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1. DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases

Author

Wielscher, M. (Matthias), Mandaviya, P. R. (Pooja R.), Kuehnel, B. (Brigitte), Joehanes, R. (Roby), Mustafa, R. (Rima), Robinson, O. (Oliver), Zhang, Y. (Yan), Bodinier, B. (Barbara), Walton, E. (Esther), Mishra, P. P. (Pashupati P.), Schlosser, P. (Pascal), Wilson, R. (Rory), Tsai, P.-C. (Pei-Chien), Palaniswamy, S. (Saranya), Marioni, R. E. (Riccardo E.), Fiorito, G. (Giovanni), Cugliari, G. (Giovanni), Karhunen, V. (Ville), Ghanbari, M. (Mohsen), Psaty, B. M. (Bruce M.), Loh, M. (Marie), Bis, J. C. (Joshua C.), Lehne, B. (Benjamin), Sotoodehnia, N. (Nona), Deary, I. J. (Ian J.), Chadeau-Hyam, M. (Marc), Brody, J. A. (Jennifer A.), Cardona, A. (Alexia), Selvin, E. (Elizabeth), Smith, A. K. (Alicia K.), Miller, A. H. (Andrew H.), Torres, M. A. (Mylin A.), Marouli, E. (Eirini), Gao, X. (Xin), van Meurs, J. B. (Joyce B. J.), Graf-Schindler, J. (Johanna), Rathmann, W. (Wolfgang), Koenig, W. (Wolfgang), Peters, A. (Annette), Weninger, W. (Wolfgang), Farlik, M. (Matthias), Zhang, T. (Tao), Chen, W. (Wei), Xia, Y. (Yujing), Teumer, A. (Alexander), Nauck, M. (Matthias), Grabe, H. J. (Hans J.), Doerr, M. (Macus), Lehtimaki, T. (Terho), Guan, W. (Weihua), Milani, L. (Lili), Tanaka, T. (Toshiko), Fisher, K. (Krista), Waite, L. L. (Lindsay L.), Kasela, S. (Silva), Vineis, P. (Paolo), Verweij, N. (Niek), van der Harst, P. (Pim), Iacoviello, L. (Licia), Sacerdote, C. (Carlotta), Panico, S. (Salvatore), Krogh, V. (Vittorio), Tumino, R. (Rosario), Tzala, E. (Evangelia), Matullo, G. (Giuseppe), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Kahonen, M. (Mika), Herzig, K.-H. (Karl-Heinz), Li, S. (Shengxu), BIOS consortium, Conneely, K. N. (Karen N.), Kooner, J. S. (Jaspal S.), Kottgen, A. (Anna), Heijmans, B. T. (Bastiaan T.), Deloukas, P. (Panos), Relton, C. (Caroline), Ong, K. K. (Ken K.), Bell, J. T. (Jordana T.), Boerwinkle, E. (Eric), Elliott, P. (Paul), Brenner, H. (Hermann), Beekman, M. (Marian), Levy, D. (Daniel), Waldenberger, M. (Melanie), Chambers, J. C. (John C.), Dehghan, A. (Abbas), Järvelin, M.-R. (Marjo-Riitta), Wielscher, M. (Matthias), Mandaviya, P. R. (Pooja R.), Kuehnel, B. (Brigitte), Joehanes, R. (Roby), Mustafa, R. (Rima), Robinson, O. (Oliver), Zhang, Y. (Yan), Bodinier, B. (Barbara), Walton, E. (Esther), Mishra, P. P. (Pashupati P.), Schlosser, P. (Pascal), Wilson, R. (Rory), Tsai, P.-C. (Pei-Chien), Palaniswamy, S. (Saranya), Marioni, R. E. (Riccardo E.), Fiorito, G. (Giovanni), Cugliari, G. (Giovanni), Karhunen, V. (Ville), Ghanbari, M. (Mohsen), Psaty, B. M. (Bruce M.), Loh, M. (Marie), Bis, J. C. (Joshua C.), Lehne, B. (Benjamin), Sotoodehnia, N. (Nona), Deary, I. J. (Ian J.), Chadeau-Hyam, M. (Marc), Brody, J. A. (Jennifer A.), Cardona, A. (Alexia), Selvin, E. (Elizabeth), Smith, A. K. (Alicia K.), Miller, A. H. (Andrew H.), Torres, M. A. (Mylin A.), Marouli, E. (Eirini), Gao, X. (Xin), van Meurs, J. B. (Joyce B. J.), Graf-Schindler, J. (Johanna), Rathmann, W. (Wolfgang), Koenig, W. (Wolfgang), Peters, A. (Annette), Weninger, W. (Wolfgang), Farlik, M. (Matthias), Zhang, T. (Tao), Chen, W. (Wei), Xia, Y. (Yujing), Teumer, A. (Alexander), Nauck, M. (Matthias), Grabe, H. J. (Hans J.), Doerr, M. (Macus), Lehtimaki, T. (Terho), Guan, W. (Weihua), Milani, L. (Lili), Tanaka, T. (Toshiko), Fisher, K. (Krista), Waite, L. L. (Lindsay L.), Kasela, S. (Silva), Vineis, P. (Paolo), Verweij, N. (Niek), van der Harst, P. (Pim), Iacoviello, L. (Licia), Sacerdote, C. (Carlotta), Panico, S. (Salvatore), Krogh, V. (Vittorio), Tumino, R. (Rosario), Tzala, E. (Evangelia), Matullo, G. (Giuseppe), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Kahonen, M. (Mika), Herzig, K.-H. (Karl-Heinz), Li, S. (Shengxu), BIOS consortium, Conneely, K. N. (Karen N.), Kooner, J. S. (Jaspal S.), Kottgen, A. (Anna), Heijmans, B. T. (Bastiaan T.), Deloukas, P. (Panos), Relton, C. (Caroline), Ong, K. K. (Ken K.), Bell, J. T. (Jordana T.), Boerwinkle, E. (Eric), Elliott, P. (Paul), Brenner, H. (Hermann), Beekman, M. (Marian), Levy, D. (Daniel), Waldenberger, M. (Melanie), Chambers, J. C. (John C.), Dehghan, A. (Abbas), and Järvelin, M.-R. (Marjo-Riitta)

