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1. Population structure discovery in meta-analyzed microbial communities and inflammatory bowel disease using MMUPHin

Author

Siyuan Ma, Dmitry Shungin, Himel Mallick, Melanie Schirmer, Long H. Nguyen, Raivo Kolde, Eric Franzosa, Hera Vlamakis, Ramnik Xavier, and Curtis Huttenhower

Subjects
Inflammatory bowel disease, Metagenomics, Dysbiosis, Meta-analysis, Batch effect, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Microbiome studies of inflammatory bowel diseases (IBD) have achieved a scale for meta-analysis of dysbioses among populations. To enable microbial community meta-analyses generally, we develop MMUPHin for normalization, statistical meta-analysis, and population structure discovery using microbial taxonomic and functional profiles. Applying it to ten IBD cohorts, we identify consistent associations, including novel taxa such as Acinetobacter and Turicibacter, and additional exposure and interaction effects. A single gradient of dysbiosis severity is favored over discrete types to summarize IBD microbiome population structure. These results provide a benchmark for characterization of IBD and a framework for meta-analysis of any microbial communities.

Published
2022
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2. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Published
2021
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3. Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data

Author

Dmitry Shungin, Simon Haworth, Kimon Divaris, Cary S. Agler, Yoichiro Kamatani, Myoung Keun Lee, Kelsey Grinde, George Hindy, Viivi Alaraudanjoki, Paula Pesonen, Alexander Teumer, Birte Holtfreter, Saori Sakaue, Jun Hirata, Yau-Hua Yu, Paul M. Ridker, Franco Giulianini, Daniel I. Chasman, Patrik K. E. Magnusson, Takeaki Sudo, Yukinori Okada, Uwe Völker, Thomas Kocher, Vuokko Anttonen, Marja-Liisa Laitala, Marju Orho-Melander, Tamar Sofer, John R. Shaffer, Alexandre Vieira, Mary L. Marazita, Michiaki Kubo, Yasushi Furuichi, Kari E. North, Steve Offenbacher, Erik Ingelsson, Paul W. Franks, Nicholas J. Timpson, and Ingegerd Johansson

Subjects
Science
Abstract

Dental caries and periodontitis are among the most common medical conditions. Here, the authors report a GWAS for measures of oral health that reveals 47 risk loci for caries, find genetic correlation with 31 other complex traits and use Mendelian randomization analyses to explore potential causal relationships.

Published
2019
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4. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3

Published
2021
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5. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Yingchang Lu, Felix R. Day, Stefan Gustafsson, Martin L. Buchkovich, Jianbo Na, Veronique Bataille, Diana L. Cousminer, Zari Dastani, Alexander W. Drong, Tõnu Esko, David M. Evans, Mario Falchi, Mary F. Feitosa, Teresa Ferreira, Åsa K. Hedman, Robin Haring, Pirro G. Hysi, Mark M. Iles, Anne E. Justice, Stavroula Kanoni, Vasiliki Lagou, Rui Li, Xin Li, Adam Locke, Chen Lu, Reedik Mägi, John R. B. Perry, Tune H. Pers, Qibin Qi, Marianna Sanna, Ellen M. Schmidt, William R. Scott, Dmitry Shungin, Alexander Teumer, Anna A. E. Vinkhuyzen, Ryan W. Walker, Harm-Jan Westra, Mingfeng Zhang, Weihua Zhang, Jing Hua Zhao, Zhihong Zhu, Uzma Afzal, Tarunveer Singh Ahluwalia, Stephan J. L. Bakker, Claire Bellis, Amélie Bonnefond, Katja Borodulin, Aron S. Buchman, Tommy Cederholm, Audrey C. Choh, Hyung Jin Choi, Joanne E. Curran, Lisette C. P. G. M. de Groot, Philip L. De Jager, Rosalie A. M. Dhonukshe-Rutten, Anke W. Enneman, Elodie Eury, Daniel S. Evans, Tom Forsen, Nele Friedrich, Frédéric Fumeron, Melissa E. Garcia, Simone Gärtner, Bok-Ghee Han, Aki S. Havulinna, Caroline Hayward, Dena Hernandez, Hans Hillege, Till Ittermann, Jack W. Kent, Ivana Kolcic, Tiina Laatikainen, Jari Lahti, Irene Mateo Leach, Christine G. Lee, Jong-Young Lee, Tian Liu, Youfang Liu, Stéphane Lobbens, Marie Loh, Leo-Pekka Lyytikäinen, Carolina Medina-Gomez, Karl Michaëlsson, Mike A. Nalls, Carrie M. Nielson, Laticia Oozageer, Laura Pascoe, Lavinia Paternoster, Ozren Polašek, Samuli Ripatti, Mark A. Sarzynski, Chan Soo Shin, Nina Smolej Narančić, Dominik Spira, Priya Srikanth, Elisabeth Steinhagen-Thiessen, Yun Ju Sung, Karin M. A. Swart, Leena Taittonen, Toshiko Tanaka, Emmi Tikkanen, Nathalie van der Velde, Natasja M. van Schoor, Niek Verweij, Alan F. Wright, Lei Yu, Joseph M. Zmuda, Niina Eklund, Terrence Forrester, Niels Grarup, Anne U. Jackson, Kati Kristiansson, Teemu Kuulasmaa, Johanna Kuusisto, Peter Lichtner, Jian'an Luan, Anubha Mahajan, Satu Männistö, Cameron D. Palmer, Janina S. Ried, Robert A. Scott, Alena Stancáková, Peter J. Wagner, Ayse Demirkan, Angela Döring, Vilmundur Gudnason, Douglas P. Kiel, Brigitte Kühnel, Massimo Mangino, Barbara Mcknight, Cristina Menni, Jeffrey R. O'Connell, Ben A. Oostra, Alan R. Shuldiner, Kijoung Song, Liesbeth Vandenput, Cornelia M. van Duijn, Peter Vollenweider, Charles C. White, Michael Boehnke, Yvonne Boettcher, Richard S. Cooper, Nita G. Forouhi, Christian Gieger, Harald Grallert, Aroon Hingorani, Torben Jørgensen, Pekka Jousilahti, Mika Kivimaki, Meena Kumari, Markku Laakso, Claudia Langenberg, Allan Linneberg, Amy Luke, Colin A. Mckenzie, Aarno Palotie, Oluf Pedersen, Annette Peters, Konstantin Strauch, Bamidele O. Tayo, Nicholas J. Wareham, David A. Bennett, Lars Bertram, John Blangero, Matthias Blüher, Claude Bouchard, Harry Campbell, Nam H. Cho, Steven R. Cummings, Stefan A. Czerwinski, Ilja Demuth, Rahel Eckardt, Johan G. Eriksson, Luigi Ferrucci, Oscar H. Franco, Philippe Froguel, Ron T. Gansevoort, Torben Hansen, Tamara B. Harris, Nicholas Hastie, Markku Heliövaara, Albert Hofman, Joanne M. Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Paul B. Knekt, Seppo Koskinen, Peter Kovacs, Terho Lehtimäki, Lars Lind, Yongmei Liu, Eric S. Orwoll, Clive Osmond, Markus Perola, Louis Pérusse, Olli T. Raitakari, Tuomo Rankinen, D. C. Rao, Treva K. Rice, Fernando Rivadeneira, Igor Rudan, Veikko Salomaa, Thorkild I. A. Sørensen, Michael Stumvoll, Anke Tönjes, Bradford Towne, Gregory J. Tranah, Angelo Tremblay, André G. Uitterlinden, Pim van der Harst, Erkki Vartiainen, Jorma S. Viikari, Veronique Vitart, Marie-Claude Vohl, Henry Völzke, Mark Walker, Henri Wallaschofski, Sarah Wild, James F. Wilson, Loïc Yengo, D. Timothy Bishop, Ingrid B. Borecki, John C. Chambers, L. Adrienne Cupples, Abbas Dehghan, Panos Deloukas, Ghazaleh Fatemifar, Caroline Fox, Terrence S. Furey, Lude Franke, Jiali Han, David J. Hunter, Juha Karjalainen, Fredrik Karpe, Robert C. Kaplan, Jaspal S. Kooner, Mark I. McCarthy, Joanne M. Murabito, Andrew P. Morris, Julia A. N. Bishop, Kari E. North, Claes Ohlsson, Ken K. Ong, Inga Prokopenko, J. Brent Richards, Eric E. Schadt, Tim D. Spector, Elisabeth Widén, Cristen J. Willer, Jian Yang, Erik Ingelsson, Karen L. Mohlke, Joel N. Hirschhorn, John Andrew Pospisilik, M. Carola Zillikens, Cecilia Lindgren, Tuomas Oskari Kilpeläinen, and Ruth J. F. Loos

Subjects
Science
Abstract

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Published
2016
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6. Coronary calcification with no flow limiting lesions: A potential cause for ischaemic dysfunction in syndrome X patients

Author

Elisabetta Palmerini, Henrik Antti, Dmitry Shungin, Stefan Soderberg, Sergio Mondillo, and Michael Y. Henein

Subjects
CACS, Coronary calcification, Stress echo, X syndrome, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Aim: Exertional angina in patients with no coronary flow limiting lesions remains a clinical puzzle. We aimed to assess the extent of coronary artery calcification (CAC) and its relationship to ventricular wall motion function using stress echocardiography in a group of patients limited by exertional angina, but no obstructive lesions. Methods: We compared CT coronary calcium score (CACS) and dobutamine stress echocardiography in 55 patients (age 64.7 ± 7.7 years), divided into Group 1 (CACS ≤ 100) and Group 2 (CACS > 100). No patient had LV ejection fraction-EF

Published
2015
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7. Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions.

Author

Dmitry Shungin, Wei Q Deng, Tibor V Varga, Jian'an Luan, Evelin Mihailov, Andres Metspalu, GIANT Consortium, Andrew P Morris, Nita G Forouhi, Cecilia Lindgren, Patrik K E Magnusson, Nancy L Pedersen, Göran Hallmans, Audrey Y Chu, Anne E Justice, Mariaelisa Graff, Thomas W Winkler, Lynda M Rose, Claudia Langenberg, L Adrienne Cupples, Paul M Ridker, Nicholas J Wareham, Ken K Ong, Ruth J F Loos, Daniel I Chasman, Erik Ingelsson, Tuomas O Kilpeläinen, Robert A Scott, Reedik Mägi, Guillaume Paré, and Paul W Franks

Subjects
Genetics, QH426-470
Abstract

Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (Pv), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm were stronger for SNPs with established marginal effects (Spearman's ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When Pv and Pm were compared for all pruned SNPs, only BMI was statistically significant (Spearman's ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the Pv distribution (Pbinomial

Published
2017
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8. Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study.

Author

Tibor V Varga, Emily Sonestedt, Dmitry Shungin, Robert W Koivula, Göran Hallmans, Stefan A Escher, Inês Barroso, Peter Nilsson, Olle Melander, Marju Orho-Melander, Frida Renström, and Paul W Franks

Subjects
Genetics, QH426-470
Abstract

Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (β = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0 × 10(-11) for TC; β = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0 × 10(-5) for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (β = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0 × 10(-5)), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (β = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1 × 10(-4)) and apolipoprotein A-I (APOA1) rs6589564 (β = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4 × 10(-8)), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P ≤ 0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.

Published
2014
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9. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

Author

Joshua C Randall, Thomas W Winkler, Zoltán Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tõnu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, Andre Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, DIAGRAM Consortium, Amélie Bonnefond, Philippe Froguel, MAGIC Investigators, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Jarvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M Van der Klauw, Jana V Van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, and Iris M Heid

Subjects
Genetics, QH426-470
Abstract

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR

Published
2013
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10. Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.

Author

Shafqat Ahmad, Gull Rukh, Tibor V Varga, Ashfaq Ali, Azra Kurbasic, Dmitry Shungin, Ulrika Ericson, Robert W Koivula, Audrey Y Chu, Lynda M Rose, Andrea Ganna, Qibin Qi, Alena Stančáková, Camilla H Sandholt, Cathy E Elks, Gary Curhan, Majken K Jensen, Rulla M Tamimi, Kristine H Allin, Torben Jørgensen, Soren Brage, Claudia Langenberg, Mette Aadahl, Niels Grarup, Allan Linneberg, Guillaume Paré, InterAct Consortium, DIRECT Consortium, Patrik K E Magnusson, Nancy L Pedersen, Michael Boehnke, Anders Hamsten, Karen L Mohlke, Louis T Pasquale, Oluf Pedersen, Robert A Scott, Paul M Ridker, Erik Ingelsson, Markku Laakso, Torben Hansen, Lu Qi, Nicholas J Wareham, Daniel I Chasman, Göran Hallmans, Frank B Hu, Frida Renström, Marju Orho-Melander, and Paul W Franks

Subjects
Genetics, QH426-470
Abstract

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

Published
2013
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11. Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.

Author

Tuomas O Kilpeläinen, Lu Qi, Soren Brage, Stephen J Sharp, Emily Sonestedt, Ellen Demerath, Tariq Ahmad, Samia Mora, Marika Kaakinen, Camilla Helene Sandholt, Christina Holzapfel, Christine S Autenrieth, Elina Hyppönen, Stéphane Cauchi, Meian He, Zoltan Kutalik, Meena Kumari, Alena Stančáková, Karina Meidtner, Beverley Balkau, Jonathan T Tan, Massimo Mangino, Nicholas J Timpson, Yiqing Song, M Carola Zillikens, Kathleen A Jablonski, Melissa E Garcia, Stefan Johansson, Jennifer L Bragg-Gresham, Ying Wu, Jana V van Vliet-Ostaptchouk, N Charlotte Onland-Moret, Esther Zimmermann, Natalia V Rivera, Toshiko Tanaka, Heather M Stringham, Günther Silbernagel, Stavroula Kanoni, Mary F Feitosa, Soren Snitker, Jonatan R Ruiz, Jeffery Metter, Maria Teresa Martinez Larrad, Mustafa Atalay, Maarit Hakanen, Najaf Amin, Christine Cavalcanti-Proença, Anders Grøntved, Göran Hallmans, John-Olov Jansson, Johanna Kuusisto, Mika Kähönen, Pamela L Lutsey, John J Nolan, Luigi Palla, Oluf Pedersen, Louis Pérusse, Frida Renström, Robert A Scott, Dmitry Shungin, Ulla Sovio, Tuija H Tammelin, Tapani Rönnemaa, Timo A Lakka, Matti Uusitupa, Manuel Serrano Rios, Luigi Ferrucci, Claude Bouchard, Aline Meirhaeghe, Mao Fu, Mark Walker, Ingrid B Borecki, George V Dedoussis, Andreas Fritsche, Claes Ohlsson, Michael Boehnke, Stefania Bandinelli, Cornelia M van Duijn, Shah Ebrahim, Debbie A Lawlor, Vilmundur Gudnason, Tamara B Harris, Thorkild I A Sørensen, Karen L Mohlke, Albert Hofman, André G Uitterlinden, Jaakko Tuomilehto, Terho Lehtimäki, Olli Raitakari, Bo Isomaa, Pål R Njølstad, Jose C Florez, Simin Liu, Andy Ness, Timothy D Spector, E Shyong Tai, Philippe Froguel, Heiner Boeing, Markku Laakso, Michael Marmot, Sven Bergmann, Chris Power, Kay-Tee Khaw, Daniel Chasman, Paul Ridker, Torben Hansen, Keri L Monda, Thomas Illig, Marjo-Riitta Järvelin, Nicholas J Wareham, Frank B Hu, Leif C Groop, Marju Orho-Melander, Ulf Ekelund, Paul W Franks, and Ruth J F Loos

Subjects
Medicine
Abstract

BackgroundThe FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).Methods and findingsAll studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents.ConclusionsThe association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.

Published
2011
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12. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Tove Fall, Anubha Mahajan, Dmitry Shungin, B. Balkau, Gerjan Navis, A. Metspalu, Anneli Pouta, Andrew A. Hicks, Ilja M. Nolte, Ian Ford, Aroon D. Hingorani, Stefan R Bornstein, Anuj Goel, Rona J. Strawbridge, Niek Verweij, Sarah H. Wild, Patricia B. Munroe, T.B. Harris, Jaana Lindström, Johnson Pcd., Nita G. Forouhi, Pierre Meneton, Patricia A. Peyser, Sarin A-P., Andrea Ganna, Timothy M. Frayling, Patrik K. E. Magnusson, Joanne M. Meyer, Yongmei Liu, Jeanette M. Stafford, Christian Herder, L Zudina, Maria G. Stathopoulou, May E. Montasser, Nicholas D. Hastie, Inês Barroso, Schwarz Peh., James B. Meigs, Perttu Salo, George Davey Smith, Gonneke Willemsen, Christopher J. Groves, Erik P A Van Iperen, M. A. Province, Veikko Salomaa, Naveed Sattar, Serena Sanna, Maria Dimitriou, Joop Jukema, Ulrika Krus, Albert V. Smith, Markku Laakso, James F. Wilson, George Nicholson, Loic Yengo, Tatijana Zemunik, Per Eriksson, Harold Snieder, Peter P. Pramstaller, Claudia Langenberg, R. Rauramaa, Alan R. Shuldiner, Pau Navarro, Veronique Vitart, Ross M. Fraser, Aaron Isaacs, C. Lecoeur, Jesper R. Gådin, Jackie F. Price, Letizia Marullo, L.F. Bielak, Sirkka Keinänen-Kiukaanniemi, Amélie Bonnefond, Michael Stumvoll, Alessia Faggian, Anke Tönjes, Tomohiro Tanaka, Wieland Kiess, Harry Campbell, Josée Dupuis, David Altshuler, João Fadista, Winfried März, G K Hovingh, Thomas Illig, Toby Johnson, H Grallert, Kari Stefansson, Reedik Mägi, Palmer Cna., de Geus Ejcn., Martina Müller-Nurasyid, Karen Kapur, Philippe Froguel, Dorret I. Boomsma, Anders Franco-Cereceda, Marcus E. Kleber, Boehnke M, Olga D. Carlson, Ozren Polasek, Andrew P. Morris, Alex S. F. Doney, Najaf Amin, Sara M. Willems, Vilmundur Gudnason, Jose C. Florez, Jeffery R. O'Connell, Nancy L. Pedersen, T. Saaristo, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Iva Miljkovic, James S. Pankow, Caroline Hayward, Hugh Watkins, Vasiliki Lagou, Johanna Kuusisto, Jaakko Tuomilehto, Alan F. Wright, Josephine M. Egan, Perry Jrb., C M van Duijn, Valeriya Lyssenko, Leif Groop, Stefania Bandinelli, Nigel W. Rayner, Tõnu Esko, Stela McLachlan, Momoko Horikoshi, Eric Boerwinkle, Rick Jansen, Richard N. Bergman, Gudmar Thorleifsson, Lyle J. Palmer, Vilmantas Giedraitis, Peter Kovacs, Nicholas J. Wareham, Luigi Ferrucci, N J Timpson, D Rybin, Anne U. Jackson, Tiinamaija Tuomi, Gonçalo R. Abecasis, Harst Pvd., Meena Kumari, Albert Hofman, Chiara Scapoli, Evelin Mihailov, Josine L. Min, Anders Hamsten, Hottenga J-J., Loos Rjf., Lars Lind, Ulf de Faire, Jaakko Kaprio, Guo Li, Beate St Pourcain, C Gieger, Amanda J. Bennett, Anna Ulrich, Nabila Bouatia-Naji, Satu Männistö, Antigone S. Dimas, Jarvelin M-R., Günther Silbernagel, F Karpe, A. Körner, David S. Siscovick, M Blüher, Rebecca J. Webster, Erik Ingelsson, Susan Campbell, Mika Kivimäki, Laura J. Rasmussen-Torvik, Heikki A. Koistinen, Sophie Visvikis-Siest, Bernhard O. Boehm, Inga Prokopenko, Ping An, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Kardia Slr., Richa Saxena, Igor Rudan, Richard M. Watanabe, Jian'an Luan, Marika Kaakinen, Shin S-Y., George Dedoussis, Panagiotis Deloukas, Mark I. McCarthy, Barbara Thorand, B.W.J.H. Penninx, Peter Vollenweider, Paul W. Franks, Leena Kinnunen, Markus Perola, Yvonne Boettcher, Timo A. Lakka, Nicole Soranzo, Stavroula Kanoni, Bakker Sjl., Winkelmann Br, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Genomics [Tartu, Estonia], University of Tartu, Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Helmholtz-Zentrum München (HZM), University of Cambridge [UK] (CAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Università degli Studi di Ferrara (UniFE), Boston University [Boston] (BU), VU University Medical Center [Amsterdam], University of Bristol [Bristol], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Imperial College London, Karolinska Institutet [Stockholm], Institute for Molecular Bioscience, University of Queensland [Brisbane], Statens Serum Institut [Copenhagen], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, National Institute on Aging [Baltimore, MD, USA] (NIH), University of Michigan [Ann Arbor], University of Michigan System, University of Maryland School of Medicine, University of Maryland System, The University of Western Australia (UWA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Wake Forest University, National Institute for Health and Welfare [Helsinki], The Wellcome Trust Sanger Institute [Cambridge], University of Iceland [Reykjavik], University of Washington [Seattle], University of Groningen [Groningen], University of Glasgow, William Harvey Research Institute, Barts and the London Medical School, Université de Lausanne (UNIL), deCODE genetics [Reykjavik], Northwestern University Feinberg School of Medicine, Uppsala Universitet [Uppsala], University of Edinburgh, Medical Faculty [Mannheim], University of Graz, Ludwig-Maximilians-Universität München (LMU), Johannes Gutenberg - Universität Mainz (JGU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Umeå University, Skane University Hospital [Malmo], Lund University [Lund], RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), University Medical Center Groningen [Groningen] (UMCG), Universität Leipzig [Leipzig], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Split, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Eastern Finland, Harokopio University of Athens, European Academy Bozen/Bolzano (EURAC), University of Kuopio, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Ninewells Hospital and Medical School [Dundee], University College of London [London] (UCL), University of Essex, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Helsinki, Leiden University Medical Center (LUMC), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Oulu, The University of Texas Health Science Center at Houston (UTHealth), University of Minnesota Medical School, University of Minnesota System, Keck School of Medicine [Los Angeles], University of Southern California (USC), Amsterdam UMC, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Universität Heidelberg [Heidelberg], King Abdulaziz University, Pirkanmaa Hospital District, Tampere University Hospital, Cedars-Sinai Medical Center, Danube University Krems, Harvard School of Public Health, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Hannover Medical School [Hannover] (MHH), Universität zu Lübeck [Lübeck], University of Exeter, Regeneron Pharmaceuticals [Tarrytown], University of Adelaide, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard T.H. Chan School of Public Health, John Radcliffe Hospital [Oxford University Hospital], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Genève (UNIGE), Big Data Institute, University of Surrey (UNIS), University of Bergen (UiB), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, University of Liverpool, University of Manchester [Manchester], Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, SIEST, Sofia, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging - DYNAHEALTH - - H20202015-04-01 - 2019-03-31 - 633595 - VALID, Beyond the Genetics of Addiction - ADDICTION - - EC:FP7:ERC2011-12-01 - 2017-05-31 - 284167 - VALID, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia - ePerMed - - H20202016-01-01 - 2018-12-31 - 692145 - VALID, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lausanne = University of Lausanne (UNIL), Karl-Franzens-Universität Graz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Amsterdam UMC - Amsterdam University Medical Center, Nanyang Technological University [Singapour], Universität zu Lübeck = University of Lübeck [Lübeck], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université de Genève = University of Geneva (UNIGE), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 633595,H2020,H2020-PHC-2014-two-stage,DYNAHEALTH(2015), European Project: 284167,EC:FP7:ERC,ERC-2011-StG_20101124,ADDICTION(2011), European Project: 692145,H2020,H2020-TWINN-2015,ePerMed(2016), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Functional Genomics, APH - Mental Health, Sociology and Social Gerontology, APH - Methodology, Hottenga, Jouke- Jan [0000-0002-5668-2368], Bouatia-Naji, Nabila [0000-0001-5424-2134], Jansen, Rick [0000-0002-3333-6737], Min, Josine L. [0000-0003-4456-9824], Faggian, Alessia [0000-0002-3799-9722], Bonnefond, Amélie [0000-0001-9976-3005], Isaacs, Aaron [0000-0001-5037-4834], Willems, Sara M. [0000-0002-6803-3007], Navarro, Pau [0000-0001-5576-8584], Jackson, Anne U. [0000-0002-9672-2547], Bielak, Lawrence F. [0000-0002-3443-8030], Saxena, Richa [0000-0003-2233-1065], Smith, Albert V. [0000-0003-1942-5845], Verweij, Niek [0000-0002-4303-7685], Goel, Anuj [0000-0003-2307-4021], Johnson, Paul C. D. [0000-0001-6663-7520], Strawbridge, Rona J. [0000-0001-8506-3585], Fall, Tove [0000-0003-2071-5866], Fraser, Ross M. [0000-0003-0488-2592], Kanoni, Stavroula [0000-0002-1691-9615], Giedraitis, Vilmantas [0000-0003-3423-2021], Kleber, Marcus E. [0000-0003-0663-7275], Müller-Nurasyid, Martina [0000-0003-3793-5910], Luan, Jian’an [0000-0003-3137-6337], Sanna, Serena [0000-0002-3768-1749], Nolte, Ilja M. [0000-0001-5047-4077], Zemunik, Tatijana [0000-0001-8120-2891], Kovacs, Peter [0000-0002-0290-5423], Wild, Sarah H. [0000-0001-7824-2569], McLachlan, Stela [0000-0003-0480-6143], Egan, Josephine [0000-0002-8945-0053], Hicks, Andrew A. [0000-0001-6320-0411], Thorand, Barbara [0000-0002-8416-6440], Hingorani, Aroon [0000-0001-8365-0081], Kivimaki, Mika [0000-0002-4699-5627], Koistinen, Heikki A. [0000-0001-7870-070X], Bakker, Stephan J. L. [0000-0003-3356-6791], Palmer, Colin N. A. [0000-0002-6415-6560], Jukema, J. Wouter [0000-0002-3246-8359], Sattar, Naveed [0000-0002-1604-2593], Snieder, Harold [0000-0003-1949-2298], Magnusson, Patrik K. [0000-0002-7315-7899], Blüher, Matthias [0000-0003-0208-2065], Wolffenbuttel, Bruce H. R. [0000-0001-9262-6921], Abecasis, Goncalo R. [0000-0003-1509-1825], Meigs, James B. [0000-0002-2439-2657], Wilson, James F. [0000-0001-5751-9178], Schwarz, Peter E. H. [0000-0001-6317-7880], Boehm, Bernhard O. [0000-0002-2706-7710], Metspalu, Andres [0000-0002-3718-796X], Deloukas, Panos [0000-0001-9251-070X], Körner, Antje [0000-0001-6001-0356], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Männistö, Satu [0000-0002-8668-3046], Franks, Paul W. [0000-0002-0520-7604], Hayward, Caroline [0000-0002-9405-9550], Vitart, Veronique [0000-0002-4991-3797], Kaprio, Jaakko [0000-0002-3716-2455], Visvikis-Siest, Sophie [0000-0001-8104-8425], Altshuler, David [0000-0002-7250-4107], Rudan, Igor [0000-0001-6993-6884], van Duijn, Cornelia M. [0000-0002-2374-9204], Pramstaller, Peter P. [0000-0002-9831-8302], Boehnke, Michael [0000-0002-6442-7754], Frayling, Timothy M. [0000-0001-8362-2603], Peyser, Patricia A. [0000-0002-9717-8459], Harst, Pim van der [0000-0002-2713-686X], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G. [0000-0002-5041-248X], Loos, Ruth J. F. [0000-0002-8532-5087], Salomaa, Veikko [0000-0001-7563-5324], Soranzo, Nicole [0000-0003-1095-3852], Boomsma, Dorret I. [0000-0002-7099-7972], Groop, Leif [0000-0002-0187-3263], Tuomi, Tiinamaija [0000-0002-8306-6202], Munroe, Patricia B. [0000-0002-4176-2947], Gudnason, Vilmundur [0000-0001-5696-0084], Lecoeur, Cecile [0000-0003-0075-6417], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Stefansson, Kari [0000-0003-1676-864X], Dermitzakis, Emmanouil T. [0000-0002-9302-6490], Lindgren, Cecilia M. [0000-0002-4903-9374], Froguel, Philippe [0000-0003-2972-0784], Kaakinen, Marika A. [0000-0002-9228-0462], Watanabe, Richard M. [0000-0003-1015-0531], Ingelsson, Erik [0000-0003-2256-6972], Dupuis, Josée [0000-0003-2871-3603], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Epidemiology, University Hospital Mannheim | Universitätsmedizin Mannheim, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Universität Leipzig, Universiteit Leiden, Universität Heidelberg [Heidelberg] = Heidelberg University, Karl-Franzens-Universität [Graz, Autriche], Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), Hottenga, Jouke-Jan [0000-0002-5668-2368], Min, Josine L [0000-0003-4456-9824], Willems, Sara M [0000-0002-6803-3007], Jackson, Anne U [0000-0002-9672-2547], Bielak, Lawrence F [0000-0002-3443-8030], Smith, Albert V [0000-0003-1942-5845], Johnson, Paul CD [0000-0001-6663-7520], Strawbridge, Rona J [0000-0001-8506-3585], Fraser, Ross M [0000-0003-0488-2592], Kleber, Marcus E [0000-0003-0663-7275], Luan, Jian'an [0000-0003-3137-6337], Nolte, Ilja M [0000-0001-5047-4077], Wild, Sarah H [0000-0001-7824-2569], Hicks, Andrew A [0000-0001-6320-0411], Koistinen, Heikki A [0000-0001-7870-070X], Bakker, Stephan JL [0000-0003-3356-6791], Palmer, Colin NA [0000-0002-6415-6560], Jukema, J Wouter [0000-0002-3246-8359], Magnusson, Patrik K [0000-0002-7315-7899], Wolffenbuttel, Bruce HR [0000-0001-9262-6921], Abecasis, Goncalo R [0000-0003-1509-1825], Meigs, James B [0000-0002-2439-2657], Wilson, James F [0000-0001-5751-9178], Schwarz, Peter EH [0000-0001-6317-7880], Boehm, Bernhard O [0000-0002-2706-7710], Wareham, Nicholas J [0000-0003-1422-2993], Franks, Paul W [0000-0002-0520-7604], van Duijn, Cornelia M [0000-0002-2374-9204], Pramstaller, Peter P [0000-0002-9831-8302], Frayling, Timothy M [0000-0001-8362-2603], Peyser, Patricia A [0000-0002-9717-8459], Forouhi, Nita G [0000-0002-5041-248X], Loos, Ruth JF [0000-0002-8532-5087], Boomsma, Dorret I [0000-0002-7099-7972], Munroe, Patricia B [0000-0002-4176-2947], Dermitzakis, Emmanouil T [0000-0002-9302-6490], Lindgren, Cecilia M [0000-0002-4903-9374], Kaakinen, Marika A [0000-0002-9228-0462], Watanabe, Richard M [0000-0003-1015-0531], Tampere University, Tays Research Services, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Fysiologie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering

Subjects
Male, Anorexia Nervosa, medicine.medical_treatment, 45/43, Insulin Resistance/genetics, SUSCEPTIBILITY, Quantitative trait, Impaired glucose tolerance, 0302 clinical medicine, Architecture, LS2_1, IMPUTATION, Insulin, ComputingMilieux_MISCELLANEOUS, Fasting, Publisher Correction, 3. Good health, [SDV] Life Sciences [q-bio], Kruppel-Like Transcription Factors/blood, Endokrinologi och diabetes, Science & Technology - Other Topics, Adult, Blood Glucose, European Continental Ancestry Group, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Kruppel-Like Transcription Factors, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio, Sex characteristics, medicine.medical_specialty, Science, 631/208/205/2138, Endocrinology and Diabetes, General Biochemistry, Genetics and Molecular Biology, White People, Gender-differences, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 692/53/2421, GLYCEMIC TRAITS, GENOME-WIDE ASSOCIATION, Glycemic, GENDER-DIFFERENCES, Science & Technology, IDENTIFICATION, 692/699/2743/2815, Blood Glucose/metabolism, Diagnostic markers, medicine.disease, Anorexia Nervosa/blood, 030104 developmental biology, Endocrinology, Glucose, Insulin/blood, Anorexia Nervosa/ethnology, Anorexia Nervosa/genetics, Anorexia Nervosa/physiopathology, Fasting/blood, Glucose Intolerance/blood, Glucose Intolerance/ethnology, Glucose Intolerance/genetics, Glucose Intolerance/physiopathology, Insulin Receptor Substrate Proteins/blood, Insulin Receptor Substrate Proteins/genetics, Kruppel-Like Transcription Factors/genetics, 0301 basic medicine, Identification, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome-wide association studies, Waist–hip ratio, LS4_5, RISK, ARCHITECTURE, Multidisciplinary, article, Type 2 diabetes, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, Pre-diabetes, Medical Genetics, Risk, PATHOPHYSIOLOGY, 030209 endocrinology & metabolism, 3121 Internal medicine, 692/163/2743/137/773, NO, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Mendelian randomization, 631/208/480, Medicinsk genetik, business.industry, General Chemistry, Impaired fasting glucose, business
Abstract

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Published
2021

13. Population structure discovery in meta-analyzed microbial communities and inflammatory bowel disease using MMUPHin

Author

Siyuan Ma, Dmitry Shungin, Himel Mallick, Melanie Schirmer, Long H. Nguyen, Raivo Kolde, Eric Franzosa, Hera Vlamakis, Ramnik Xavier, and Curtis Huttenhower

Subjects
Microbiota, Dysbiosis, Humans, Inflammatory Bowel Diseases, Gastrointestinal Microbiome
Abstract

Microbiome studies of inflammatory bowel diseases (IBD) have achieved a scale for meta-analysis of dysbioses among populations. To enable microbial community meta-analyses generally, we develop MMUPHin for normalization, statistical meta-analysis, and population structure discovery using microbial taxonomic and functional profiles. Applying it to ten IBD cohorts, we identify consistent associations, including novel taxa such as Acinetobacter and Turicibacter, and additional exposure and interaction effects. A single gradient of dysbiosis severity is favored over discrete types to summarize IBD microbiome population structure. These results provide a benchmark for characterization of IBD and a framework for meta-analysis of any microbial communities.

Published
2021

14. Perinatal famine is associated with excess risk of proliferative retinopathy in patients with type 2 diabetes

Author

Türküler Özgümüs, Deepak Jain, Andrea O.Y. Luk, Rashmi B. Prasad, Tetiana Svietleisha, Isabella Artner, Nadiya Khalimon, Valeriya Lyssenko, Tetiana Buldenko, Rafael Simó, Olena Fedotkina, Dmitry Shungin, Olga Simó-Servat, Allan Vaag, Ruchi Jain, Mykola Khalangot, Liubov Cherviakova, Alexander Vaiserman, Victor Kravchenko, Peter M. Nilsson, Juliana C.N. Chan, and Cristina Hernández

Subjects
medicine.medical_specialty, Type 2 diabetes, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Diabetes mellitus, Humans, Medicine, Registries, Aged, Diabetic Retinopathy, Famine, business.industry, Obstetrics, Absolute risk reduction, General Medicine, Diabetic retinopathy, Middle Aged, medicine.disease, Ophthalmology, Malnutrition, Diabetes Mellitus, Type 2, Case-Control Studies, Prenatal Exposure Delayed Effects, 030221 ophthalmology & optometry, Hong Kong, Small for gestational age, Female, Ukraine, business, 030217 neurology & neurosurgery, Retinopathy
Abstract

PURPOSE: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR).METHODS: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932-1933) and the WWII (1941-1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942-1945.RESULTS: During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05).CONCLUSION: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications. (Less)

Published
2021

15. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases

Author

Nadim J. Ajami, Gholamali Rahnavard, Melanie Schirmer, Ashwin N. Ananthakrishnan, Kevin S. Bonham, Lee A. Denson, Clary B. Clish, Kathleen Lake, Yoshiki Vázquez-Baeza, Dermot P.B. McGovern, David Casero, Dmitry Shungin, Jonathan Braun, Antonio Gonzalez, Mahadev Prasad, Thomas G. Graeber, Joseph F. Petrosino, Carol J. Landers, Damian R. Plichta, Hera Vlamakis, Subra Kugathasan, Jenny S. Sauk, Janet K. Jansson, Elizabeth Andrews, Rob Knight, A. Brantley Hall, Harland S. Winter, Richard A. White, Curtis Huttenhower, Himel Mallick, Colin J. Brislawn, Tiffany W. Poon, Holly Courtney, Eric A. Franzosa, Julian Avila-Pacheco, Thaddeus S. Stappenbeck, Jason Lloyd-Price, Ramnik J. Xavier, and Cesar Arze

Subjects
Proteomics, 0301 basic medicine, Systems analysis, Disease, Biology, Inflammatory bowel disease, Article, Clostridia, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, Biopsy, medicine, Animals, Humans, Ecosystem, Phylogeny, Multidisciplinary, medicine.diagnostic_test, Fungi, Obligate anaerobe, Inflammatory Bowel Diseases, medicine.disease, biology.organism_classification, Ulcerative colitis, Gastrointestinal Microbiome, 3. Good health, Crohn's disease, 030104 developmental biology, Health, Viruses, Immunology, 030211 gastroenterology & hepatology, Microbiome, Transcriptome, Dysbiosis, Biomarkers, Human Microbiome Project
Abstract

Inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis, affect several million individuals worldwide. Crohn’s disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study’s infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi’omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases., The Inflammatory Bowel Disease Multi’omics Database includes longitudinal data encompassing a multitude of analyses of stool, blood and biopsies of more than 100 individuals, and provides a comprehensive description of host and microbial activities in inflammatory bowel diseases.

Published
2019

16. A fully adjusted two-stage procedure for rank-normalization in genetic association studies

Author

Dmitry Shungin, Jeffrey R. O'Connell, Xiuwen Zheng, Kelsey Grinde, Solomon K. Musani, Ramachandran S. Vasan, Tamar Sofer, Ramon A. Durazo-Arvizo, John R. Shaffer, L. Adrienne Cupples, Kenneth Rice, Stephanie M. Gogarten, Cathy C. Laurie, Cecelia A. Laurie, Laura M. Raffield, Alex P. Reiner, and Leslie A. Lange

Subjects
Normalization (statistics), 0303 health sciences, Epidemiology, media_common.quotation_subject, 030305 genetics & heredity, food and beverages, Rate control, Statistical power, 03 medical and health sciences, Linear regression, Statistics, Trait, Genetics (clinical), Normality, 030304 developmental biology, Type I and type II errors, media_common, Mathematics, Genetic association
Abstract

When testing genotype–phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse ...

Published
2019

17. Metabolomics Insights in Early Childhood Caries

Author

Kimon Divaris, Aurea Simon-Soro, Alena Orlenko, H D Spangler, Jason H. Moore, Miguel Simancas-Pallares, Dmitry Shungin, A G Ferreira Zandoná, Jeannie Ginnis, P Ramamoorthy, Jeff Roach, John Tim Wright, Hunyong Cho, Di Wu, Lara H. Heimisdottir, Apoena de Aguiar Ribeiro, Hyun Koo, and Bridget M Lin

Subjects
0301 basic medicine, Dental Caries Susceptibility, Metabolite, Dentistry, Dental Caries, Disease activity, Correlation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Metabolomics, Metabolome, North Carolina, Prevalence, Medicine, Humans, Child, General Dentistry, business.industry, Imidazole propionate, Research Reports, 030206 dentistry, medicine.disease, stomatognathic diseases, 030104 developmental biology, Cross-Sectional Studies, chemistry, Child, Preschool, Multiple comparisons problem, business, Early childhood caries
Abstract

Dental caries is characterized by a dysbiotic shift at the biofilm–tooth surface interface, yet comprehensive biochemical characterizations of the biofilm are scant. We used metabolomics to identify biochemical features of the supragingival biofilm associated with early childhood caries (ECC) prevalence and severity. The study’s analytical sample comprised 289 children ages 3 to 5 (51% with ECC) who attended public preschools in North Carolina and were enrolled in a community-based cross-sectional study of early childhood oral health. Clinical examinations were conducted by calibrated examiners in community locations using International Caries Detection and Classification System (ICDAS) criteria. Supragingival plaque collected from the facial/buccal surfaces of all primary teeth in the upper-left quadrant was analyzed using ultra-performance liquid chromatography–tandem mass spectrometry. Associations between individual metabolites and 18 clinical traits (based on different ECC definitions and sets of tooth surfaces) were quantified using Brownian distance correlations (dCor) and linear regression modeling of log2-transformed values, applying a false discovery rate multiple testing correction. A tree-based pipeline optimization tool (TPOT)–machine learning process was used to identify the best-fitting ECC classification metabolite model. There were 503 named metabolites identified, including microbial, host, and exogenous biochemicals. Most significant ECC-metabolite associations were positive (i.e., upregulations/enrichments). The localized ECC case definition (ICDAS ≥1 caries experience within the surfaces from which plaque was collected) had the strongest correlation with the metabolome (dCor P = 8 × 10−3). Sixteen metabolites were significantly associated with ECC after multiple testing correction, including fucose ( P = 3.0 × 10−6) and N-acetylneuraminate (p = 6.8 × 10−6) with higher ECC prevalence, as well as catechin ( P = 4.7 × 10−6) and epicatechin ( P = 2.9 × 10−6) with lower. Catechin, epicatechin, imidazole propionate, fucose, 9,10-DiHOME, and N-acetylneuraminate were among the top 15 metabolites in terms of ECC classification importance in the automated TPOT model. These supragingival biofilm metabolite findings provide novel insights in ECC biology and can serve as the basis for the development of measures of disease activity or risk assessment.

Published
2021

18. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Stavroula Kanoni, Bakker Sjl., Winkelmann Br, Wieland Kiess, Josée Dupuis, Palmer Cna., James F. Wilson, Schwarz Peh., Maria Dimitriou, Joop Jukema, Sara M. Willems, J L Min, R. Rauramaa, Perry Jrb., Momoko Horikoshi, Timo A. Lakka, Nicole Soranzo, J Kaprio, Niek Verweij, Martina Müller-Nurasyid, Jaana Lindström, Toby Johnson, Olga D. Carlson, Nita G. Forouhi, George Dedoussis, Johnson Pcd., Patrick K.E. Magnusson, Gonçalo R. Abecasis, Ozren Polasek, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Nancy L. Pedersen, Beate St Pourcain, Erik P A Van Iperen, Iva Miljkovic, Stefania Bandinelli, M. A. Province, Veikko Salomaa, Andrew A. Hicks, Evelin Mihailov, Rick Jansen, James B. Meigs, D Rybin, Peter Kovacs, George Davey Smith, Rona J. Strawbridge, Gudmar Thorleifsson, Meena Kumari, Chiara Scapoli, Christopher J. Groves, Barbara Thorand, T.B. Harris, Ulf de Faire, Inga Prokopenko, Stela McLachlan, Ping An, Anubha Mahajan, L.F. Bielak, Rebecca J. Webster, David Altshuler, Susan Campbell, Bernhard O. Boehm, A. Metspalu, Perttu Salo, D.I. Boomsma, Ilja M. Nolte, Andrea Ganna, Timothy M. Frayling, Pau Navarro, N J Timpson, Kardia Slr., Jeanette M. Stafford, Tõnu Esko, Ulrika Krus, Richa Saxena, Per Eriksson, Peter P. Pramstaller, Anne U. Jackson, V Lagou, Anders Franco-Cereceda, David S. Siscovick, Josephine M. Egan, Loos Rjf., C Gieger, Amanda J. Bennett, Anna Ulrich, Satu Männistö, Mika Kivimäki, Loic Yengo, Caroline Hayward, George Nicholson, C M van Duijn, Anke Tönjes, Nigel W. Rayner, Jose C. Florez, Leif Groop, Valeri Lyssenko, Lyle J. Palmer, Vilmantas Giedraitis, Maria G. Stathopoulou, B. Balkau, Anneli Pouta, Anuj Goel, Pierre Meneton, Serena Sanna, Jesper R. Gådin, Claudia Langenberg, Alessia Faggian, H Grallert, Karen Kapur, Marcus E. Kleber, Philippe Froguel, Boehnke M, Harry Campbell, Anders Hamsten, T. Saaristo, Antigone S. Dimas, Jarvelin M-R., F Karpe, A. Körner, Leena Kinnunen, Markus Perola, Joanne M. Meyer, May E. Montasser, Erik Ingelsson, Naveed Sattar, Yvonne Boettcher, Sirkka Keinänen-Kiukaanniemi, Aaron Isaacs, Gerjan Navis, Ian Ford, Amélie Bonnefond, Reedik Mägi, Tove Fall, Dmitry Shungin, Jenna Price, Igor Rudan, Richard M. Watanabe, Luigi Ferrucci, Jian'an Luan, Harst Pvd., Marika Kaakinen, Tatijana Zemunik, Christian Herder, Shin S-Y., Veronique Vitart, Ross M. Fraser, Alan R. Shuldiner, Panagiotis Deloukas, C. Lecoeur, Letizia Marullo, Kari Stefansson, Lars Lind, Winfried März, L Zudina, Aroon D. Hingorani, Gonneke Willemsen, de Geus Ejcn., Albert V. Smith, Jeffery R. O'Connell, Yongmei Liu, James S. Pankow, Sarah H. Wild, Patricia B. Munroe, Patricia A. Peyser, Nicholas J. Wareham, Tiinamaija Tuomi, Nicholas D. Hastie, Markku Laakso, Albert Hofman, J. Tuomilehto, Emmanouil T. Dermitzakis, Thomas Illig, Tomohiro Tanaka, Cecilia M. Lindgren, Sarin A-P., Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Andrew P. Morris, Richard N. Bergman, Mark I. McCarthy, Nabila Bouatia-Naji, Günther Silbernagel, João Fadista, Harold Snieder, Ins Barroso, Michael Stumvoll, B.W.J.H. Penninx, M Blüher, Stefan R Bornstein, Laura J. Rasmussen-Torvik, Alan F. Wright, Peter Vollenweider, G K Hovingh, Heikki A. Koistinen, Sophie Visvikis-Siest, Vilmundur Gudnason, Eric Boerwinkle, Hottenga J-J., Guo Li, Paul W. Franks, Université de Lille, Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay

Subjects
Genetics, Multidisciplinary, Science, Insulin, medicine.medical_treatment, General Physics and Astronomy, Diagnostic marker, Genome-wide association study, General Chemistry, Type 2 diabetes, Quantitative trait locus, Biology, medicine.disease, GeneralLiterature_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, Fasting glucose, Sexual dimorphism, Pre diabetes, [SDU]Sciences of the Universe [physics], ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, medicine
Abstract

The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.

Published
2021

19. Population Structure Discovery in Meta-Analyzed Microbial Communities and Inflammatory Bowel Disease

Author

Siyuan Ma, Dmitry Shungin, Raivo Kolde, Eric A. Franzosa, Himel Mallick, Melanie Schirmer, Ramnik J. Xavier, Long H. Nguyen, Hera Vlamakis, and Curtis Huttenhower

Subjects
Treatment response, Population structure, Human microbiome, medicine, Disease, Computational biology, Microbiome, Biology, medicine.disease, Health outcomes, Random effects model, Inflammatory bowel disease
Abstract

Microbial community studies in general, and of the human microbiome in inflammatory bowel disease (IBD) in particular, have now achieved a scale at which it is practical to associate features of the microbiome with environmental exposures and health outcomes across multiple large-scale populations. This permits the development of rigorous meta-analysis methods, of particular importance in IBD as a means by which the heterogeneity of disease etiology and treatment response might be explained. We have thus developed MMUPHin (Meta-analysis Methods with a Uniform Pipeline for Heterogeneity in microbiome studies) for joint normalization, meta-analysis, and population structure discovery using microbial community taxonomic and functional profiles. Applying this method to ten IBD cohorts (5,151 total samples), we identified a single consistent axis of microbial associations among studies, including newly associated taxa such as Acinetobacter and Turicibacter detected due to the sensitivity of meta-analysis. Linear random effects models further revealed associations with medications, disease location, and interaction effects consistent within and between studies. Finally, multiple unsupervised clustering metrics and dissimilarity measures agreed on a lack of discrete microbiome “types” in the IBD gut microbiome. These results thus provide a benchmark for consistent characterization of the IBD gut microbiome and a general framework applicable to meta-analysis of any microbial community types.

Published
2020

20. Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level

Author

Douglas J. Kenny, Ramachandran S. Vasan, Hera Vlamakis, Dmitry Shungin, Nitzan Koppel, Damian R. Plichta, Beverly Fu, Stanley Y. Shaw, A. Brantley Hall, Emily P. Balskus, and Ramnik J. Xavier

Subjects
microbial dark matter, microbiome, Gut flora, Microbiology, Article, hydroxysteroid dehydrogenase, 03 medical and health sciences, chemistry.chemical_compound, Feces, 0302 clinical medicine, Metabolomics, coprostanol, Virology, Humans, Microbiome, 030304 developmental biology, Clostridium cluster IV, 0303 health sciences, biology, Bacteria, Framingham Heart Study, Cholesterol, Human microbiome, Biochemistry and Molecular Biology, biology.organism_classification, Lipid Metabolism, metagenomic species, Sterol, Gastrointestinal Microbiome, Coprostanol, Cholestanol, chemistry, Metagenomics, Parasitology, lipids (amino acids, peptides, and proteins), Oxidoreductases, 030217 neurology & neurosurgery, Biokemi och molekylärbiologi
Abstract

Summary The human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a clade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health., Graphical Abstract, Highlights • Bioinformatics enabled discovery of ismA, a microbial cholesterol dehydrogenase • Metagenomic species with ismA genes form coprostanol in microbial communities • ismA+ species are associated with decreased fecal and serum cholesterol in humans • Effect sizes of ismA+ species on serum cholesterol are on par with human genetics, The consequences of cholesterol metabolism by the gut microbiome were largely unknown. Kenny, Plichta et al. identified and characterized microbial cholesterol dehydrogenase enzymes encoded by uncultured metagenomic species of bacteria. The presence of these cholesterol-metabolizing bacteria is associated with decreased stool and serum total cholesterol in human cohorts.

Published
2020

21. Nonfermented milk and other dairy products: associations with all-cause mortality

Author

Jan-Håkan Jansson, Frida Renström, Gianluca Tognon, Maria Wennberg, Dmitry Shungin, Lauren Lissner, Anna Winkvist, Ingegerd Johansson, and Lena Maria Nilsson

Subjects
Adult, Male, 0301 basic medicine, Milk intake, Food consumption, Physical activity, Medicine (miscellaneous), Body weight, Polymorphism, Single Nucleotide, 03 medical and health sciences, chemistry.chemical_compound, Lactose Intolerance, Risk Factors, Cause of Death, Environmental health, Animals, Humans, Medicine, Food science, Lactose, Life Style, Sweden, 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, food and beverages, Feeding Behavior, Middle Aged, Dietary Fats, Diet, Original Research Communications, Milk, chemistry, Butter, Female, Dairy Products, Energy Intake, business, Body mass index, All cause mortality, Cohort study
Abstract

Background: A positive association between nonfermented milk intake and increased all-cause mortality was recently reported, but overall, the association between dairy intake and mortality is inconclusive. Objective: We studied associations between intake of dairy products and all-cause mortality with an emphasis on nonfermented milk and fat content. Design: A total of 103,256 adult participants (women: 51.0%) from Northern Sweden were included (7121 deaths; mean follow-up: 13.7 y). Associations between all-cause mortality and reported intakes of nonfermented milk (total or by fat content), fermented milk, cheese, and butter were tested with the use of Cox proportional hazards models that were adjusted for age, sex, body mass index, smoking status, education, energy intake, examination year, and physical activity. To circumvent confounding, Mendelian randomization was applied in a subsample via the lactase LCT-13910 C/T single nucleotide polymorphism that is associated with lactose tolerance and milk intake. Results: High consumers of nonfermented milk (≥2.5 times/d) had a 32% increased hazard (HR: 1.32; 95% CI: 1.18, 1.48) for all-cause mortality compared with that of subjects who consumed milk ≤1 time/wk. The corresponding value for butter was 11% (HR: 1.11; 95% CI: 1.07, 1.21). All nonfermented milk-fat types were independently associated with increased HRs, but compared with full-fat milk, HRs were lower in consumers of medium- and low-fat milk. Fermented milk intake (HR: 0.90; 95% CI: 0.86, 0.94) and cheese intake (HR: 0.93; 95% CI: 0.91, 0.96) were negatively associated with mortality. Results were slightly attenuated by lifestyle adjustments but were robust in sensitivity analyses. Mortality was not significantly associated with the LCT-13910 C/T genotype in the smaller subsample. The amount and type of milk intake was associated with lifestyle variables. Conclusions: In the present Swedish cohort study, intakes of nonfermented milk and butter are associated with higher all-cause mortality, and fermented milk and cheese intakes are associated with lower all-cause mortality. Residual confounding by lifestyle cannot be excluded, and Mendelian randomization needs to be examined in a larger sample.

Published
2017

22. Protocols, Methods, and Tools for Genome-Wide Association Studies (GWAS) of Dental Traits

Author

Dmitry Shungin, Beau D Meyer, Andrea Ferreira Zandona, Kari E. North, John L. Cantrell, Paige Schmadeke, Jason Luo, Cary S. Agler, John R. Shaffer, Arne S. Schaefer, Kimon Divaris, Thomas D. Pahel, and Patricia V. Basta

Subjects
0301 basic medicine, Genotyping Techniques, Genome-wide association study, Genomics, Disease, Computational biology, Biology, Dental Caries, Population stratification, Article, 03 medical and health sciences, 0302 clinical medicine, Humans, Genotyping, Periodontal Diseases, Genetic association, Genome, Human, 030206 dentistry, DNA, Precision medicine, Omics, stomatognathic diseases, 030104 developmental biology, Phenotype, Tooth Diseases, Software, Genome-Wide Association Study
Abstract

Oral health and disease are known to be influenced by complex interactions between environmental (e.g., social and behavioral) factors and innate susceptibility. Although the exact contribution of genomics and other layers of "omics" to oral health is an area of active research, it is well established that the susceptibility to dental caries, periodontal disease, and other oral and craniofacial traits is substantially influenced by the human genome. A comprehensive understanding of these genomic factors is necessary for the realization of precision medicine in the oral health domain. To aid in this direction, the advent and increasing affordability of high-throughput genotyping has enabled the simultaneous interrogation of millions of genetic polymorphisms for association with oral and craniofacial traits. Specifically, genome-wide association studies (GWAS) of dental caries and periodontal disease have provided initial insights into novel loci and biological processes plausibly implicated in these two common, complex, biofilm-mediated diseases. This paper presents a summary of protocols, methods, tools, and pipelines for the conduct of GWAS of dental caries, periodontal disease, and related traits. The protocol begins with the consideration of different traits for both diseases and outlines procedures for genotyping, quality control, adjustment for population stratification, heritability and association analyses, annotation, reporting, and interpretation. Methods and tools available for GWAS are being constantly updated and improved; with this in mind, the presented approaches have been successfully applied in numerous GWAS and meta-analyses among tens of thousands of individuals, including dental traits such as dental caries and periodontal disease. As such, they can serve as a guide or template for future genomic investigations of these and other traits.

Published
2019

23. A Fully-Adjusted Two-Stage Procedure for Rank Normalization in Genetic Association Studies

Author

Jeffrey R. O'Connell, Tamar Sofer, Leslie A. Lange, Xiuwen Zheng, Kelsey Grinde, Solomon K. Musani, Kenneth Rice, L. Adrienne Cupples, Laura M. Raffield, Alex P. Reiner, Ramon A. Durazo-Arvizo, Cathy C. Laurie, Cecelia A. Laurie, Ramachandran S. Vasan, Dmitry Shungin, John R. Shaffer, and Stephanie M. Gogarten

Subjects
Normalization (statistics), 0303 health sciences, Genotype, Models, Genetic, 030305 genetics & heredity, Confounding, Hispanic or Latino, Statistical power, Regression, Article, 03 medical and health sciences, Hemoglobins, Phenotype, Linear regression, Statistics, Covariate, Trait, Linear Models, Humans, Computer Simulation, Genetic Association Studies, 030304 developmental biology, Mathematics, Type I and type II errors, Genome-Wide Association Study
Abstract

When testing genotype-phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse consequences for rarer variants. While it has been shown that applying a rank-normalization transformation to trait values before testing may improve these statistical properties, the factor driving them is not the trait distribution itself, but its residual distribution after regression on both covariates and genotype. Because genotype is expected to have a small effect (if any) investigators now routinely use a two-stage method, in which they first regress the trait on covariates, obtain residuals, rank-normalize them, and then secondly use the rank-normalized residuals in association analysis with the genotypes. Potential confounding signals are assumed to be removed at the first stage, so in practice no further adjustment is done in the second stage. Here, we show that this widely-used approach can lead to tests with undesirable statistical properties, due to both a combination of a mis-specified mean-variance relationship, and remaining covariate associations between the rank-normalized residuals and genotypes. We demonstrate these properties theoretically, and also in applications to genome-wide and whole-genome sequencing association studies. We further propose and evaluate an alternative fully-adjusted two-stage approach that adjusts for covariates both when residuals are obtained, and in the subsequent association test. This method can reduce excess Type I errors and improve statistical power.

Published
2019

24. The Supragingival Biofilm in Early Childhood Caries: Clinical and Laboratory Protocols and Bioinformatics Pipelines Supporting Metagenomics, Metatranscriptomics, and Metabolomics Studies of the Oral Microbiome

Author

Dmitry Shungin, Andrea Ferreira Zandona, Kimon Divaris, Natasha Butz, Adaris Rodríguez-Cortés, Sivapriya Ramamoorthy, Jakub Kwintkiewicz, Jason M. Kinchen, Patricia V. Basta, Jeannie Ginnis, M. Andrea Azcarate-Peril, Apoena de Aguiar Ribeiro, Jeff Roach, Hunyong Cho, and Di Wu

Subjects
DNA, Bacterial, 0301 basic medicine, Population, Gingiva, Context (language use), Disease, Dental Caries, Bioinformatics, Article, Specimen Handling, 03 medical and health sciences, 0302 clinical medicine, Humans, Metabolomics, Medicine, Microbiome, Tooth, Deciduous, education, education.field_of_study, Bacteria, Sequence Analysis, RNA, business.industry, Gene Expression Profiling, Microbiota, Sequence Analysis, DNA, 030206 dentistry, medicine.disease, RNA, Bacterial, stomatognathic diseases, 030104 developmental biology, Metagenomics, Biofilms, Child, Preschool, Oral Microbiome, Transcriptome, business, Dysbiosis, Software, Early childhood caries
Abstract

Early childhood caries (ECC) is a biofilm-mediated disease. Social, environmental, and behavioral determinants as well as innate susceptibility are major influences on its incidence; however, from a pathogenetic standpoint, the disease is defined and driven by oral dysbiosis. In other words, the disease occurs when the natural equilibrium between the host and its oral microbiome shifts toward states that promote demineralization at the biofilm-tooth surface interface. Thus, a comprehensive understanding of dental caries as a disease requires the characterization of both the composition and the function or metabolic activity of the supragingival biofilm according to well-defined clinical statuses. However, taxonomic and functional information of the supragingival biofilm is rarely available in clinical cohorts, and its collection presents unique challenges among very young children. This paper presents a protocol and pipelines available for the conduct of supragingival biofilm microbiome studies among children in the primary dentition, that has been designed in the context of a large-scale population-based genetic epidemiologic study of ECC. The protocol is being developed for the collection of two supragingival biofilm samples from the maxillary primary dentition, enabling downstream taxonomic (e.g., metagenomics) and functional (e.g., transcriptomics and metabolomics) analyses. The protocol is being implemented in the assembly of a pediatric precision medicine cohort comprising over 6000 participants to date, contributing social, environmental, behavioral, clinical, and biological data informing ECC and other oral health outcomes.

Published
2019

25. Established BMI-associated genetic variants and their prospective associations with BMI and other cardiometabolic traits: the GLACIER Study

Author

Frida Renström, Paul W. Franks, Shafqat Ahmad, Alaitz Poveda, Dmitry Shungin, Inês Barroso, and Göran Hallmans

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Genotype, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Blood Pressure, 030209 endocrinology & metabolism, Genome-wide association study, Polymorphism, Single Nucleotide, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Internal medicine, Genetic variation, Humans, Medicine, Genetic Predisposition to Disease, Obesity, Prospective Studies, Prospective cohort study, Triglycerides, Nutrition and Dietetics, business.industry, Genetic Variation, nutritional and metabolic diseases, Fasting, Middle Aged, medicine.disease, Cholesterol, Cross-Sectional Studies, Glucose, Phenotype, 030104 developmental biology, Endocrinology, Medical genetics, Female, business, Body mass index, Genome-Wide Association Study, Demography
Abstract

Recent cross-sectional genome-wide scans have reported associations of 97 independent loci with body mass index (BMI). In 3541 middle-aged adult participants from the GLACIER Study, we tested whether these loci are associated with 10-year changes in BMI and other cardiometabolic traits (fasting and 2-h glucose, triglycerides, total cholesterol, and systolic and diastolic blood pressures).A BMI-specific genetic risk score (GRS) was calculated by summing the BMI-associated effect alleles at each locus. Trait-specific cardiometabolic GRSs comprised only the loci that show nominal association (P⩽0.10) with the respective trait in the original cross-sectional study. In longitudinal genetic association analyses, the second visit trait measure (assessed ~10 years after baseline) was used as the dependent variable and the models were adjusted for the baseline measure of the outcome trait, age, age(2), fasting time (for glucose and lipid traits), sex, follow-up time and population substructure.The BMI-specific GRS was associated with increased BMI at follow-up (β=0.014 kg m(-2) per allele per 10-year follow-up, s.e.=0.006, P=0.019) as were three loci (PARK2 rs13191362, P=0.005; C6orf106 rs205262, P=0.043; and C9orf93 rs4740619, P=0.01). Although not withstanding Bonferroni correction, a handful of single-nucleotide polymorphisms was nominally associated with changes in blood pressure, glucose and lipid levels.Collectively, established BMI-associated loci convey modest but statistically significant time-dependent associations with long-term changes in BMI, suggesting a role for effect modification by factors that change with time in this population.

Published
2016

26. Tooth loss is a complex measure of oral disease : determinants and methodological considerations

Author

Paul W. Franks, Nicholas J. Timpson, Ingegerd Johansson, So Young Kwak, Min Jeong Shin, Steven Thomas, Hae Young Kim, Simon Haworth, Nicola X West, and Dmitry Shungin

Subjects
Adult, Male, Health Status, Large population, Oral Health, Dental Caries, Odontologi, 03 medical and health sciences, Tooth Loss, 0302 clinical medicine, stomatognathic system, tooth loss, Republic of Korea, Complex measure, Tooth loss, Medicine, Humans, 030212 general & internal medicine, Meaning (existential), Longitudinal Studies, General Dentistry, Periodontal Diseases, caries, business.industry, DMF Index, Public Health, Environmental and Occupational Health, Public Health, Global Health, Social Medicine and Epidemiology, 030206 dentistry, Original Articles, Middle Aged, Nutrition Surveys, stomatognathic diseases, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Dentistry, Original Article, Female, epidemiology, Oral disease, medicine.symptom, Periodontal Index, business, Mouth Diseases, periodontal diseases, Clinical psychology
Abstract

Objectives Counts of missing teeth or measures of incident tooth loss are gaining attention as a simple way to measure dental status in large population studies. We explore the meaning of these metrics and how missing teeth might influence other measures of dental status. Methods An observational study was performed in 2 contrasting adult populations. In total, 62 522 adult participants were available with clinically assessed caries and periodontal indices from the Swedish arm of the Gene‐Lifestyle Interactions and Dental Endpoints Study (GLIDE) and the Korea National Health and Nutrition Examination Survey (KNHANES) in the Republic of Korea. Longitudinal measures of tooth loss were available for 28 244 participants in GLIDE with median follow‐up of 10.6 years. Results In longitudinal analysis, hazard for tooth loss was associated with baseline dental status (previous tooth loss, periodontal status and caries status) and socio‐demographic variables (age, smoking status and highest educational level). Analysis of cross‐sectional data suggested that indices of caries exposure were not independent of periodontal status. The strength and direction of association varied between groups, even for measures specifically intended to avoid measuring tooth loss. Individuals with impaired periodontal health (community periodontal index [CPI] 3 or higher in any sextant) had higher standardized decayed and filled surfaces (DFS; number of DFS divided by total number of tooth surfaces) in GLIDE (incidence risk ratio [IRR] 1.05 [95% CI: 1.04, 1.07], but lower standardized DFS in KNHANES (IRR: 0.95 [0.92, 0.98]) than individuals with better periodontal health (CPI

Published
2018

27. Consortium genome-wide meta-analysis for childhood dental caries traits

Author

Ingegerd Johansson, Raimo Joro, Fernando Rivadeneira, Nicola X West, Daniel W. McNeil, Tom Dudding, Carolina Medina-Gomez, Klaus Bønnelykke, Pia Elisabeth Nørrisgaard, Nicholas J. Timpson, Steven Thomas, Marie Standl, Eppo B. Wolvius, Frank Geller, Olja Grgic, Myoung Keun Lee, Aino-Maija Eloranta, Edwin M. Ongkosuwito, John R. Shaffer, Justin T van der Tas, Anu Vierola, Ilkka Seppälä, Terho Lehtimäki, Jan Kühnisch, Bjarke Feenstra, Ellen A. Nohr, Hans Bisgaard, Paul W. Franks, Rebecca L. Slayton, Carol A. Wang, Olli T. Raitakari, Mary L. Marazita, Simon Haworth, Johannes Waage, Steven M. Levy, Strahinja Vucic, Mads Melbye, Elisabeth Thiering, Timo A. Lakka, Dmitry Shungin, Victor Yakimov, Craig E. Pennell, and Leon Eyrich Jessen

Subjects
0303 health sciences, Genetic heterogeneity, business.industry, Genome-wide association study, 030206 dentistry, Odds ratio, Environmental exposure, Heritability, Population stratification, 03 medical and health sciences, 0302 clinical medicine, Medicine, business, Allele frequency, 030304 developmental biology, Demography, Permanent teeth
Abstract

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from 9 contributing centers. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage (imputed to Haplotype Reference Consortium or 1000 Genomes phase 1 version 3 panels) accounting for population stratification. Fixed–effects meta-analysis was performed weighted by inverse standard error. Analysis included up to 19,003 individuals (7,530 affected) for primary teeth and 13,353 individuals (5,875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth (intronic within ALLC, Odds Ratio (OR) 0.85, Effect Allele Frequency (EAF) 0.60, p 4.13e-8) and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, p 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low (h2 of 1% [95% CI: 0%:7%] and 6% [95% CI 0%:13%] for primary and permanent dentitions, respectively) compared to corresponding within-study estimates (h2 of 28%, [95% CI: 9%:48%] and 17% [95% CI:2%:31%]) or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.Author summaryDental caries (tooth decay) is a common disease in children. Previous studies suggest genetic factors alter caries risk, but to date there is a gap of knowledge in identifying which specific genetic variants are responsible. We undertook analysis in a consortium including around 19,000 children and investigated whether any of 8 million common genetic variants were associated with risk of caries in primary (milk) or permanent teeth. If identified, these variants are used as ‘tags’ to highlight genes which may be involved in a disease. We identified variants in two loci associated with caries status; in the primary (rs1594318) and permanent dentition (rs7738851). The former is intronic in ALLC, a gene with poorly understood function. The latter is an intronic variant within NEDD9, a gene which has several known functions including a role in development of craniofacial structures. To gain a more comprehensive understanding of genetic effects which influence caries larger studies and a better understanding of environmental modifiers or interactions with genetic effects are required.

Published
2017

28. Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults

Author

Panos Deloukas, Göran Hallmans, Dmitry Shungin, Frida Renström, Paul W. Franks, Azra Kurbasic, Pontus Eriksson, Yan Chen, George Hindy, Nicholas J. Wareham, Jian'an Luan, Marju Orho-Melander, Christina-Alexandra Schulz, Robert A. Scott, Tibor V. Varga, Mattias Aine, Peter M. Nilsson, Claudia Langenberg, Adnan Ali, Olle Melander, Iněs Barroso, Erik Ingelsson, Lars Lind, Stefan Gustafsson, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, genetic epidemiology, Genotype, Epidemiology, Physiology, Blood lipids, Single-nucleotide polymorphism, Genome-wide association study, morbidity, Coronary Artery Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, White People, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, single nucleotide polymorphism, Cardiovascular Disease, medicine, Humans, Prospective Studies, triglycerides, Genetic association, Aged, Sweden, business.industry, total cholesterol, longitudinal analysis, General Medicine, Middle Aged, medicine.disease, Lipids, 030104 developmental biology, Cross-Sectional Studies, Genetic epidemiology, Prospective cohort study, Genetic Loci, Medical genetics, Female, business, Genome-Wide Association Study
Abstract

BACKGROUND: Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on long-term changes in blood lipids. METHODS: Participants from the GLACIER Study (Nmax = 3492) were genotyped with the MetaboChip array, from which 29 387 SNPs (single nucleotide polymorphisms; replication, fine-mapping regions and wildcard SNPs for lipid traits) were extracted for association tests with 10-year change in total cholesterol (ΔTC) and triglycerides (ΔTG). Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; Nmax = 8263 participants) were used for replication. We conducted an in silico look-up for association with coronary artery disease (CAD) in the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAMplusC4D) Consortium (N ∼ 190 000) and functional annotation for the top ranking variants. RESULTS: In total, 956 variants were associated (P < 0.01) with either ΔTC or ΔTG in GLACIER. In GLACIER, chr19:50121999 at APOE was associated with ΔTG and multiple SNPs in the APOA1/A4/C3/A5 region at genome-wide significance (P < 5 × 10-8), whereas variants in four loci, DOCK7, BRE, SYNE1 and KCNIP1, reached study-wide significance (P < 1.7 × 10-6). The rs7412 variant at APOE was associated with ΔTC in GLACIER (P < 1.7 × 10-6). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with ΔTC and for ΔTG, respectively (P < 10-3). Of these, a variant at CAPN3 (P = 1.2 × 10-4), multiple variants at HPR (Pmin = 1.5 × 10-6) and a variant at SIX5 (P = 1.9 × 10-4) showed evidence for association with CAD. CONCLUSIONS: We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk.

Published
2017

29. Circulating copper and zinc levels and risk of hepatobiliary cancers in Europeans

Author

Klas Sjöberg, Cristina Lasheras, Nicholas J. Wareham, Petra H.M. Peeters, Elisabete Weiderpass, Lutz Schomburg, Sandra Hybsier, Anne Tjønneland, Amanda J. Cross, Christina Bamia, Verena Katzke, Krasimira Aleksandrova, Salvatore Panico, Aurelio Barricarte, Elena Molina-Portillo, José María Huerta, David J. Hughes, Mathilde His, Pagona Lagiou, Kay-Tee Khaw, Antonia Trichopoulou, Dmitry Shungin, Heinz Freisling, Rosario Tumino, Magdalena Stepien, H B As Bueno-de-Mesquita, Catalina Bonet, Ruth C. Travis, Fulvio Ricceri, Tilman Kühn, Mårten Werner, Phlippos Orfanos, Kim Overvad, Bodil Ohlsson, Mazda Jenab, Marie-Christine Boutron-Ruault, Miren Dorronsoro, Domenico Palli, Sabina Sieri, Aurélie Affret, Stepien, Magdalena, Hughes, David J, Hybsier, Sandra, Bamia, Christina, Tjønneland, Anne, Overvad, Kim, Affret, Aurélie, His, Mathilde, Boutron Ruault, Marie Christine, Katzke, Verena, Kühn, Tilman, Aleksandrova, Krasimira, Trichopoulou, Antonia, Lagiou, Pagona, Orfanos, Phlippo, Palli, Domenico, Sieri, Sabina, Tumino, Rosario, Ricceri, Fulvio, Panico, Salvatore, Bueno de Mesquita, H. B. A, Peeters, Petra H, Weiderpass, Elisabete, Lasheras, Cristina, Bonet Bonet, Catalina, Molina Portillo, Elena, Dorronsoro, Miren, Huerta, José María, Barricarte, Aurelio, Ohlsson, Bodil, Sjöberg, Kla, Werner, Mårten, Shungin, Dmitry, Wareham, Nick, Khaw, Kay Tee, Travis, Ruth C, Freisling, Heinz, Cross, Amanda J, Schomburg, Lutz, Jenab, Mazda, Wareham, Nicholas [0000-0003-1422-2993], Khaw, Kay-Tee [0000-0002-8802-2903], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Cancer Research, Epidemiology, Physiology, SERUM COPPER, HEPATITIS-C, 0302 clinical medicine, cancer risk factors, nested case-control study, HEPATOCELLULAR-CARCINOMA, Medicine, Prospective Studies, OXIDATIVE STRESS, BILIARY-TRACT, Aged, Biliary Tract Neoplasms, Carcinoma, Hepatocellular, Case-Control Studies, Copper, Europe, Female, Humans, Liver Neoplasms, Middle Aged, Zinc, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, biology, zinc, Public Health, Global Health, Social Medicine and Epidemiology, hepatocellular carcinoma, Micronutrient, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Life Sciences & Biomedicine, prospective cohort, Serum copper, chemistry.chemical_element, CERULOPLASMIN, 03 medical and health sciences, RATIO, INFLAMMATION, Journal Article, COHORT, Oncology & Carcinogenesis, FATTY LIVER-DISEASE, Cancer och onkologi, Science & Technology, business.industry, Carcinoma, Case-control study, Hepatocellular, nested case–control study, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 030104 developmental biology, chemistry, Cancer and Oncology, copper, Immunology, biology.protein, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business, Ceruloplasmin, 1112 Oncology And Carcinogenesis
Abstract

This work was supported by the French National Cancer Institute (L'Institut National du Cancer; INCA; grant number 2009-139; PI: M Jenab) and the Health Research Board of Ireland (award number HRA_PHS/2013/397; PI: DJ Hughes). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada), Regional Governments of Andalucia, Asturias, Basque Country, Murcia (No. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk and MR/M012190/1 to EPIC- Oxford) (UK); Medical Research Council (1000143 to EPIC- Norfolk) (UK). For information on how to submit an application for gaining access to EPIC data and/or bio-specimens, please follow the instructions at http://epic.iarc.fr/access/index.php, Stepien, M., Hughes, D.J., Hybsier, S., Bamia, C., Tjønneland, A., Overvad, K., Affret, A., His, M., Boutron-Ruault, M.-C., Katzke, V., Kühn, T., Aleksandrova, K., Trichopoulou, A., Lagiou, P., Orfanos, P., Palli, D., Sieri, S., Tumino, R., Ricceri, F., Panico, S., Bueno-De-Mesquita, H.B., Peeters, P.H., Weiderpass, E., Lasheras, C., Bonet Bonet, C., Molina-Portillo, E., Dorronsoro, M., Huerta, J.M., Barricarte, A., Ohlsson, B., Sjöberg, K., Werner, M., Shungin, D., Wareham, N., Khaw, K.-T., Travis, R.C., Freisling, H., Cross, A.J., Schomburg, L., Jenab, M.

Published
2017

30. Common variants associated with plasma triglycerides and risk for coronary artery disease

Author

Richard S. Cooper, Angela Döring, Cisca Wijmenga, Jerome I. Rotter, Linda S. Adair, Tõnu Esko, Jennifer L. Bragg-Gresham, Danish Saleheen, Narisu Narisu, Xiaohui Li, Kathleen Stirrups, Ulf de Faire, Nicholas G. Martin, Dmitry Shungin, Peter Vollenweider, Yii-Der Ida Chen, Dharambir K. Sanghera, George Dedoussis, Toshiko Tanaka, Manjinder S. Sandhu, Anne U. Jackson, Nancy L. Pedersen, Maria Dimitriou, Shih-Yi Lin, David P. Strachan, Isleifur Olafsson, Ruth J. F. Loos, Kay-Tee Khaw, Antero Kesäniemi, Rainer Rauramaa, Wendy L. McArdle, Gonneke Willemsen, Dena G. Hernandez, May E. Montasser, Amy J. Swift, Colin A. McKenzie, Aaron Isaacs, Latonya F. Been, Leif Groop, Massimo Mangino, Martina Müller-Nurasyid, Karen L. Mohlke, Ci Song, Sailaja Vedantam, Anna-Liisa Hartikainen, Lori L. Bonnycastle, Ilja M. Nolte, Jaakko Kaprio, Anneli Pouta, Unnur Thorsteinsdottir, Paul Elliott, Muredach P. Reilly, Jean Ferrières, Daniel J. Rader, Elizabeth H. Young, Jaspal S. Kooner, Leena Moilanen, Markku Laakso, Albert Hofman, Kelly A. Volcik, Sekar Kathiresan, Tamara B. Harris, Eric Kim, Aimo Ruokonen, Andrea Ganna, Serena Sanna, John J.P. Kastelein, Martha L. Gravito, Ronald M. Krauss, Ken K. Ong, Paul M. Ridker, Kristian Hveem, Ayse Demirkan, Alena Stančáková, Pierre Meneton, Thomas Quertermous, John Danesh, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Christopher J. Groves, Jaakko Tuomilehto, Michael Boehnke, Jose M. Ordovas, Alan B. Feranil, Chao A. Hsiung, Wayne Huey-Herng Sheu, Igor Rudan, Christa Meisinger, Rebecca N. Nsubuga, Bruna Gigante, Inger Njølstad, Göran Hallmans, Aroon D. Hingorani, Jouko Saramies, Deepti Gurdasani, Fernando Rivadeneira, Andres Metspalu, Stephen E. Epstein, Gonçalo R. Abecasis, Braxton D. Mitchell, Devin Absher, Marcus E. Kleber, Sonia Shah, Pierre Fontanillas, Jeffrey R. O'Connell, Louise A. Donnelly, Jing Hua Zhao, Martin L. Buchkovich, Francis S. Collins, Gabrielle Müller, Matti Uusitupa, Evelin Mihailov, Nicholas J. Wareham, Andrew A. Hicks, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Jaana Lindström, Mark I. McCarthy, Evita G. Van Den Herik, Kirsten Ohm Kyvik, Vilmundur Gudnason, Jackie F. Price, Joel N. Hirschhorn, Winfried März, Aravinda Chakravarti, Pontiano Kaleebu, James F. Wilson, Lindsay L. Waite, Leo-Pekka Lyytikäinen, Sebanti Sengupta, Mika Kivimäki, David Altshuler, Hilma Holm, Rona J. Strawbridge, Harald Grallert, Ramaiah Nagaraja, Laurence Tiret, G. Kees Hovingh, Meena Kumari, Nilesh J. Samani, Daniel F. Freitag, Nelson B. Freimer, Thomas Illig, Panos Deloukas, Bernhard O. Boehm, Nicholas W.J. Wainwright, Mark J. Daly, Mika Kähönen, Michel Burnier, Norman Klopp, L. Adrienne Cupples, Aarno Palotie, Markus Perola, Bamidele O. Tayo, Timo A. Lakka, Matthew Jones, Sarah H. Wild, Patricia B. Munroe, Antti Jula, François Mach, Peter J. Koudstaal, Pirjo Komulainen, Eric Boerwinkle, L. Joost van Pelt, Veikko Salomaa, Ann-Kristin Petersen, Ida Surakka, Andrew Wong, Caroline Hayward, Chi Gao, Cristen J. Willer, Stephen S. Rich, Yi Jen Hung, Peter P. Pramstaller, Diana Kuh, Ron Do, Dominique Arveiler, Mark O. Goodarzi, Ross M. Fraser, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Mary Susan Burnett, Patrik K. E. Magnusson, John C. Chambers, Benjamin M. Neale, Peter Schwarz, Jennifer L. Bolton, Murielle Bochud, Heleen M. den Hertog, Christian Gieger, Cristina Pomilla, Teresa Ferreira, Lars Wallentin, Richa Saxena, André G. Uitterlinden, Kaisa Silander, Ying Wu, Bruce M. Psaty, Jian'an Luan, Hsing-Yi Chang, Jin Chen, Daniel I. Chasman, Ulf Gyllensten, Kari Stefansson, Kauko Heikkilä, Tom Wilsgaard, Alan R. Shuldiner, Carlos Iribarren, Stavroula Kanoni, John Whitfield, Gershim Asiki, Marika Kaakinen, Georg Ehret, Elina Hyppönen, Claudia Langenberg, Gina M. Peloso, Cecilia M. Lindgren, Carlo Sidore, Gudmundur I. Eyjolfsson, Cameron D. Palmer, Jacques S. Beckmann, Hubert Scharnagl, Tanya M. Teslovich, Mary F. Feitosa, Terho Lehtimäki, Steve E. Humphries, Chris Power, Benjamin F. Voight, Stefania Bandinelli, Andrew D. Morris, Gudmar Thorleifsson, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Themistocles L. Assimes, Pascal Bovet, Luigi Ferrucci, Johannes Kettunen, Inês Barroso, Franklyn I. Bennett, Stefan Gustafsson, Paolo Brambilla, Theodore Papamarkou, Elena Tremoli, Janet Seeley, Alex S. F. Doney, Johanna Kuusisto, Giancarlo Cesana, Bruce H. R. Wolffenbuttel, Lars Lind, Stefan R. Bornstein, Åsa Johansson, Anders Hamsten, Marjo-Riitta Järvelin, Krista Fischer, Agneta Siegbahn, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, Do, Ron, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Hyppönen, Elina, Kathiresan, Sekar, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Do, R, Willer, C, Schmidt, E, Sengupta, S, Gao, C, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stančáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Altshuler, D, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Mohlke, K, Ingelsson, E, Abecasis, G, Daly, M, Neale, B, and Kathiresan, S

Subjects
Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Heart disease, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, ISCHEMIC-HEART-DISEASE, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Polymorphism (computer science), Risk Factors, High-density-lipoprotein, Genetic epidemiology, 11 Medical and Health Sciences, Genetics & Heredity, 0303 health sciences, Cholesterol, HDL/blood, Cholesterol levels, Loci, Contribute, Single Nucleotide, LDL/blood, Triglycerides/blood, Cholesterol, Cholesterol, LDL/blood, HDL/blood, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Human, medicine.medical_specialty, TYPE-2 DIABETES-MELLITUS, Biology, Polymorphism, Single Nucleotide, Article, HIGH-DENSITY-LIPOPROTEIN ISCHEMIC-HEART-DISEASE TYPE-2 DIABETES-MELLITUS MENDELIAN RANDOMIZATION CARDIOVASCULAR-DISEASE GENETIC EPIDEMIOLOGY CHOLESTEROL LEVELS LOCI CONTRIBUTE THERAPY, 03 medical and health sciences, Coronary Artery Disease/blood, SDG 3 - Good Health and Well-being, Cardiovascular-disease, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Polymorphism, plasma, Triglycerides, 030304 developmental biology, Science & Technology, Risk Factor, Cholesterol, HDL, Biological Transport, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, Heart-disease, lipoproteins, Endocrinology, chemistry, Therapy, Developmental Biology
Abstract

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved.

Published
2013

31. Discovery and refinement of loci associated with lipid levels

Author

Benjamin F. Voight, Stefania Bandinelli, Pascal Bovet, Latonya F. Been, Ci Song, Luigi Ferrucci, Johannes Kettunen, Andrew D. Morris, Mary Susan Burnett, Ronald M. Krauss, Igor Rudan, Heleen M. den Hertog, Stavroula Kanoni, G. Kees Hovingh, Elina Hyppönen, Kauko Heikkilä, Richard S. Cooper, Daniel I. Chasman, Bruna Gigante, Stefan Gustafsson, Jian'an Luan, Sarah H. Wild, Patricia B. Munroe, Göran Hallmans, Jeffrey R. O'Connell, Danish Saleheen, Aarno Palotie, Leena Moilanen, Jerome I. Rotter, Caroline Hayward, Jennifer L. Bragg-Gresham, Nicholas G. Martin, Claudia Langenberg, George Dedoussis, Carlo Sidore, Ulf Gyllensten, Marika Kaakinen, Jing Hua Zhao, Aimo Ruokonen, Diana Kuh, Maria Dimitriou, Shih-Yi Lin, Gina M. Peloso, Marcus E. Kleber, Christopher J. Groves, Alena Stančáková, Michel Burnier, Patrik K. E. Magnusson, John C. Chambers, Giancarlo Cesana, Francis S. Collins, Gabrielle Müller, Angela Döring, Colin A. McKenzie, Paul Elliott, Lars Lind, Vilmundur Gudnason, Dharambir K. Sanghera, Jean Ferrières, Toshiko Tanaka, Stefan R. Bornstein, Gershim Asiki, Jacques S. Beckmann, Anneli Pouta, Timo A. Lakka, Daniel J. Rader, Elizabeth H. Young, Kelly A. Volcik, Dena G. Hernandez, Ann-Kristin Petersen, Kristian Hveem, Amy J. Swift, Murielle Bochud, Pierre Meneton, Paul M. Ridker, Kathleen Stirrups, Stephen S. Rich, Isleifur Olafsson, Ruth J. F. Loos, Serena Sanna, Markus Perola, Meena Kumari, Cameron D. Palmer, Carlos Iribarren, Nancy L. Pedersen, Mark O. Goodarzi, Panos Deloukas, Norman Klopp, Cristina Pomilla, Stephen E. Epstein, Antti Jula, Themistocles L. Assimes, Martina Müller-Nurasyid, Marjo-Riitta Järvelin, Chao A. Hsiung, Sonia Shah, Christian Gieger, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Nicholas J. Wareham, Krista Fischer, Wendy L. McArdle, Linda S. Adair, Kay-Tee Khaw, Bruce M. Psaty, André G. Uitterlinden, Aaron Isaacs, Tõnu Esko, Jennifer L. Bolton, Rebecca N. Nsubuga, Eric Boerwinkle, L. Joost van Pelt, Jouko Saramies, François Mach, Pierre Fontanillas, Teresa Ferreira, Lars Wallentin, Michael Boehnke, Christa Meisinger, Wayne Huey-Herng Sheu, Gonçalo R. Abecasis, Inês Barroso, Franklyn I. Bennett, Dmitry Shungin, Jaakko Kaprio, Kirsten Ohm Kyvik, Deepti Gurdasani, Anne U. Jackson, Paolo Brambilla, Georg Ehret, Cecilia M. Lindgren, Fernando Rivadeneira, Theodore Papamarkou, Jaakko Tuomilehto, Cristen J. Willer, Martin L. Buchkovich, Antero Kesäniemi, Hubert Scharnagl, Xiaohui Li, Elena Tremoli, Nelson B. Freimer, Mika Kähönen, Ron Do, Karen L. Mohlke, Thomas Illig, Gudmar Thorleifsson, Peter J. Koudstaal, Andres Metspalu, Ulf de Faire, Dominique Arveiler, Harald Grallert, Jaana Lindström, Laurence Tiret, Jaspal S. Kooner, Braxton D. Mitchell, Sebanti Sengupta, Gonneke Willemsen, Anna-Liisa Hartikainen, Terho Lehtimäki, Steve E. Humphries, Peter Schwarz, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Tom Wilsgaard, Janet Seeley, Alex S. F. Doney, Alan R. Shuldiner, John Whitfield, Markku Laakso, Peter Vollenweider, Gudmundur I. Eyjolfsson, Winfried März, Mika Kivimäki, Ying Wu, Johanna Kuusisto, Andrew A. Hicks, Bruce H. R. Wolffenbuttel, May E. Montasser, Bamidele O. Tayo, Unnur Thorsteinsdottir, Muredach P. Reilly, Leo-Pekka Lyytikäinen, Eric Kim, John Danesh, Ida Surakka, Åsa Johansson, Anders Hamsten, Thomas Quertermous, Hsing-Yi Chang, Jin Chen, Agneta Siegbahn, Narisu Narisu, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, Sekar Kathiresan, Manjinder S. Sandhu, Leif Groop, Jose M. Ordovas, Alan B. Feranil, Evelin Mihailov, Hilma Holm, Pontiano Kaleebu, Lindsay L. Waite, Ramaiah Nagaraja, Andrew Wong, Rona J. Strawbridge, David P. Strachan, Yii-Der Ida Chen, Tamara B. Harris, Jackie F. Price, Aravinda Chakravarti, Veikko Salomaa, Sailaja Vedantam, Albert Hofman, Devin Absher, Ross M. Fraser, Kaisa Silander, Pirjo Komulainen, Yi Jen Hung, Peter P. Pramstaller, Kari Stefansson, Aroon D. Hingorani, Tanya M. Teslovich, Matti Uusitupa, L. Adrienne Cupples, Cisca Wijmenga, Lori L. Bonnycastle, Ilja M. Nolte, Andrea Ganna, Ken K. Ong, Inger Njølstad, Bernhard O. Boehm, Nicholas W.J. Wainwright, Richa Saxena, Rainer Rauramaa, Louise A. Donnelly, James F. Wilson, Matthew Jones, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Massimo Mangino, John J.P. Kastelein, Martha L. Gravito, Mark I. McCarthy, Evita G. Van Den Herik, Joel N. Hirschhorn, Nilesh J. Samani, Daniel F. Freitag, Ayse Demirkan, Mary F. Feitosa, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Chris Power, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Willer, C, Schmidt, E, Sengupta, S, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Do, R, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stancáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Kathiresan, S, Mohlke, K, Ingelsson, E, Abecasis, G, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Ehret, Georg Benedikt, Mach, François, Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, National Institute for Health Research, Global Lipids Genetics Consortium, Willer, Cristen, Sengupta, Sebanti, Peloso, Gina, Hypponen, Elina Tuulikki, and Abecasis, Gonçalo R

Subjects
Netherlands Twin Register (NTR), HOMEOSTASIS, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Blood lipids, Genome-wide association study, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, European Continental Ancestry Group/genetics, triglycerides, IDENTIFIES 13, 11 Medical and Health Sciences, African Continental Ancestry Group, 2. Zero hunger, Genetics, Genetics & Heredity, ddc:616, RISK, 0303 health sciences, Cholesterol, HDL/blood, PLASMA, Global Lipids Genetics Consortium, Cholesterol, HDL/blood/genetics, Lipid, Lipids, 3. Good health, LDL/blood, Triglycerides/blood, Lipids/blood/genetics, Cholesterol, Cholesterol, LDL/blood, DENSITY-LIPOPROTEIN CHOLESTEROL, CARDIOVASCULAR-DISEASE, HDL/blood, CORONARY-ARTERY-DISEASE, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, coronary artery disease, TRAITS, Human, Coronary Artery Disease/blood/genetics, Asian Continental Ancestry Group, Genotype, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Black People, HEART-DISEASE, Biology, Article, White People, lipids, 03 medical and health sciences, Coronary Artery Disease/blood, CORONARY-ARTERY-DISEASE DENSITY-LIPOPROTEIN CHOLESTEROL GENOME-WIDE ASSOCIATION HEART-DISEASE CARDIOVASCULAR-DISEASE SUSCEPTIBILITY LOCI IDENTIFIES 13 RISK GENE METAANALYSIS, Triglycerides/blood/genetics, Asian People, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Humans, Asian Continental Ancestry Group/genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Genotyping, Triglycerides, METAANALYSIS, 030304 developmental biology, Science & Technology, Lipids/blood, Cholesterol, HDL, cholesterol, African Continental Ancestry Group/genetics, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, GENE, chemistry, Cholesterol, LDL/blood/genetics, Lipoprotein, Developmental Biology, Genome-Wide Association Study
Abstract

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10 -8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research. © 2013 Nature America, Inc. All rights reserved.

Published
2013
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32. Statistical power considerations in genotype-based recall randomized controlled trials

Author

Mattias Ohlsson, Adnan Ali, Ewan R. Pearson, Erik Ingelsson, Naeimeh Atabaki-Pasdar, Dmitry Shungin, Paul W. Franks, and Azra Kurbasic

Subjects
0301 basic medicine, Gerontology, Genotype, Organic Cation Transport Proteins, Type 2 diabetes, Endocrinology and Diabetes, Placebo, Polymorphism, Single Nucleotide, Statistical power, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Gene Frequency, law, Outcome Assessment, Health Care, Medicine, Humans, Hypoglycemic Agents, 030212 general & internal medicine, Allele frequency, Exercise, Randomized Controlled Trials as Topic, Multidisciplinary, business.industry, Incidence (epidemiology), medicine.disease, Metformin, Clinical trial, 030104 developmental biology, Diabetes Mellitus, Type 2, Sample size determination, Sample Size, Endokrinologi och diabetes, business, Demography
Abstract

Randomized controlled trials (RCT) are often underpowered for validating gene-treatment interactions. Using published data from the Diabetes Prevention Program (DPP), we examined power in conventional and genotype-based recall (GBR) trials. We calculated sample size and statistical power for gene-metformin interactions (vs. placebo) using incidence rates, gene-drug interaction effect estimates and allele frequencies reported in the DPP for the rs8065082 SLC47A1 variant, a metformin transported encoding locus. We then calculated statistical power for interactions between genetic risk scores (GRS), metformin treatment and intensive lifestyle intervention (ILI) given a range of sampling frames, clinical trial sample sizes, interaction effect estimates, and allele frequencies; outcomes were type 2 diabetes incidence (time-to-event) and change in small LDL particles (continuous outcome). Thereafter, we compared two recruitment frameworks: GBR (participants recruited from the extremes of a GRS distribution) and conventional sampling (participants recruited without explicit emphasis on genetic characteristics). We further examined the influence of outcome measurement error on statistical power. Under most simulated scenarios, GBR trials have substantially higher power to observe gene-drug and gene-lifestyle interactions than same-sized conventional RCTs. GBR trials are becoming popular for validation of gene-treatment interactions; our analyses illustrate the strengths and weaknesses of this design.

Published
2016
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33. Genome-wide association studies in East Asians identify new loci for waist-hip ratio and waist circumference

Author

Dabeeru C. Rao, Mitsuhiro Yokota, Yoon Shin Cho, Chien-Hsiun Chen, Tangchun Wu, Joo Yeon Hwang, Juyoung Lee, Dmitry Shungin, Bo Youl Choi, Xingwang Ye, Masahiro Nakatochi, Karen L. Mohlke, Matthew A. Allison, Tetsuro Miki, Jiajun Shi, Wei Zheng, Yong-Bing Xiang, Zengnan Mo, Xu Lin, Yoshikuni Kita, Jer-Yuarn Wu, Jun Liang, Tao Huang, Dongxin Lin, Sanghoon Moon, Meian He, Sun Ha Jee, Shengxu Li, Linda S. Adair, Lu Qi, Qiuyin Cai, James E. Hixson, Jae Woong Sull, Jiang He, Min Jin Go, Yanling Hu, Xingyi Guo, Masato Isono, Keum Ji Jung, Jianjun Liu, E. Shyong Tai, Yan Zheng, Nanette R. Lee, Aihua Tan, Jeannette Lee, Xiaomin Zhang, Fuu Jen Tsai, Ken Yamamoto, Norihiro Kato, Soriul Kim, Koichi Akiyama, Rajkumar Dorajoo, Young Jin Kim, Ying Wu, