), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Gharib, S.A. (Sina), Swenson, B.R. (Brenton R.), Liang, L. (Liming), Demeo, D.L. (Dawn), O'Connor, G.T. (George), Herceg, Z. (Zdenko), Ressler, K.J. (Kerry J.), Conneely, K.N. (Karen N.), Sotoodehnia, N. (Nona), Kardia, S.L.R. (Sharon L. R.), Melzer, D. (David), Baccarelli, A.A. (Andrea), Meurs, J.B.J. (Joyce) van, Romieu, I. (Isabelle), Arnett, D.K. (Donna), Ong, K.K. (Ken K.), Liu, Y. (YongMei), Waldenberger, M. (Melanie), Deary, I.J. (Ian), Fornage, M. (Myriam), Levy, D. (Daniel), and London, S.J. (Stephanie J.)
- Abstract
Background-DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results-To comprehensively determine the association between cigarette smoki
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- 2016
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39. Association between biomarkers of tissue inflammation and progression of osteoarthritis: evidence from the Rotterdam study cohort
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Hosnijeh, F.S. (Fatemeh Saberi), Siebuhr, A.S. (Anne Sofie), Uitterlinden, A.G. (André), Oei, E.H.G. (Edwin), Hofman, A. (Albert), Karsdal, M.A. (Ma), Bierma-Zeinstra, S.M. (Sita), Bay-Jensen, A.C. (Anne), Meurs, J.B.J. (Joyce) van, Hosnijeh, F.S. (Fatemeh Saberi), Siebuhr, A.S. (Anne Sofie), Uitterlinden, A.G. (André), Oei, E.H.G. (Edwin), Hofman, A. (Albert), Karsdal, M.A. (Ma), Bierma-Zeinstra, S.M. (Sita), Bay-Jensen, A.C. (Anne), and Meurs, J.B.J. (Joyce) van
- Abstract
__Background:__ We aimed to investigate the prognostic value of two biomarkers of tissue inflammation, matrix metalloproteinase-dependent degradation of C-reactive protein (CRPM) and connective tissue type I collagen turnover (C1M), on the incidence and progression of radiographic osteoarthritis (OA) in the Rotterdam Study, a prospective cohort. Moreover, the independent effect of these biomarkers with respect to the established biomarkers of OA progression, like urinary type II collagen degradation (uCTX-II) and serum cartilage oligomeric protein (COMP), was evaluated. __Methods:__ Serum levels of C1M, CRPM, COMP and CRP of 1335 participants aged >55 years were measured in fasting serum using ELISA. The commercial ELISA detecting CTX-II was used in urine. Radiographs at baseline and 5-year follow-up were scored for OA stage by Kellgren-Lawrence grade. The associations between progression and incidence of OA and the baseline biomarkers were examined using logistic regression and generalized estimating equations adjusted for age, sex, BMI, and possible other confounders. __Results:__ The uCTX-II, COMP, and CRP concentrations were associated with the incidence and progression of OA. Moreover, OA progression was positively associated with CRPM (OR = 1.3, p = 0.01) and CRP (OR = 1.3, p = 0.01) levels with similar effect size as uCTX-II (OR = 1.3, p = 0.01) and COMP (OR = 1.2, p = 0.02). CRPM had prognostic value for progression of OA independent from the uCTX-II and COMP. __Conclusions:__ Our study confirmed the associations between uCTX-II and COMP concentrations and OA progression. Importantly, we showed for the first time that CRPM predicts the risk of OA progression independent of the established biomarkers uCTX-II and COMP.
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- 2016
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40. Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs
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Ricaño-Ponce, I. (Isis), Zhernakova, A. (Alexandra), Deelen, P. (Patrick), Luo, O. (Oscar), Li, X. (Xingwang), Isaacs, A. (Aaron), Karjalainen, J. (Juha), Di Tommaso, J. (Jennifer), Borek, Z.A. (Zuzanna Agnieszka), Zorro, M.M. (Maria M.), Gutierrez-Achury, J. (Javier), Uitterlinden, A.G. (André), Hofman, A. (Albert), Meurs, J.B.J. (Joyce) van, Netea, M.G. (Mihai), Jonkers, I.H. (Iris H.), Withoff, S. (Sebo), Duijn, C.M. (Cornelia) van, Li, Y. (Yang), Ruan, Y. (Yijun), Franke, L. (Lude), Wijmenga, C. (Cisca), Kumar, V. (Vinod), BIOS consortium, Ricaño-Ponce, I. (Isis), Zhernakova, A. (Alexandra), Deelen, P. (Patrick), Luo, O. (Oscar), Li, X. (Xingwang), Isaacs, A. (Aaron), Karjalainen, J. (Juha), Di Tommaso, J. (Jennifer), Borek, Z.A. (Zuzanna Agnieszka), Zorro, M.M. (Maria M.), Gutierrez-Achury, J. (Javier), Uitterlinden, A.G. (André), Hofman, A. (Albert), Meurs, J.B.J. (Joyce) van, Netea, M.G. (Mihai), Jonkers, I.H. (Iris H.), Withoff, S. (Sebo), Duijn, C.M. (Cornelia) van, Li, Y. (Yang), Ruan, Y. (Yijun), Franke, L. (Lude), Wijmenga, C. (Cisca), Kumar, V. (Vinod), and BIOS consortium
- Abstract
Genome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene closest to the AID SNP, which was the case in nearly 50% of cases.
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- 2016
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41. Tobacco smoking is associated with DNA methylation of diabetes susceptibility genes
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Ligthart, S. (Symen), Steenaard, R.V. (Rebecca), Peters, M.J. (Marjolein), Meurs, J.B.J. (Joyce) van, Sijbrands, E.J.G. (Eric), Uitterlinden, A.G. (André), Bonder, M.J. (Marc), Hofman, A. (Albert), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Ligthart, S. (Symen), Steenaard, R.V. (Rebecca), Peters, M.J. (Marjolein), Meurs, J.B.J. (Joyce) van, Sijbrands, E.J.G. (Eric), Uitterlinden, A.G. (André), Bonder, M.J. (Marc), Hofman, A. (Albert), Franco, O.H. (Oscar), and Dehghan, A. (Abbas)
- Abstract
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 = 0.0
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- 2016
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42. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis
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Castaño Betancourt, M.C. (Martha), Evans, D.S. (Daniel), Ramos, Y.F.M. (Yolande), Boer, C.G. (Cindy G.), Metrustry, S. (Sarah), Liu, Y. (Youfang), Hollander, W. (Wouter) den, Rooij, J.G.J. (Jeroen) van, Kraus, V.B. (Virginia B.), Yau, M.S. (Michelle S.), Mitchell, B.D. (Braxton), Muir, K. (Kenneth), Hofman, A. (Albert), Doherty, M. (Michael), Doherty, S. (Sally), Zhang, W. (Weiya), Kraaij, R. (Robert), Rivadeneira Ramirez, F. (Fernando), Barrett-Connor, E. (Elizabeth), MacIewicz, R.A. (Rose), Arden, N.K. (Nigel), Nelissen, R.G.H.H. (Rob), Kloppenburg, M. (Margreet), Jordan, J.M. (Joanne M.), Nevitt, M.C. (Michael), Slagboom, P.E. (Eline), Hart, D. (Deborah), Lafeber, F.P.J.G. (Floris), Styrkarsdottir, U. (Unnur), Zeggini, E. (Eleftheria), Evangelou, E. (Evangelos), Spector, T.D. (Timothy), Uitterlinden, A.G. (André), Lane, N.E., Meulenbelt, I. (Ingrid), Valdes, A.M. (Ana Maria), Meurs, J.B.J. (Joyce) van, Castaño Betancourt, M.C. (Martha), Evans, D.S. (Daniel), Ramos, Y.F.M. (Yolande), Boer, C.G. (Cindy G.), Metrustry, S. (Sarah), Liu, Y. (Youfang), Hollander, W. (Wouter) den, Rooij, J.G.J. (Jeroen) van, Kraus, V.B. (Virginia B.), Yau, M.S. (Michelle S.), Mitchell, B.D. (Braxton), Muir, K. (Kenneth), Hofman, A. (Albert), Doherty, M. (Michael), Doherty, S. (Sally), Zhang, W. (Weiya), Kraaij, R. (Robert), Rivadeneira Ramirez, F. (Fernando), Barrett-Connor, E. (Elizabeth), MacIewicz, R.A. (Rose), Arden, N.K. (Nigel), Nelissen, R.G.H.H. (Rob), Kloppenburg, M. (Margreet), Jordan, J.M. (Joanne M.), Nevitt, M.C. (Michael), Slagboom, P.E. (Eline), Hart, D. (Deborah), Lafeber, F.P.J.G. (Floris), Styrkarsdottir, U. (Unnur), Zeggini, E. (Eleftheria), Evangelou, E. (Evangelos), Spector, T.D. (Timothy), Uitterlinden, A.G. (André), Lane, N.E., Meulenbelt, I. (Ingrid), Valdes, A.M. (Ana Maria), and Meurs, J.B.J. (Joyce) van
- Abstract
Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547
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- 2016
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43. Translation of clinical problems in osteoarthritis into pathophysiological research goals
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Kraan, P.M. (Peter) van der, Berenbaum, F. (Francis), Blanco, F.J. (Francisco J.), Cosimo, D.B. (De Bari), Lafeber, F.P.J.G. (Floris), Hauge, E. (Ellen), Higginbottom, A. (Adele), Ioan-Facsinay, A. (Andrea), Loughlin, J. (John), Meulenbelt, I. (Ingrid), Moilanen, E. (Eeva), Pitsillidou, I. (Irene), Tsezou, A. (Aspasia), Meurs, J.B.J. (Joyce) van, Vincent, T.L., Wittoek, R. (Ruth), Lories, R.J. (Rik), Kraan, P.M. (Peter) van der, Berenbaum, F. (Francis), Blanco, F.J. (Francisco J.), Cosimo, D.B. (De Bari), Lafeber, F.P.J.G. (Floris), Hauge, E. (Ellen), Higginbottom, A. (Adele), Ioan-Facsinay, A. (Andrea), Loughlin, J. (John), Meulenbelt, I. (Ingrid), Moilanen, E. (Eeva), Pitsillidou, I. (Irene), Tsezou, A. (Aspasia), Meurs, J.B.J. (Joyce) van, Vincent, T.L., Wittoek, R. (Ruth), and Lories, R.J. (Rik)
- Abstract
Osteoarthritis (OA) accounts for more disability among the elderly than any other disease and is associated with an increased mortality rate. The prevalence in Europe will rise in the future since this continent has a strongly ageing population and an obesity epidemic; obesity and age both being major risk factors for OA. No adequate therapeutic options, besides joint replacement, are available, although they are greatly needed and should be acquired by adequate research investments. However, the perspective on OA from a researcher's point of view is not always aligned with the perspective of a patient with OA. Researchers base their views on OA mainly on abnormalities in structure and function while patients consider OA as a collection of symptoms. In this viewpoint paper, we discuss the possibility of translating the most important clinical problems into pathophysiological research goals to facilitate the translation from bench to bedside and vice versa. This viewpoint is the outcome of a dialogue within the 'European League Against Rheumatism study group on OA' and People with Arthritis/Rheumatism across Europe (PARE) representatives.
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- 2016
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44. Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms
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Slieker, R. (Roderick), Iterson, M. (Maarten) van, Luijk, R. (René), Beekman, M. (Marian), Zhernakova, A. (Alexandra), Moed, H. (Heleen), Mei, S. (Shan), Van Galen, M. (Michiel), Deelen, P. (Patrick), Bonder, M.J. (Marc), Uitterlinden, A.G. (André), Tigchelaar, E.F. (Ettje F.), Stehouwer, C.D.A. (Coen D.A.), Schalkwijk, C.G. (Casper), Kallen, C.J. van der, Hofman, A. (Albert), Heemst, D. (Diana) van, Geus, E.J.C. (Eco) de, Dongen, J. (Jenny) van, Deelen, J. (Joris), Berg, L.H. (Leonard) van den, Meurs, J.B.J. (Joyce) van, Jansen, R., Hoen, P.A.C. (Peter) 't, Franke, L. (Lude), Wijmenga, C. (Cisca), Veldink, J.H. (Jan), Swertz, M. (Morris), Greevenbroek, M.M. van, Duijn, C.M. (Cornelia) van, Boomsma, D.I. (Dorret), Slagboom, P.E. (Eline), Heijmans, B.T. (Bastiaan), Slieker, R. (Roderick), Iterson, M. (Maarten) van, Luijk, R. (René), Beekman, M. (Marian), Zhernakova, A. (Alexandra), Moed, H. (Heleen), Mei, S. (Shan), Van Galen, M. (Michiel), Deelen, P. (Patrick), Bonder, M.J. (Marc), Uitterlinden, A.G. (André), Tigchelaar, E.F. (Ettje F.), Stehouwer, C.D.A. (Coen D.A.), Schalkwijk, C.G. (Casper), Kallen, C.J. van der, Hofman, A. (Albert), Heemst, D. (Diana) van, Geus, E.J.C. (Eco) de, Dongen, J. (Jenny) van, Deelen, J. (Joris), Berg, L.H. (Leonard) van den, Meurs, J.B.J. (Joyce) van, Jansen, R., Hoen, P.A.C. (Peter) 't, Franke, L. (Lude), Wijmenga, C. (Cisca), Veldink, J.H. (Jan), Swertz, M. (Morris), Greevenbroek, M.M. van, Duijn, C.M. (Cornelia) van, Boomsma, D.I. (Dorret), Slagboom, P.E. (Eline), and Heijmans, B.T. (Bastiaan)
- Abstract
Background: Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages. Results: Here, we report on the large-scale identification of 6366 age-related variably methylated positions (aVMPs) identified in 3295 whole blood DNA methylation profiles, 2044 of which have a matching RNA-seq gene expression profile. aVMPs are enriched at polycomb repressed regions and, accordingly, methylation at those positions is associated with the expression of genes encoding components of polycomb repressive complex 2 (PRC2) in trans. Further analysis revealed trans-associations for 1816 aVMPs with an additional 854 genes. These trans-associated aVMPs are characterized by either an age-related g
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- 2016
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45. Association of Forced Vital Capacity with the Developmental Gene NCOR2
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Minelli, C. (Cosetta), Dean, C.H. (Charlotte H.), Hind, M. (Matthew), Alves, A.C. (Alexessander Couto), Amaral, A.F.S. (André), Siroux, V. (V.), Huikari, V. (Ville), Artigas, M.S., Evans, D.M. (David M.), Loth, D.W. (Daan), Bossé, Y. (Yohan), Postma, D.S. (Dirkje), Sin, D.D., Thompson, J.R. (John), Demenais, F. (Florence), Henderson, J. (John), Bouzigon, E. (Emmanuelle), Jarvis, D.L. (Deborah), Jarvelin, M.-R. (Marjo-Riitta), Burney, P.G., Gharib, S.A. (Sina), Wain, L.V. (Louise), Franceschini, N. (Nora), Koch, B. (Beate), Pottinger, T.D. (Tess), Smith, A.V. (Albert), Duan, Q. (Qing), Oldmeadow, C. (Christopher), Lee, M.K. (Mi Kyeong), Strachan, D.P. (David P.), James, A.L. (Alan L.), Huffman, J.E. (Jennifer), Vitart, V. (Veronique), Ramasamy, A. (Adaikalavan), Wareham, N.J. (Nicholas J.), Kaprio, J. (Jaakko), Wang, X.-Q. (Xin-Qun), Trochet, H. (Holly), Kähönen, M. (Mika), Flexeder, C. (Claudia), Albrecht, E. (Eva), Lopez, L.M. (Lorna M.), Jong, K. (Kim) de, Thyagarajan, B. (Bharat), Enroth, S. (Stefan), Omenaas, E. (Ernst), Joshi, P.K. (Peter), Fall, M. (Magnus), Viñuela, A. (Ana), Launer, L.J. (Lenore), Loehr, L.R. (Laura), Fornage, M. (Myriam), Li, G. (Guo), Wilk, J.B. (Jemma), Tang, W. (Wenbo), Manichaikul, A. (Ani), Lahousse, L. (Lies), Harris, T.B. (Tamara), North, K.E. (Kari E.), Rudnicka, A.R. (Alicja), Hui, J. (Jennie), Gu, X. (Xiangjun), Lumley, T. (Thomas), Wright, A.F. (Alan F.), Hastie, N. (Nick), Campbell, S. (Susan), Kumar, R. (Rajesh), Pin, I. (Isabelle), Scott, R.A. (Robert), Pietilainen, K.H. (Kirsi Hannele), Surakka, I. (Ida), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Schulz, H. (Holger), Heinrich, J. (Joachim), Davies, G. (Gail), MVonk, J. (Judith), Wojczynski, M.K. (Mary ), Pouta, A. (Anneli), Johansson, A. (Åsa), Wild, S. (Sarah), Ingelsson, E. (Erik), Rivadeneira Ramirez, F. (Fernando), Völzke, H. (Henry), Hysi, P.G. (Pirro), Eiriksdottir, G. (Gudny), Morrison, A.C. (Alanna), Rotter, J.I. (Jerome I.), Gao, W. (Wei), White, W.B. (Wendy), Rich, S.S. (Stephen S.), Hofman, A. (Albert), Aspelund, T. (Thor), Couper, D.J. (David), Smith, L.J. (Lewis J.), Psaty, B.M. (Bruce), Lohman, K. (Kurt), Burchard, E.G. (Esteban), Uitterlinden, A.G. (André), Garcia, M. (Melissa), Joubert, B.R. (Bonnie), McArdle, W.L. (Wendy), Musk, A.B. (A Bill), Hansel, C.R.W. (Christian), Heckbert, S.R. (Susan), Zgaga, L. (Lina), Meurs, J.B.J. (Joyce) van, Navarro, P. (Pau), Rudan, I. (Igor), Oh, Y.-M. (Yeon-Mok), Redline, S. (Susan), Jarvis, D.L. (Deborah L.), Zhao, J.H. (Jing Hua), Rantanen, T. (Taina), Connor, G.T. (George) O', Ripatti, S. (Samuli), Scott, R.J. (Rodney), Karrasch, S. (Stefan), Grallert, H. (Harald), Gaddis, N.C. (Nathan C.), MStarr, J. (John), Wijmenga, C. (Cisca), Minster, R.L. (Ryan), Lederer, C.W. (Carsten), Pekkanen, J. (Juha), Gyllensten, U. (Ulf), Campbell, H. (Harry), Morris, A.P. (Andrew), Gläser, S. (Sven), Hammond, C.J. (Christopher J.), MBurkart, K. (Kristin), Beilby, J. (John), Kritchevsky, S.B. (Stephen B.), Gudnason, V. (Vilmundur), Hancock, D.B. (Dana), Williams, O. (O'Dale), Polasek, O. (Ozren), Zemunik, T. (Tatijana), Kolcic, I. (Ivana), Petrini, M.F. (Marcy), Wjst, M. (Matthias), Kim, W.J. (Woo Jin), Porteous, D.J. (David J.), Scotland, G. (Generation), Smith, B.H. (Blair), Viljanen, A. (Anne), Heliovaara, M. (Markku), Attia, J. (John), Sayers, I. (Ian), Hampel, R. (Regina), Gieger, C. (Christian), Deary, I.J. (Ian), Boezen, H.M. (Marike), Newman, A.B. (Anne B.), Wilson, J.F. (James F), Lind, L. (Lars), Stricker, B.H.Ch. (Bruno), Teumer, A. (Alexander), Spector, T.D. (Timothy), Melén, E. (Erik), Peters, M.J. (Marjolein), Lange, L.A. (Leslie), Barr, R.G. (Graham), Bracke, K.R. (Ken), MVerhamme, F. (Fien), Sung, J. (Joohon), Hiemstra, P.S. (Pieter), Cassano, P.A. (Patricia), Sood, A. (Akshay), Hayward, C. (Caroline), Dupuis, J. (Josée), Hall, I.P. (Ian), Brusselle, G.G. (Guy), Tobin, M.D. (Martin), London, S.J. (Stephanie J), Minelli, C. (Cosetta), Dean, C.H. (Charlotte H.), Hind, M. (Matthew), Alves, A.C. (Alexessander Couto), Amaral, A.F.S. (André), Siroux, V. (V.), Huikari, V. (Ville), Artigas, M.S., Evans, D.M. (David M.), Loth, D.W. (Daan), Bossé, Y. (Yohan), Postma, D.S. (Dirkje), Sin, D.D., Thompson, J.R. (John), Demenais, F. (Florence), Henderson, J. (John), Bouzigon, E. (Emmanuelle), Jarvis, D.L. (Deborah), Jarvelin, M.-R. (Marjo-Riitta), Burney, P.G., Gharib, S.A. (Sina), Wain, L.V. (Louise), Franceschini, N. (Nora), Koch, B. (Beate), Pottinger, T.D. (Tess), Smith, A.V. (Albert), Duan, Q. (Qing), Oldmeadow, C. (Christopher), Lee, M.K. (Mi Kyeong), Strachan, D.P. (David P.), James, A.L. (Alan L.), Huffman, J.E. (Jennifer), Vitart, V. (Veronique), Ramasamy, A. (Adaikalavan), Wareham, N.J. (Nicholas J.), Kaprio, J. (Jaakko), Wang, X.-Q. (Xin-Qun), Trochet, H. (Holly), Kähönen, M. (Mika), Flexeder, C. (Claudia), Albrecht, E. (Eva), Lopez, L.M. (Lorna M.), Jong, K. (Kim) de, Thyagarajan, B. (Bharat), Enroth, S. (Stefan), Omenaas, E. (Ernst), Joshi, P.K. (Peter), Fall, M. (Magnus), Viñuela, A. (Ana), Launer, L.J. (Lenore), Loehr, L.R. (Laura), Fornage, M. (Myriam), Li, G. (Guo), Wilk, J.B. (Jemma), Tang, W. (Wenbo), Manichaikul, A. (Ani), Lahousse, L. (Lies), Harris, T.B. (Tamara), North, K.E. (Kari E.), Rudnicka, A.R. (Alicja), Hui, J. (Jennie), Gu, X. (Xiangjun), Lumley, T. (Thomas), Wright, A.F. (Alan F.), Hastie, N. (Nick), Campbell, S. (Susan), Kumar, R. (Rajesh), Pin, I. (Isabelle), Scott, R.A. (Robert), Pietilainen, K.H. (Kirsi Hannele), Surakka, I. (Ida), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Schulz, H. (Holger), Heinrich, J. (Joachim), Davies, G. (Gail), MVonk, J. (Judith), Wojczynski, M.K. (Mary ), Pouta, A. (Anneli), Johansson, A. (Åsa), Wild, S. (Sarah), Ingelsson, E. (Erik), Rivadeneira Ramirez, F. (Fernando), Völzke, H. (Henry), Hysi, P.G. (Pirro), Eiriksdottir, G. (Gudny), Morrison, A.C. (Alanna), Rotter, J.I. (Jerome I.), Gao, W. (Wei), White, W.B. (Wendy), Rich, S.S. (Stephen S.), Hofman, A. (Albert), Aspelund, T. (Thor), Couper, D.J. (David), Smith, L.J. (Lewis J.), Psaty, B.M. (Bruce), Lohman, K. (Kurt), Burchard, E.G. (Esteban), Uitterlinden, A.G. (André), Garcia, M. (Melissa), Joubert, B.R. (Bonnie), McArdle, W.L. (Wendy), Musk, A.B. (A Bill), Hansel, C.R.W. (Christian), Heckbert, S.R. (Susan), Zgaga, L. (Lina), Meurs, J.B.J. (Joyce) van, Navarro, P. (Pau), Rudan, I. (Igor), Oh, Y.-M. (Yeon-Mok), Redline, S. (Susan), Jarvis, D.L. (Deborah L.), Zhao, J.H. (Jing Hua), Rantanen, T. (Taina), Connor, G.T. (George) O', Ripatti, S. (Samuli), Scott, R.J. (Rodney), Karrasch, S. (Stefan), Grallert, H. (Harald), Gaddis, N.C. (Nathan C.), MStarr, J. (John), Wijmenga, C. (Cisca), Minster, R.L. (Ryan), Lederer, C.W. (Carsten), Pekkanen, J. (Juha), Gyllensten, U. (Ulf), Campbell, H. (Harry), Morris, A.P. (Andrew), Gläser, S. (Sven), Hammond, C.J. (Christopher J.), MBurkart, K. (Kristin), Beilby, J. (John), Kritchevsky, S.B. (Stephen B.), Gudnason, V. (Vilmundur), Hancock, D.B. (Dana), Williams, O. (O'Dale), Polasek, O. (Ozren), Zemunik, T. (Tatijana), Kolcic, I. (Ivana), Petrini, M.F. (Marcy), Wjst, M. (Matthias), Kim, W.J. (Woo Jin), Porteous, D.J. (David J.), Scotland, G. (Generation), Smith, B.H. (Blair), Viljanen, A. (Anne), Heliovaara, M. (Markku), Attia, J. (John), Sayers, I. (Ian), Hampel, R. (Regina), Gieger, C. (Christian), Deary, I.J. (Ian), Boezen, H.M. (Marike), Newman, A.B. (Anne B.), Wilson, J.F. (James F), Lind, L. (Lars), Stricker, B.H.Ch. (Bruno), Teumer, A. (Alexander), Spector, T.D. (Timothy), Melén, E. (Erik), Peters, M.J. (Marjolein), Lange, L.A. (Leslie), Barr, R.G. (Graham), Bracke, K.R. (Ken), MVerhamme, F. (Fien), Sung, J. (Joohon), Hiemstra, P.S. (Pieter), Cassano, P.A. (Patricia), Sood, A. (Akshay), Hayward, C. (Caroline), Dupuis, J. (Josée), Hall, I.P. (Ian), Brusselle, G.G. (Guy), Tobin, M.D. (Martin), and London, S.J. (Stephanie J)
- Abstract
Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 chil
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- 2016
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46. Gene transcripts associated with muscle strength: A CHARGE meta-analysis of 7,781 persons
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Pilling, L.C. (Luke), Joehanes, R. (Roby), Kacprowski, T. (Tim), Peters, M.J. (Marjolein), Jansen, R., Karasik, D. (David), Kiel, D.P. (Douglas P.), Harries, L.W. (Lorna), Teumer, A. (Alexander), Powell, J., Levy, D. (Daniel), Lin, H., Lunetta, K.L. (Kathryn), Munson, P.J. (Peter), Bandinelli, S. (Stefania), Henley, W., Hernandez, D.G. (Dena), Singleton, A., Tanaka, T., Grootheest, G. (Gerard) van, Hofman, A. (Albert), Uitterlinden, A.G. (André), Biffar, R. (Reiner), Gläser, S., Homuth, G. (Georg), Malsch, C., Völker, U. (Uwe), Penninx, B.W.J.H. (Brenda W.J.H.), Meurs, J.B.J. (Joyce) van, Ferrucci, L. (Luigi), Kocher, T., Murabito, J. (Joanne), Melzer, D. (David), Pilling, L.C. (Luke), Joehanes, R. (Roby), Kacprowski, T. (Tim), Peters, M.J. (Marjolein), Jansen, R., Karasik, D. (David), Kiel, D.P. (Douglas P.), Harries, L.W. (Lorna), Teumer, A. (Alexander), Powell, J., Levy, D. (Daniel), Lin, H., Lunetta, K.L. (Kathryn), Munson, P.J. (Peter), Bandinelli, S. (Stefania), Henley, W., Hernandez, D.G. (Dena), Singleton, A., Tanaka, T., Grootheest, G. (Gerard) van, Hofman, A. (Albert), Uitterlinden, A.G. (André), Biffar, R. (Reiner), Gläser, S., Homuth, G. (Georg), Malsch, C., Völker, U. (Uwe), Penninx, B.W.J.H. (Brenda W.J.H.), Meurs, J.B.J. (Joyce) van, Ferrucci, L. (Luigi), Kocher, T., Murabito, J. (Joanne), and Melzer, D. (David)
- Abstract
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 l
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- 2016
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47. To the editor: Uncompromised 10-year survival of oldest old carrying somatic mutations in DNMT3A and TET2
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Akker, E.B. (Erik) van den, Pitts, S.J. (Steven J.), Deelen, J. (Joris), Moed, H. (Heleen), Potluri, S. (Shobha), Rooij, J.G.J. (Jeroen) van, Suchiman, H.E.D. (Eka), Lakenberg, N. (Nico), De Dijcker, W.J. (Wesley J.), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Hofman, A. (Albert), De Craen, A.J.M. (Anton J. M.), Houwing-Duistermaat, J.J. (Jeanine), Van Ommen, G.-J.B. (Gert-Jan B.), Cox, D.R. (David), Meurs, J.B.J. (Joyce) van, Beekman, M. (Marian), Reinders, M.J. (Marcel), Slagboom, P.E. (Eline), Akker, E.B. (Erik) van den, Pitts, S.J. (Steven J.), Deelen, J. (Joris), Moed, H. (Heleen), Potluri, S. (Shobha), Rooij, J.G.J. (Jeroen) van, Suchiman, H.E.D. (Eka), Lakenberg, N. (Nico), De Dijcker, W.J. (Wesley J.), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Hofman, A. (Albert), De Craen, A.J.M. (Anton J. M.), Houwing-Duistermaat, J.J. (Jeanine), Van Ommen, G.-J.B. (Gert-Jan B.), Cox, D.R. (David), Meurs, J.B.J. (Joyce) van, Beekman, M. (Marian), Reinders, M.J. (Marcel), and Slagboom, P.E. (Eline)
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- 2016
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48. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index
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Felix, J.F. (Janine), Bradfield, J.P. (Jonathan), Poppelaars-Monnereau, C. (Claire), Valk, R.J.P. (Ralf) van der, Stergiakouli, E. (Evie), Chesi, A. (Alessandra), Gaillard, R. (Romy), Feenstra, B. (Bjarke), Thiering, E. (Elisabeth), Kreiner-Møller, E. (Eskil), Mahajan, A. (Anubha), Pitkänen, N. (Niina), Joro, R. (Raimo), Cavadino, A. (Alana), Huikari, V. (Ville), Franks, S. (Steve), Groen-Blokhuis, M. (Maria), Cousminer, D.L. (Diana), Marsh, J.A. (Julie), Lehtimäki, T. (Terho), Curtin, J.A. (John), Vioque, J. (Jesus), Ahluwalia, T.S. (Tarunveer Singh), Myhre, R. (Ronny), Price, T.S. (Thomas), Vilor-Tejedor, N. (Natalia), Yengo, L. (Loic), Grarup, N. (Niels), Ntalla, I. (Ioanna), Ang, W.Q. (Wei), Atalay, M. (Mustafa), Bisgaard, H. (Hans), Blakemore, A.I.F. (Alexandra), Bonnefond, A. (Amélie), Carstensen, L. (Lisbeth), Eriksson, J.G. (Johan G.), Flexeder, C. (Claudia), Franke, L. (Lude), Geller, F. (Frank), Geserick, M. (Mandy), Hartikainen, A.L., Haworth, C.M.A. (Claire M.), Hirschhorn, J.N. (Joel N.), Hofman, A. (Albert), Holm, J.-C. (Jens-Christian), Horikoshi, M. (Momoko), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Kadarmideen, H.N. (Haja N.), Kähönen, M. (Mika), Kiess, W. (Wieland), Lakka, T.A. (Timo), Lewin, A. (Alex), Liang, L. (Liming), Lyytikäinen, L.-P. (Leo-Pekka), Ma, B. (Baoshan), Magnus, P. (Per), McCormack, S.E. (Shana E.), Mcmahon, G. (George), Mentch, F.D. (Frank), Middeldorp, C.M. (Christel), Murray, C.S. (Clare S.), Pahkala, K. (Katja), Pers, T.H. (Tune), Pfäffle, R. (Roland), Postma, D.S. (Dirkje), Power, C. (Christine), Simpson, A. (Angela), Sengpiel, V. (Verena), Tiesler, C. (Carla), Torrent, M. (Maties), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Vinding, R. (Rebecca), Waage, J. (Johannes), Wardle, J. (Jane), Zeggini, E. (Eleftheria), Zemel, B.S. (Babette S.), Dedoussis, G.V. (George), Pedersen, O. (Oluf), Froguel, P. (Philippe), Sunyer, J. (Jordi), Plomin, R. (Robert), Jacobsson, B. (Bo), Hansen, T. (Torben), Gonzalez, J.R. (Juan R.), Custovic, A. (Adnan), Raitakari, O.T. (Olli T.), Pennell, C.E. (Craig), Widén, E. (Elisabeth), Boomsma, D.I. (Dorret), Koppelman, G.H. (Gerard), Sebert, S. (Sylvain), Jarvelin, M.-R. (Marjo-Riitta), Hypponen, E. (Elina), McCarthy, M.I. (Mark), Lindi, V. (Virpi), Harri, N. (Niinikoski), Körner, A. (Antje), Bønnelykke, K. (Klaus), Heinrich, J. (Joachim), Melbye, M. (Mads), Rivadeneira Ramirez, F. (Fernando), Hakonarson, H. (Hakon), Ring, S.M. (Susan), Smith, A.V. (Davey), Sørensen, T.I.A. (Thorkild I.A.), Timpson, N.J. (Nicholas), Grant, S.F.A. (Struan), Jaddoe, V.W.V. (Vincent), Kalkwarf, H.J. (Heidi J.), Lappe, J.M. (Joan M.), Gilsanz, V. (Vicente), Oberfield, S.E. (Sharon E.), Shepherd, J.A. (John A.), Kelly, A. (Andrea), Felix, J.F. (Janine), Bradfield, J.P. (Jonathan), Poppelaars-Monnereau, C. (Claire), Valk, R.J.P. (Ralf) van der, Stergiakouli, E. (Evie), Chesi, A. (Alessandra), Gaillard, R. (Romy), Feenstra, B. (Bjarke), Thiering, E. (Elisabeth), Kreiner-Møller, E. (Eskil), Mahajan, A. (Anubha), Pitkänen, N. (Niina), Joro, R. (Raimo), Cavadino, A. (Alana), Huikari, V. (Ville), Franks, S. (Steve), Groen-Blokhuis, M. (Maria), Cousminer, D.L. (Diana), Marsh, J.A. (Julie), Lehtimäki, T. (Terho), Curtin, J.A. (John), Vioque, J. (Jesus), Ahluwalia, T.S. (Tarunveer Singh), Myhre, R. (Ronny), Price, T.S. (Thomas), Vilor-Tejedor, N. (Natalia), Yengo, L. (Loic), Grarup, N. (Niels), Ntalla, I. (Ioanna), Ang, W.Q. (Wei), Atalay, M. (Mustafa), Bisgaard, H. (Hans), Blakemore, A.I.F. (Alexandra), Bonnefond, A. (Amélie), Carstensen, L. (Lisbeth), Eriksson, J.G. (Johan G.), Flexeder, C. (Claudia), Franke, L. (Lude), Geller, F. (Frank), Geserick, M. (Mandy), Hartikainen, A.L., Haworth, C.M.A. (Claire M.), Hirschhorn, J.N. (Joel N.), Hofman, A. (Albert), Holm, J.-C. (Jens-Christian), Horikoshi, M. (Momoko), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Kadarmideen, H.N. (Haja N.), Kähönen, M. (Mika), Kiess, W. (Wieland), Lakka, T.A. (Timo), Lewin, A. (Alex), Liang, L. (Liming), Lyytikäinen, L.-P. (Leo-Pekka), Ma, B. (Baoshan), Magnus, P. (Per), McCormack, S.E. (Shana E.), Mcmahon, G. (George), Mentch, F.D. (Frank), Middeldorp, C.M. (Christel), Murray, C.S. (Clare S.), Pahkala, K. (Katja), Pers, T.H. (Tune), Pfäffle, R. (Roland), Postma, D.S. (Dirkje), Power, C. (Christine), Simpson, A. (Angela), Sengpiel, V. (Verena), Tiesler, C. (Carla), Torrent, M. (Maties), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Vinding, R. (Rebecca), Waage, J. (Johannes), Wardle, J. (Jane), Zeggini, E. (Eleftheria), Zemel, B.S. (Babette S.), Dedoussis, G.V. (George), Pedersen, O. (Oluf), Froguel, P. (Philippe), Sunyer, J. (Jordi), Plomin, R. (Robert), Jacobsson, B. (Bo), Hansen, T. (Torben), Gonzalez, J.R. (Juan R.), Custovic, A. (Adnan), Raitakari, O.T. (Olli T.), Pennell, C.E. (Craig), Widén, E. (Elisabeth), Boomsma, D.I. (Dorret), Koppelman, G.H. (Gerard), Sebert, S. (Sylvain), Jarvelin, M.-R. (Marjo-Riitta), Hypponen, E. (Elina), McCarthy, M.I. (Mark), Lindi, V. (Virpi), Harri, N. (Niinikoski), Körner, A. (Antje), Bønnelykke, K. (Klaus), Heinrich, J. (Joachim), Melbye, M. (Mads), Rivadeneira Ramirez, F. (Fernando), Hakonarson, H. (Hakon), Ring, S.M. (Susan), Smith, A.V. (Davey), Sørensen, T.I.A. (Thorkild I.A.), Timpson, N.J. (Nicholas), Grant, S.F.A. (Struan), Jaddoe, V.W.V. (Vincent), Kalkwarf, H.J. (Heidi J.), Lappe, J.M. (Joan M.), Gilsanz, V. (Vicente), Oberfield, S.E. (Sharon E.), Shepherd, J.A. (John A.), and Kelly, A. (Andrea)
- Abstract
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown.We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores.We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10-8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10-10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in streng
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- 2016
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49. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns
- Author
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Joubert, B.R. (Bonnie), Dekker, H.T. (Herman) den, Felix, J.F. (Janine), Bohlin, J. (Jon), Ligthart, S. (Symen), Beckett, E. (Emma), Tiemeier, H.W. (Henning), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Håberg, S.E. (Siri E), Reese, S.E. (Sarah E.), Peters, M.J. (Marjolein), Kulle Andreassen, B. (Bettina), Steegers, E.A.P. (Eric), Nilsen, R.M. (Roy M.), Vollset, S.E. (Stein E.), Midttun, . (Øivind), Ueland, P.M. (Per), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Jongste, J.C. (Johan) de, Wu, M.C. (Michael), Wang, T. (Tianyuan), Peddada, S.D. (Shyamal D.), Jaddoe, V.W.V. (Vincent), Nystad, W. (Wenche), Duijts, L. (Liesbeth), London, S.J. (Stephanie J), Joubert, B.R. (Bonnie), Dekker, H.T. (Herman) den, Felix, J.F. (Janine), Bohlin, J. (Jon), Ligthart, S. (Symen), Beckett, E. (Emma), Tiemeier, H.W. (Henning), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Håberg, S.E. (Siri E), Reese, S.E. (Sarah E.), Peters, M.J. (Marjolein), Kulle Andreassen, B. (Bettina), Steegers, E.A.P. (Eric), Nilsen, R.M. (Roy M.), Vollset, S.E. (Stein E.), Midttun, . (Øivind), Ueland, P.M. (Per), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Jongste, J.C. (Johan) de, Wu, M.C. (Michael), Wang, T. (Tianyuan), Peddada, S.D. (Shyamal D.), Jaddoe, V.W.V. (Vincent), Nystad, W. (Wenche), Duijts, L. (Liesbeth), and London, S.J. (Stephanie J)
- Abstract
Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina" s HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.
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- 2016
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50. Genetic and environmental influences interact with age and sex in shaping the human methylome
- Author
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Dongen, J. (Jenny) van, Nivard, M. (Michel), Willemsen, G.A.H.M. (Gonneke), Hottenga, J.J. (Jouke Jan), Helmer, Q. (Quinta), Dolan, C.V. (Conor), Ehli, E.A. (Erik), Davies, G.E. (Gareth), Iterson, M. (Maarten) van, Breeze, C.E. (Charles E.), Beck, S. (Stephan), Suchiman, H.E.D. (Eka), Jansen, R., Meurs, J.B.J. (Joyce) van, Heijmans, B.T. (Bastiaan), Slagboom, P.E. (Eline), Boomsma, D.I. (Dorret), Dongen, J. (Jenny) van, Nivard, M. (Michel), Willemsen, G.A.H.M. (Gonneke), Hottenga, J.J. (Jouke Jan), Helmer, Q. (Quinta), Dolan, C.V. (Conor), Ehli, E.A. (Erik), Davies, G.E. (Gareth), Iterson, M. (Maarten) van, Breeze, C.E. (Charles E.), Beck, S. (Stephan), Suchiman, H.E.D. (Eka), Jansen, R., Meurs, J.B.J. (Joyce) van, Heijmans, B.T. (Bastiaan), Slagboom, P.E. (Eline), and Boomsma, D.I. (Dorret)
- Abstract
The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex-and age-related physiological variation and disease susceptibility. Here we estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.
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- 2016
- Full Text
- View/download PDF
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