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1. Equivalent DNA methylation variation between monozygotic co-twins and unrelated individuals reveals universal epigenetic inter-individual dissimilarity

Author

Planterose Jiménez, B. (Benjamin), Liu, F. (Fan), Caliebe, A. (Amke), Montiel González, D. (Diego), Bell, J.T. (Jordana T.), Kayser, M.H. (Manfred), Vidaki, A. (Athina), Planterose Jiménez, B. (Benjamin), Liu, F. (Fan), Caliebe, A. (Amke), Montiel González, D. (Diego), Bell, J.T. (Jordana T.), Kayser, M.H. (Manfred), and Vidaki, A. (Athina)

Abstract

Background: Although the genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging. Particularly for young and healthy monozygotic twins, DNA methylation divergence, if any, may be restricted to stochastic processes occurring post-twinning during embryonic development and early life. However, to what extent such stochastic mechanisms can systematically provide a stable source of inter-individual epigenetic variation remains uncertain until now. Results: We enriched for inter-individual stochastic variation by using an equivalence testing-based statistical approach on whole blood methylation microarray data from healthy adolescent monozygotic twins. As a result, we identified 333 CpGs displaying similarly large methylation variation between monozygotic co-twins and unrelated individuals. Although their methylation variation surpasses measurement error and is stable in a short timescale, susceptibility to aging is apparent in the long term. Additionally, 46% of these CpGs were replicated in adipose tissue. The identified sites are significantly enriched at the clustered protocadherin loci, known for stochastic methylation in developing neurons. We also confirmed an enrichment in monozygotic twin DNA methylation discordance at these loci in whole genome bisulfite sequencing data from blood and adipose tissue. Conclusions: We have isolated a component of stochastic methylation variation, distinct from genetic influence, measurement error, and epigenetic drift. Biomarkers enriched in this component may serve in the future as the basis for universal epigenetic fingerprinting, relevant for instance in the discrimination of monozygotic twin individuals in forensic applications, currently impossible with standard DNA profiling.

Published
2021
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2. An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis

Author

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.

Published
2019
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3. Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

Author

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.

Published
2018
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4. Investigating the epigenetic discrimination of identical twins using buccal swabs, saliva, and cigarette butts in the forensic setting

Author

Vidaki, A. (Athina), Kalamara, V. (Vivian), Carnero-Montoro, E. (Elena), Spector, T.D. (Timothy), Bell, J.T. (Jordana T.), Kayser, M.H. (Manfred), Vidaki, A. (Athina), Kalamara, V. (Vivian), Carnero-Montoro, E. (Elena), Spector, T.D. (Timothy), Bell, J.T. (Jordana T.), and Kayser, M.H. (Manfred)

Abstract

Monozygotic (MZ) twins are typically indistinguishable via forensic DNA profiling. Recently, we demonstrated that epigenetic differentiation of MZ twins is feasible; however, proportions of twin differentially methylated CpG sites (tDMSs) identified in reference-type blood DNA were not replicated in trace-type blood DNA. Here we investigated buccal swabs as typical forensic reference material, and saliva and cigarette butts as commonly encountered forensic trace materials. As an analog to a forensic case, we analyzed one MZ twin pair. Epigenome-wide microarray analysis in reference-type buccal DNA revealed 25 candidate tDMSs with >0.5 twin-to-twin differences. MethyLight quantitative PCR (qPCR) of 22 selected tDMSs in trace-type DNA revealed in saliva DNA that six tDMSs (27.3%) had >0.1 twin-to-twin differences, seven (31.8%) had smaller (<0.1) but robustly detected differences, whereas for nine (40.9%) the differences were in the opposite direction relative to the microarray data; for cigarette butt DNA, results were 50%, 22.7%, and 27.3%, respectively. The discrepancies between reference-type and trace-type DNA outcomes can be explained by cell composition differences, method-to-method variation, and other technical reasons including bisulfite conversion inefficiency. Our study highlights the importance of the DNA source and that careful characterization of biological and technical effects is needed before epigenetic MZ twin differentiation is applicable in forensic casework.

Published
2018
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5. Meta-analysis of human genome-microbiome association studies: The MiBioGen consortium initiative

Author

Wang, J. (Jun), Kurilshikov, A. (Alexander), Radjabzadeh, D. (Djawad), Turpin, W. (Williams), Croitoru, K. (Kenneth), Bonder, M.J. (Marc), Jackson, M.A. (Matthew A.), Medina-Gomez, M.C. (Carolina), Frost, F. (Fabian), Homuth, G. (Georg), Rühlemann, M. (Malte), Hughes, D. (David), Kim, H.-N. (Han-na), Spector, T.D. (Timothy), Bell, J.T. (Jordana T.), Steves, C.J. (Claire), Timpson, N. (Nicolas), Franke, A. (Andre), Wijmenga, C. (Cisca), Meyer, K. (Katie), Kacprowski, T. (Tim), Franke, L. (Lude), Paterson, A.D. (Andrew), Raes, J. (Jeroen), Kraaij, R. (Robert), Zhernakova, A. (Alexandra), Wang, J. (Jun), Kurilshikov, A. (Alexander), Radjabzadeh, D. (Djawad), Turpin, W. (Williams), Croitoru, K. (Kenneth), Bonder, M.J. (Marc), Jackson, M.A. (Matthew A.), Medina-Gomez, M.C. (Carolina), Frost, F. (Fabian), Homuth, G. (Georg), Rühlemann, M. (Malte), Hughes, D. (David), Kim, H.-N. (Han-na), Spector, T.D. (Timothy), Bell, J.T. (Jordana T.), Steves, C.J. (Claire), Timpson, N. (Nicolas), Franke, A. (Andre), Wijmenga, C. (Cisca), Meyer, K. (Katie), Kacprowski, T. (Tim), Franke, L. (Lude), Paterson, A.D. (Andrew), Raes, J. (Jeroen), Kraaij, R. (Robert), and Zhernakova, A. (Alexandra)

Abstract

Background: In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Results: Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition shows that we can reduce the potential artifacts introduced by technical differences in generating microbiota data. We are now in the process of benchmarking the association tests and performing meta-analyses of genome-wide associations. All pipeline and summary statistics results will be shared using public data repositories. Conclusion: We present the largest consortium to date devoted to microbiota-GWAS. We have adapted our analytical pipelines to suit multi-cohort analyses and expect to gain insight into host-microbiota cross-talk at the genome-wide level. And, as an open consortium, we invite more cohorts to join us (by contacting one of the corresponding authors) and to follow the analytical pipeline we have developed.

Published
2018
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6. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity

Author

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

Published
2017
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7. Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density

Author

Morris, J.A. (John A.), Tsai, P.-C. (Pei-Chien), Joehanes, R. (Roby), Zheng, J. (Jie), Trajanoska, K. (Katerina), Soerensen, M. (Mette), Forgetta, V. (Vincenzo), Castillo-Fernandez, J.E. (Juan Edgar), Frost, M. (Morten), Spector, T.D. (Timothy), Christensen, K. (Kaare), Christiansen, L. (Lene), Rivadeneira Ramirez, F. (Fernando), Tobias, J.H. (Jon), Evans, D.M. (David M.), Kiel, D.P. (Douglas P.), Hsu, Y.-H. (Yi-Hsiang), Richards, J.B. (Brent), Bell, J.T. (Jordana T.), Morris, J.A. (John A.), Tsai, P.-C. (Pei-Chien), Joehanes, R. (Roby), Zheng, J. (Jie), Trajanoska, K. (Katerina), Soerensen, M. (Mette), Forgetta, V. (Vincenzo), Castillo-Fernandez, J.E. (Juan Edgar), Frost, M. (Morten), Spector, T.D. (Timothy), Christensen, K. (Kaare), Christiansen, L. (Lene), Rivadeneira Ramirez, F. (Fernando), Tobias, J.H. (Jon), Evans, D.M. (David M.), Kiel, D.P. (Douglas P.), Hsu, Y.-H. (Yi-Hsiang), Richards, J.B. (Brent), and Bell, J.T. (Jordana T.)

Abstract

Genetic and environmental determinants of skeletal phenotypes such as bone mineral density (BMD) may converge through the epigenome, providing a tool to better understand osteoporosis pathophysiology. Because the epigenetics of BMD have been largely unexplored in humans, we performed an epigenome-wide association study (EWAS) of BMD. We undertook a large-scale BMD EWAS using the Infinium HumanMethylation450 array to measure site-specific DNA methylation in up to 5515 European-descent individuals (NDiscovery= 4614, NValidation= 901). We associated methylation at multiple cytosine-phosphate-guanine (CpG) sites with dual-energy X-ray absorptiometry (DXA)-derived femoral neck and lumbar spine BMD. We performed sex-combined and stratified analyses, controlling for age, weight, smoking status, estimated white blood cell proportions, and random effects for relatedness and batch effects. A 5% false-discovery rate was used to identify CpGs associated with BMD. We identified one CpG site, cg23196985, significantly associated with femoral neck BMD in 3232 females (p = 7.9 × 10−11) and 4614 females and males (p = 3.0 × 10−8). cg23196985 was not associated with femoral neck BMD in an additional sample of 474 females (p = 0.64) and 901 males and females (p = 0.60). Lack of strong consistent association signal indicates that among the tested probes, no large-effect epigenetic changes in whole blood associated with BMD, suggesting future epigenomic studies of musculoskeletal traits measure DNA methylation in a different tissue with extended genome coverage.

Published
2017
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