Abstract

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

Published
2022

2. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author

Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), Codd, V. (Veryan), Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), and Codd, V. (Veryan)

Abstract

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Published
2020
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3. Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults

Author

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

Published
2018
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4. Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults

Author

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

Published
2018
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5. Risk thresholds for alcohol consumption:combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Wood, A. M. (Angela M.), Kaptoge, S. (Stephen), Butterworth, A. S. (Adam S.), Willeit, P. (Peter), Warnakula, S. (Samantha), Bolton, T. (Thomas), Paige, E. (Ellie), Paul, D. S. (Dirk S.), Sweeting, M. (Michael), Burgess, S. (Stephen), Bell, S. (Steven), Astle, W. (William), Stevens, D. (David), Koulman, A. (Albert), Selmer, R. M. (Randi M.), Verschuren, W. M. (W. M. Monique), Sato, S. (Shinichi), Njolstad, I. (Inger), Woodward, M. (Mark), Salomaa, V. (Veikko), Nordestgaard, B. G. (Borge G.), Yeap, B. B. (Bu B.), Fletcher, A. (Astrid), Melander, O. (Olle), Kuller, L. H. (Lewis H.), Balkau, B. (Beverley), Marmot, M. (Michael), Koenig, W. (Wolfgang), Casiglia, E. (Edoardo), Cooper, C. (Cyrus), Arndt, V. (Volker), Franco, O. H. (Oscar H.), Wennberg, P. (Patrik), Gallacher, J. (John), de la Camara, A. G. (Agustin Gomez), Volzke, H. (Henry), Dahm, C. C. (Christina C.), Dale, C. E. (Caroline E.), Bergmann, M. M. (Manuela M.), Crespo, C. J. (Carlos J.), van der Schouw, Y. T. (Yvonne T.), Kaaks, R. (Rudolf), Simons, L. A. (Leon A.), Lagiou, P. (Pagona), Schoufour, J. D. (Josje D.), Boer, J. M. (Jolanda M. A.), Key, T. J. (Timothy J.), Rodriguez, B. (Beatriz), Moreno-Iribas, C. (Conchi), Davidson, K. W. (Karina W.), Taylor, J. O. (James O.), Sacerdote, C. (Carlotta), Wallace, R. B. (Robert B.), Quiros, J. R. (J. Ramon), Tumino, R. (Rosario), Blazer, D. G. (Dan G., II), Linneberg, A. (Allan), Daimon, M. (Makoto), Panico, S. (Salvatore), Howard, B. (Barbara), Skeie, G. (Guri), Strandberg, T. (Timo), Weiderpass, E. (Elisabete), Nietert, P. J. (Paul J.), Psaty, B. M. (Bruce M.), Kromhout, D. (Daan), Salamanca-Fernandez, E. (Elena), Kiechl, S. (Stefan), Krumholz, H. M. (Harlan M.), Grioni, S. (Sara), Palli, D. (Domenico), Huerta, J. M. (Jose M.), Price, J. (Jackie), Sundstrom, J. (Johan), Arriola, L. (Larraitz), Arima, H. (Hisatomi), Travis, R. C. (Ruth C.), Panagiotakos, D. B. (Demosthenes B.), Karakatsani, A. (Anna), Trichopoulou, A. (Antonia), Kuhn, T. (Tilman), Grobbee, D. E. (Diederick E.), Barrett-Connor, E. (Elizabeth), van Schoor, N. (Natasja), Boeing, H. (Heiner), Overvad, K. (Kim), Kauhanen, J. (Jussi), Wareham, N. (Nick), Langenberg, C. (Claudia), Forouhi, N. (Nita), Wennberg, M. (Maria), Despres, J.-P. (Jean-Pierre), Cushman, M. (Mary), Cooper, J. A. (Jackie A.), Rodriguez, C. J. (Carlos J.), Sakurai, M. (Masaru), Shaw, J. E. (Jonathan E.), Knuiman, M. (Matthew), Voortman, T. (Trudy), Meisinger, C. (Christa), Tjonneland, A. (Anne), Brenner, H. (Hermann), Palmieri, L. (Luigi), Dallongeville, J. (Jean), Brunner, E. J. (Eric J.), Assmann, G. (Gerd), Trevisan, M. (Maurizio), Gillum, R. F. (Richard F.), Ford, I. (Ian), Sattar, N. (Naveed), Lazo, M. (Mariana), Thompson, S. G. (Simon G.), Ferrari, P. (Pietro), Leon, D. A. (David A.), Smith, G. D. (George Davey), Peto, R. (Richard), Jackson, R. (Rod), Banks, E. (Emily), Di Angelantonio, E. (Emanuele), Danesh, J. (John), Wood, A. M. (Angela M.), Kaptoge, S. (Stephen), Butterworth, A. S. (Adam S.), Willeit, P. (Peter), Warnakula, S. (Samantha), Bolton, T. (Thomas), Paige, E. (Ellie), Paul, D. S. (Dirk S.), Sweeting, M. (Michael), Burgess, S. (Stephen), Bell, S. (Steven), Astle, W. (William), Stevens, D. (David), Koulman, A. (Albert), Selmer, R. M. (Randi M.), Verschuren, W. M. (W. M. Monique), Sato, S. (Shinichi), Njolstad, I. (Inger), Woodward, M. (Mark), Salomaa, V. (Veikko), Nordestgaard, B. G. (Borge G.), Yeap, B. B. (Bu B.), Fletcher, A. (Astrid), Melander, O. (Olle), Kuller, L. H. (Lewis H.), Balkau, B. (Beverley), Marmot, M. (Michael), Koenig, W. (Wolfgang), Casiglia, E. (Edoardo), Cooper, C. (Cyrus), Arndt, V. (Volker), Franco, O. H. (Oscar H.), Wennberg, P. (Patrik), Gallacher, J. (John), de la Camara, A. G. (Agustin Gomez), Volzke, H. (Henry), Dahm, C. C. (Christina C.), Dale, C. E. (Caroline E.), Bergmann, M. M. (Manuela M.), Crespo, C. J. (Carlos J.), van der Schouw, Y. T. (Yvonne T.), Kaaks, R. (Rudolf), Simons, L. A. (Leon A.), Lagiou, P. (Pagona), Schoufour, J. D. (Josje D.), Boer, J. M. (Jolanda M. A.), Key, T. J. (Timothy J.), Rodriguez, B. (Beatriz), Moreno-Iribas, C. (Conchi), Davidson, K. W. (Karina W.), Taylor, J. O. (James O.), Sacerdote, C. (Carlotta), Wallace, R. B. (Robert B.), Quiros, J. R. (J. Ramon), Tumino, R. (Rosario), Blazer, D. G. (Dan G., II), Linneberg, A. (Allan), Daimon, M. (Makoto), Panico, S. (Salvatore), Howard, B. (Barbara), Skeie, G. (Guri), Strandberg, T. (Timo), Weiderpass, E. (Elisabete), Nietert, P. J. (Paul J.), Psaty, B. M. (Bruce M.), Kromhout, D. (Daan), Salamanca-Fernandez, E. (Elena), Kiechl, S. (Stefan), Krumholz, H. M. (Harlan M.), Grioni, S. (Sara), Palli, D. (Domenico), Huerta, J. M. (Jose M.), Price, J. (Jackie), Sundstrom, J. (Johan), Arriola, L. (Larraitz), Arima, H. (Hisatomi), Travis, R. C. (Ruth C.), Panagiotakos, D. B. (Demosthenes B.), Karakatsani, A. (Anna), Trichopoulou, A. (Antonia), Kuhn, T. (Tilman), Grobbee, D. E. (Diederick E.), Barrett-Connor, E. (Elizabeth), van Schoor, N. (Natasja), Boeing, H. (Heiner), Overvad, K. (Kim), Kauhanen, J. (Jussi), Wareham, N. (Nick), Langenberg, C. (Claudia), Forouhi, N. (Nita), Wennberg, M. (Maria), Despres, J.-P. (Jean-Pierre), Cushman, M. (Mary), Cooper, J. A. (Jackie A.), Rodriguez, C. J. (Carlos J.), Sakurai, M. (Masaru), Shaw, J. E. (Jonathan E.), Knuiman, M. (Matthew), Voortman, T. (Trudy), Meisinger, C. (Christa), Tjonneland, A. (Anne), Brenner, H. (Hermann), Palmieri, L. (Luigi), Dallongeville, J. (Jean), Brunner, E. J. (Eric J.), Assmann, G. (Gerd), Trevisan, M. (Maurizio), Gillum, R. F. (Richard F.), Ford, I. (Ian), Sattar, N. (Naveed), Lazo, M. (Mariana), Thompson, S. G. (Simon G.), Ferrari, P. (Pietro), Leon, D. A. (David A.), Smith, G. D. (George Davey), Peto, R. (Richard), Jackson, R. (Rod), Banks, E. (Emily), Di Angelantonio, E. (Emanuele), and Danesh, J. (John)

Abstract

Background: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. Methods: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies. Findings: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality ris

Published
2018

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

Author

Parmar, P. (Priyanka), Lowry, E. (Estelle), Cugliari, G. (Giovanni), Suderman, M. (Matthew), 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 R.), Kasela, S. (Silva), Nano, J. (Jana), Zhang, W. (Weihua), Zhang, Y. (Yan), Uitterlinden, A. G. (Andre G.), Peters, A. (Annette), Schoettker, B. (Ben), Gieger, C. (Christian), Anderson, D. (Denise), Boomsma, D. I. (Dorret, I), Grabe, H. J. (Hans J.), Panico, S. (Salvatore), Veldink, J. H. (Jan H.), van Meurs, J. B. (Joyce B. J.), van den Berg, L. (Leonard), Beilin, L. J. (Lawrence J.), Franke, L. (Lude), Loh, M. (Marie), van Greevenbroek, M. M. (Marleen M. J.), Nauck, M. (Matthias), Kahonen, M. (Mika), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Franco, O. H. (Oscar H.), Slagboom, P. E. (P. Eline), van der Harst, P. (Pim), Kunze, S. (Sonja), Felix, S. B. (Stephan B.), Zhang, T. (Tao), Chen, W. (Wei), Mori, T. A. (Trevor A.), Bonnefond, A. (Amelie), 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), Lehtimaki, T. (Terho), Rathmann, W. (Wolfgang), Relton, C. L. (Caroline L.), Matullo, G. (Giuseppe), Brenner, H. (Hermann), Verweij, N. (Niek), Li, S. (Shengxu), Chambers, J. C. (John C.), Jarvelin, M.-R. (Marjo-Riitta), Sebert, S. (Sylvain), Parmar, P. (Priyanka), Lowry, E. (Estelle), Cugliari, G. (Giovanni), Suderman, M. (Matthew), 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 R.), Kasela, S. (Silva), Nano, J. (Jana), Zhang, W. (Weihua), Zhang, Y. (Yan), Uitterlinden, A. G. (Andre G.), Peters, A. (Annette), Schoettker, B. (Ben), Gieger, C. (Christian), Anderson, D. (Denise), Boomsma, D. I. (Dorret, I), Grabe, H. J. (Hans J.), Panico, S. (Salvatore), Veldink, J. H. (Jan H.), van Meurs, J. B. (Joyce B. J.), van den Berg, L. (Leonard), Beilin, L. J. (Lawrence J.), Franke, L. (Lude), Loh, M. (Marie), van Greevenbroek, M. M. (Marleen M. J.), Nauck, M. (Matthias), Kahonen, M. (Mika), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Franco, O. H. (Oscar H.), Slagboom, P. E. (P. Eline), van der Harst, P. (Pim), Kunze, S. (Sonja), Felix, S. B. (Stephan B.), Zhang, T. (Tao), Chen, W. (Wei), Mori, T. A. (Trevor A.), Bonnefond, A. (Amelie), 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), Lehtimaki, T. (Terho), Rathmann, W. (Wolfgang), Relton, C. L. (Caroline L.), Matullo, G. (Giuseppe), Brenner, H. (Hermann), Verweij, N. (Niek), Li, S. (Shengxu), Chambers, J. C. (John C.), Jarvelin, 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

Published
2018

7. 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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8. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Scott, R.A. (Robert), Freitag, C.M. (Christine), Li, L. (Li), Chu, A.Y. (Audrey), Surendran, P. (Praveen), Young, R. (Robin), Grarup, N. (Niels), Stancáková, A. (Alena), Chen, Y. (Yuning), Varga, T.V. (Tibor V.), Yaghootkar, H. (Hanieh), Luan, J. (Jian'An), Zhao, J.H. (Jing Hua), Willems, S.M. (Sara), Wessel, J. (Jennifer), Wang, S. (Shuai), Maruthur, N.M. (Nisa M), Michailidou, K. (Kyriaki), Pirie, A. (Ailith), Lee, S.J. (Sven) van der, Gillson, C.J. (Christopher), Al Olama, A.A. (Ali Amin), Amouyel, P. (Philippe), Arriola, L. (Larraitz), Arveiler, D. (Dominique), Aviles-Olmos, I. (Iciar), Balkau, B. (Beverley), Barricarte, A. (Aurelio), Barroso, I.E. (Inês), Garcia, S.B. (Sara Benlloch), Bis, J.C. (Joshua), Blankenberg, S. (Stefan), Boehnke, M. (Michael), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borecki, I.B. (Ingrid), Bork-Jensen, J. (Jette), Bowden, S. (Sarah), Caldas, C. (Carlos), Caslake, M. (Muriel), Cupples, L.A. (Adrienne), Cruchaga, C. (Carlos), Czajkowski, J. (Jacek), Hoed, M. (Marcel) den, Dunn, J.A. (Janet A.), Earl, H. (Helena), Ehret, G.B. (Georg), Ferrannini, E. (Ele), Ferrieres, J. (Jean), Foltynie, T. (Thomas), Ford, I. (Ian), Forouhi, N.G. (Nita), Gianfagna, F. (Francesco), Gonzalez, C. (Carlos), Grioni, S. (Sara), Hiller, L. (Louise), Jansson, J.H., Jørgensen, M.E. (Marit E.), Jukema, J.W. (Jan Wouter), Kaaks, R. (Rudolf), Kee, F. (Frank), Kerrison, N.D. (Nicola D.), Key, T. (Tim), Kontto, J. (Jukka), Kote-Jarai, Z., Kraja, A. (Aldi), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Linneberg, A. (Allan), Liu, C. (Chunyu), Marenne, G. (Gaëlle), Mohlke, K.L. (Karen), Morris, A.P. (Andrew), Muir, K.R. (K.), Müller-Nurasyid, M. (Martina), Munroe, P. (Patricia), Navarro, C. (Carmen), Nielsen, S.F. (Sune), Nilsson, P. (Peter), Nordestgaard, B.G. (Børge), Packard, C.J. (Chris J.), Palli, D. (Domenico), Panico, S. (Salvatore), Peloso, G.M. (Gina), Perola, M. (Markus), Peters, A. (Annette), Poole, C.J. (Christopher J.), Quirós, J.R., Rolandsson, O. (Olov), Sacerdote, C. (Carlotta), Salomaa, V. (Veikko), Sánchez, M.-J. (María-José), Sattar, N. (Naveed), Sharp, S.J. (Stephen), Sims, R. (Rebecca), Slimani, N. (Nadia), Smith, J.A. (Jennifer A), Thompson, D. (Deborah), Trompet, S. (Stella), Tumino, R. (Rosario), Van Der A, D.L. (Daphne L.), Schouw, Y.T. (Yvonne) van der, Virtamo, J. (Jarmo), Walker, M. (Mark), Walter, K. (Klaudia), Abraham, J.E. (Jean E.), Amundadottir, L.T. (Laufey T.), Butterworth, A.S. (Adam), Aponte, J.L. (Jennifer L), Dupuis, J. (Josée), Easton, D.F. (Douglas F.), Eeles, R. (Rosalind), Erdmann, J. (Jeanette), Franks, P.W. (Paul), Frayling, T.M. (Timothy), Hansen, T. (T.), Howson, J.M.M. (Joanna M.M.), Jorgensen, T. (Torben), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), McCarthy, M.I. (Mark), Pankow, J.S. (James), Pedersen, O. (Oluf), Riboli, E. (Elio), Rotter, J.I. (Jerome I.), Saleheen, D. (Danish), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Vollenweider, P. (Peter), O'Rahilly, S. (Stephen), Deloukas, P. (Panagiotis), Danesh, J. (John), Goodarzi, M. (Mark), Kathiresan, S. (Sekar), Meigs, J.B. (James), Ehm, M.G. (Margaret G), Wareham, N.J. (Nick), Waterworth, D. (Dawn), Scott, R.A. (Robert), Freitag, C.M. (Christine), Li, L. (Li), Chu, A.Y. (Audrey), Surendran, P. (Praveen), Young, R. (Robin), Grarup, N. (Niels), Stancáková, A. (Alena), Chen, Y. (Yuning), Varga, T.V. (Tibor V.), Yaghootkar, H. (Hanieh), Luan, J. (Jian'An), Zhao, J.H. (Jing Hua), Willems, S.M. (Sara), Wessel, J. (Jennifer), Wang, S. (Shuai), Maruthur, N.M. (Nisa M), Michailidou, K. (Kyriaki), Pirie, A. (Ailith), Lee, S.J. (Sven) van der, Gillson, C.J. (Christopher), Al Olama, A.A. (Ali Amin), Amouyel, P. (Philippe), Arriola, L. (Larraitz), Arveiler, D. (Dominique), Aviles-Olmos, I. (Iciar), Balkau, B. (Beverley), Barricarte, A. (Aurelio), Barroso, I.E. (Inês), Garcia, S.B. (Sara Benlloch), Bis, J.C. (Joshua), Blankenberg, S. (Stefan), Boehnke, M. (Michael), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borecki, I.B. (Ingrid), Bork-Jensen, J. (Jette), Bowden, S. (Sarah), Caldas, C. (Carlos), Caslake, M. (Muriel), Cupples, L.A. (Adrienne), Cruchaga, C. (Carlos), Czajkowski, J. (Jacek), Hoed, M. (Marcel) den, Dunn, J.A. (Janet A.), Earl, H. (Helena), Ehret, G.B. (Georg), Ferrannini, E. (Ele), Ferrieres, J. (Jean), Foltynie, T. (Thomas), Ford, I. (Ian), Forouhi, N.G. (Nita), Gianfagna, F. (Francesco), Gonzalez, C. (Carlos), Grioni, S. (Sara), Hiller, L. (Louise), Jansson, J.H., Jørgensen, M.E. (Marit E.), Jukema, J.W. (Jan Wouter), Kaaks, R. (Rudolf), Kee, F. (Frank), Kerrison, N.D. (Nicola D.), Key, T. (Tim), Kontto, J. (Jukka), Kote-Jarai, Z., Kraja, A. (Aldi), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Linneberg, A. (Allan), Liu, C. (Chunyu), Marenne, G. (Gaëlle), Mohlke, K.L. (Karen), Morris, A.P. (Andrew), Muir, K.R. (K.), Müller-Nurasyid, M. (Martina), Munroe, P. (Patricia), Navarro, C. (Carmen), Nielsen, S.F. (Sune), Nilsson, P. (Peter), Nordestgaard, B.G. (Børge), Packard, C.J. (Chris J.), Palli, D. (Domenico), Panico, S. (Salvatore), Peloso, G.M. (Gina), Perola, M. (Markus), Peters, A. (Annette), Poole, C.J. (Christopher J.), Quirós, J.R., Rolandsson, O. (Olov), Sacerdote, C. (Carlotta), Salomaa, V. (Veikko), Sánchez, M.-J. (María-José), Sattar, N. (Naveed), Sharp, S.J. (Stephen), Sims, R. (Rebecca), Slimani, N. (Nadia), Smith, J.A. (Jennifer A), Thompson, D. (Deborah), Trompet, S. (Stella), Tumino, R. (Rosario), Van Der A, D.L. (Daphne L.), Schouw, Y.T. (Yvonne) van der, Virtamo, J. (Jarmo), Walker, M. (Mark), Walter, K. (Klaudia), Abraham, J.E. (Jean E.), Amundadottir, L.T. (Laufey T.), Butterworth, A.S. (Adam), Aponte, J.L. (Jennifer L), Dupuis, J. (Josée), Easton, D.F. (Douglas F.), Eeles, R. (Rosalind), Erdmann, J. (Jeanette), Franks, P.W. (Paul), Frayling, T.M. (Timothy), Hansen, T. (T.), Howson, J.M.M. (Joanna M.M.), Jorgensen, T. (Torben), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), McCarthy, M.I. (Mark), Pankow, J.S. (James), Pedersen, O. (Oluf), Riboli, E. (Elio), Rotter, J.I. (Jerome I.), Saleheen, D. (Danish), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Vollenweider, P. (Peter), O'Rahilly, S. (Stephen), Deloukas, P. (Panagiotis), Danesh, J. (John), Goodarzi, M. (Mark), Kathiresan, S. (Sekar), Meigs, J.B. (James), Ehm, M.G. (Margaret G), Wareham, N.J. (Nick), and Waterworth, D. (Dawn)

Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11, 806 individuals by targeted exome sequencing and follow-up in 39, 979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Published
2016
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9. Rare coding variants and X-linked loci associated with age at menarche

Author

Lunetta, K.L. (Kathryn), Day, F.R. (Felix), Sulem, P. (Patrick), Ruth, K.S. (Katherine S.), Tung, J.Y. (Joyce Y.), Hinds, D.A. (David A.), Esko, T. (Tõnu), Elks, C.E. (Cathy), Altmaier, E.L. (Elizabeth), He, C. (Chunyan), Huffman, J.E. (Jennifer), Mihailov, E. (Evelin), Porcu, E. (Eleonora), Robino, A. (Antonietta), Rose, L.M. (Lynda), Schick, U.M. (Ursula), Stolk, L. (Lisette), Teumer, A. (Alexander), Thompson, D. (Deborah), Traglia, M. (Michela), Wang, C.A. (Carol A.), Yerges-Armstrong, L.M. (Laura), Antoniou, A.C. (Antonis), Barbieri, C. (Caterina), Coviello, A.D. (Andrea), Cucca, F. (Francesco), Demerath, E.W. (Ellen), Dunning, A.M. (Alison), Gandin, I. (Ilaria), Grove, M.L. (Megan L.), Gudbjartsson, D.F. (Daniel), Hocking, L.J. (Lynne), Hofman, A. (Albert), Huang, J. (Jian), Jackson, R.D. (Rebecca), Karasik, D. (David), Kriebel, J. (Jennifer), Lange, E.M. (Ethan), Lange, L.A. (Leslie), Langenberg, C. (Claudia), Li, X. (Xin), Luan, J., Mägi, R. (Reedik), Morrison, A.C. (Alanna), Padmanabhan, S. (Sandosh), Pirie, A. (Ailith), Polasek, O. (Ozren), Porteous, D.J. (David J.), Reiner, A. (Alexander), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Sala, C. (Cinzia), Schlessinger, D. (David), Scott, R.A. (Robert), Stöckl, D. (Doris), Visser, J.A. (Jenny), Völker, U. (Uwe), Vozzi, D. (Diego), Wilson, J.G. (James), Zygmunt, M. (Marek), Boerwinkle, E.A. (Eric), Buring, J.E. (Julie), Crisponi, L. (Laura), Easton, D.F. (Douglas), Hayward, C. (Caroline), Hu, F.B. (Frank), Liu, S. (Simin), Metspalu, A. (Andres), Pennell, C.E. (Craig), Ridker, P.M. (Paul), Strauch, K. (Konstantin), Streeten, E.A. (Elizabeth), Toniolo, D. (Daniela), Uitterlinden, A.G. (André), Ulivi, S. (Shelia), Völzke, H. (Henry), Wareham, N.J. (Nick), Wellons, M. (Melissa), Franceschini, N. (Nora), Chasman, D.I. (Daniel), Thorsteinsdottir, U. (Unnur), Murray, A. (Anna), Zwart, J-A. (John-Anker), Murabito, J. (Joanne), Ong, K.K. (Ken), Perry, J.R.B. (John), Forouhi, N.G. (Nita G.), Kerrison, N.D. (Nicola D.), Sharp, S.J. (Stephen J.), Sims, M.A. (Matthew), Barroso, I.E. (Inês), Deloukas, P. (Panagiotis), McCarthy, M.I. (Mark), Arriola, L. (Larraitz), Balkau, B. (Beverley), Barricarte, A. (Aurelio), Boeing, H. (Heiner), Franks, P.W., Gonzalez, C. (Carlos), Grioni, S. (Sara), Kaaks, R. (Rudolf), Key, T.J. (Timothy J.), Navarro, C. (Carmen), Nilsson, P.M. (Peter M.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Quirós, J.R., Rolandsson, O. (Olov), Sacerdote, C. (Carlotta), Sánchez, M.-J. (María-José), Slimani, N. (Nadia), Tjonneland, A. (Anne), Tumino, R. (Rosario), Van Der A, D.L. (Daphne L.), Schouw, Y.T. (Yvonne) van der, Riboli, E. (Elio), Smith, B.H. (Blair), Campbell, A. (Archie), Deary, I.J. (Ian), McIntosh, A.M. (Andrew), Lunetta, K.L. (Kathryn), Day, F.R. (Felix), Sulem, P. (Patrick), Ruth, K.S. (Katherine S.), Tung, J.Y. (Joyce Y.), Hinds, D.A. (David A.), Esko, T. (Tõnu), Elks, C.E. (Cathy), Altmaier, E.L. (Elizabeth), He, C. (Chunyan), Huffman, J.E. (Jennifer), Mihailov, E. (Evelin), Porcu, E. (Eleonora), Robino, A. (Antonietta), Rose, L.M. (Lynda), Schick, U.M. (Ursula), Stolk, L. (Lisette), Teumer, A. (Alexander), Thompson, D. (Deborah), Traglia, M. (Michela), Wang, C.A. (Carol A.), Yerges-Armstrong, L.M. (Laura), Antoniou, A.C. (Antonis), Barbieri, C. (Caterina), Coviello, A.D. (Andrea), Cucca, F. (Francesco), Demerath, E.W. (Ellen), Dunning, A.M. (Alison), Gandin, I. (Ilaria), Grove, M.L. (Megan L.), Gudbjartsson, D.F. (Daniel), Hocking, L.J. (Lynne), Hofman, A. (Albert), Huang, J. (Jian), Jackson, R.D. (Rebecca), Karasik, D. (David), Kriebel, J. (Jennifer), Lange, E.M. (Ethan), Lange, L.A. (Leslie), Langenberg, C. (Claudia), Li, X. (Xin), Luan, J., Mägi, R. (Reedik), Morrison, A.C. (Alanna), Padmanabhan, S. (Sandosh), Pirie, A. (Ailith), Polasek, O. (Ozren), Porteous, D.J. (David J.), Reiner, A. (Alexander), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Sala, C. (Cinzia), Schlessinger, D. (David), Scott, R.A. (Robert), Stöckl, D. (Doris), Visser, J.A. (Jenny), Völker, U. (Uwe), Vozzi, D. (Diego), Wilson, J.G. (James), Zygmunt, M. (Marek), Boerwinkle, E.A. (Eric), Buring, J.E. (Julie), Crisponi, L. (Laura), Easton, D.F. (Douglas), Hayward, C. (Caroline), Hu, F.B. (Frank), Liu, S. (Simin), Metspalu, A. (Andres), Pennell, C.E. (Craig), Ridker, P.M. (Paul), Strauch, K. (Konstantin), Streeten, E.A. (Elizabeth), Toniolo, D. (Daniela), Uitterlinden, A.G. (André), Ulivi, S. (Shelia), Völzke, H. (Henry), Wareham, N.J. (Nick), Wellons, M. (Melissa), Franceschini, N. (Nora), Chasman, D.I. (Daniel), Thorsteinsdottir, U. (Unnur), Murray, A. (Anna), Zwart, J-A. (John-Anker), Murabito, J. (Joanne), Ong, K.K. (Ken), Perry, J.R.B. (John), Forouhi, N.G. (Nita G.), Kerrison, N.D. (Nicola D.), Sharp, S.J. (Stephen J.), Sims, M.A. (Matthew), Barroso, I.E. (Inês), Deloukas, P. (Panagiotis), McCarthy, M.I. (Mark), Arriola, L. (Larraitz), Balkau, B. (Beverley), Barricarte, A. (Aurelio), Boeing, H. (Heiner), Franks, P.W., Gonzalez, C. (Carlos), Grioni, S. (Sara), Kaaks, R. (Rudolf), Key, T.J. (Timothy J.), Navarro, C. (Carmen), Nilsson, P.M. (Peter M.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Quirós, J.R., Rolandsson, O. (Olov), Sacerdote, C. (Carlotta), Sánchez, M.-J. (María-José), Slimani, N. (Nadia), Tjonneland, A. (Anne), Tumino, R. (Rosario), Van Der A, D.L. (Daphne L.), Schouw, Y.T. (Yvonne) van der, Riboli, E. (Elio), Smith, B.H. (Blair), Campbell, A. (Archie), Deary, I.J. (Ian), and McIntosh, A.M. (Andrew)

Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10-8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10-13) and FAAH2 (rs5914101, P=4.9 × 10-10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10-11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

Published
2015
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10. Social inequalities and mortality in europe - results from a large multi-national cohort

Author

Gallo, V. (Valentina), Mackenbach, J.P. (Johan), Ezzati, M. (Majid), Menvielle, G. (Gwenn), Kunst, A.E. (Anton), Rohrmann, S. (Sabine), Kaaks, R. (Rudolf), Teucher, B. (Birgit), Boeing, H. (Heiner), Bergmann, M.M. (Manuela), Tjønneland, A. (Anne), Dalton, S.O. (Susanne), Overvad, K. (Kim), Redondo, M.-L. (Maria-Luisa), Agudo, A. (Antonio), Daponte, A. (Antonio), Arriola, L. (Larraitz), Navarro, C. (Carmen), Barricante Gurrea, A. (Aurelio), Khaw, K-T. (Kay-Tee), Wareham, N.J. (Nick), Key, T. (Tim), Naska, A. (Androniki), Trichopoulou, A. (Antonia), Trichopoulos, D. (Dimitrios), Masala, G. (Giovanna), Panico, S. (Salvatore), Contiero, P. (Paolo), Tumino, R. (Rosario), Bueno-De-Mesquita, H.B. (Bas), Siersema, P.D. (Peter), Peeters, P.H.M. (Petra), Zackrisson, S. (Sophia), Almquist, M. (Martin), Eriksson, S. (Sture), Hallmans, G. (Göran), Skeie, G. (Guri), Braaten, T. (Tonje), Lund, E. (Eiliv), Illner, A.-K. (Anne-Kathrin), Mouw, T. (Traci), Riboli, E. (Elio), Vineis, P. (Paolo), Gallo, V. (Valentina), Mackenbach, J.P. (Johan), Ezzati, M. (Majid), Menvielle, G. (Gwenn), Kunst, A.E. (Anton), Rohrmann, S. (Sabine), Kaaks, R. (Rudolf), Teucher, B. (Birgit), Boeing, H. (Heiner), Bergmann, M.M. (Manuela), Tjønneland, A. (Anne), Dalton, S.O. (Susanne), Overvad, K. (Kim), Redondo, M.-L. (Maria-Luisa), Agudo, A. (Antonio), Daponte, A. (Antonio), Arriola, L. (Larraitz), Navarro, C. (Carmen), Barricante Gurrea, A. (Aurelio), Khaw, K-T. (Kay-Tee), Wareham, N.J. (Nick), Key, T. (Tim), Naska, A. (Androniki), Trichopoulou, A. (Antonia), Trichopoulos, D. (Dimitrios), Masala, G. (Giovanna), Panico, S. (Salvatore), Contiero, P. (Paolo), Tumino, R. (Rosario), Bueno-De-Mesquita, H.B. (Bas), Siersema, P.D. (Peter), Peeters, P.H.M. (Petra), Zackrisson, S. (Sophia), Almquist, M. (Martin), Eriksson, S. (Sture), Hallmans, G. (Göran), Skeie, G. (Guri), Braaten, T. (Tonje), Lund, E. (Eiliv), Illner, A.-K. (Anne-Kathrin), Mouw, T. (Traci), Riboli, E. (Elio), and Vineis, P. (Paolo)

Abstract

Background: Socio-economic inequalities in mortality are observed at the country level in both North America and Europe. The purpose of this work is to investigate the contribution of specific risk factors to social inequalities in cause-specific mortality using a large multi-country cohort of Europeans. Methods: A total of 3,456,689 person/years follow-up of the European Prospective Investigation into Cancer and Nutrition (EPIC) was analysed. Educational level of subjects coming from 9 European countries was recorded as proxy for socio-economic status (SES). Cox proportional hazard model's with a step-wise inclusion of explanatory variables were used to explore the association between SES and mortality; a Relative Index of Inequality (RII) was calculated as measure of relative inequality. Results: Total mortality among men with the highest education level is reduced by 43% compared to men with the lowest (HR 0.57, 95% C.I. 0.52-0.61); among women by 29% (HR 0.71, 95% C.I. 0.64-0.78). The risk reduction was attenuated by 7% in men and 3% in women by the introduction of smoking and to a lesser extent (2% in men and 3% in women) by introducing body mass index and additional explanatory variables (alcohol consumption, leisure physical activity, fruit and vegetable intake) (3% in men and 5% in women). Social inequalities were highly statistically significant for all causes of death examined in men. In women, social inequalities were less strong, but statistically significant for all causes of death except for cancer-related mortality and injuries. Discussion: In this European study, substantial social inequalities in mortality among European men and women which cannot be fully explained away by accounting for known common risk factors for chronic diseases are reported.

Published
2012
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11. The role of smoking and diet in explaining educational inequalities in lung cancer incidence

Author

Menvielle, G. (Gwenn), Boshuizen, H.C. (Hendriek), Kunst, A.E. (Anton), Dalton, S.O. (Susanne), Vineis, P. (Paolo), Bergmann, M.M. (Manuela), Hermann, S. (Silke), Ferrari, P. (Pietro), Raaschou-Nielsen, O. (Ole), Tjønneland, A. (Anne), Kaaks, R. (Rudolf), Linseisen, J. (Jakob), Kosti, M. (Maria), Trichopoulou, A. (Antonia), Dilis, V. (Vardis), Palli, D. (Domenico), Krogh, V. (Vittorio), Panico, S. (Salvatore), Tumino, R. (Rosario), Büchner, F.L. (Frederike), Gils, C.H. (Carla) van, Peeters, P.H.M., Braaten, T. (Tonje), Gram, I.T. (Inger), Lund, E. (Eiliv), Rodriguez, L. (Laudina), Agudo, A. (Antonio), Sánchez, M.J., Tormo, M.J., Ardanaz, E. (Eva), Manjer, J. (Jonas), Wirfält, E. (Elisabet), Hallmans, G. (Göran), Rasmuson, T. (Torgny), Bingham, S. (Sheila), Khaw, K-T. (Kay-Tee), Allen, N.E. (Naomi), Key, T. (Tim), Boffetta, P. (Paolo), Duell, E.J. (Eric), Slimani, N. (Nadia), Gallo, V. (Valentina), Riboli, E. (Elio), Bueno-De-Mesquita, H.B. (Bas), Menvielle, G. (Gwenn), Boshuizen, H.C. (Hendriek), Kunst, A.E. (Anton), Dalton, S.O. (Susanne), Vineis, P. (Paolo), Bergmann, M.M. (Manuela), Hermann, S. (Silke), Ferrari, P. (Pietro), Raaschou-Nielsen, O. (Ole), Tjønneland, A. (Anne), Kaaks, R. (Rudolf), Linseisen, J. (Jakob), Kosti, M. (Maria), Trichopoulou, A. (Antonia), Dilis, V. (Vardis), Palli, D. (Domenico), Krogh, V. (Vittorio), Panico, S. (Salvatore), Tumino, R. (Rosario), Büchner, F.L. (Frederike), Gils, C.H. (Carla) van, Peeters, P.H.M., Braaten, T. (Tonje), Gram, I.T. (Inger), Lund, E. (Eiliv), Rodriguez, L. (Laudina), Agudo, A. (Antonio), Sánchez, M.J., Tormo, M.J., Ardanaz, E. (Eva), Manjer, J. (Jonas), Wirfält, E. (Elisabet), Hallmans, G. (Göran), Rasmuson, T. (Torgny), Bingham, S. (Sheila), Khaw, K-T. (Kay-Tee), Allen, N.E. (Naomi), Key, T. (Tim), Boffetta, P. (Paolo), Duell, E.J. (Eric), Slimani, N. (Nadia), Gallo, V. (Valentina), Riboli, E. (Elio), and Bueno-De-Mesquita, H.B. (Bas)

Abstract

Background: Studies in many countries have reported higher lung cancer incidence and mortality in individuals with lower socioeconomic status. Methods: To investigate the role of smoking in these inequalities, we used data from 391 251 participants in the European Prospective Investigation into Cancer and Nutrition study, a cohort of individuals in 10 European countries. We collected informatio

Published
2009
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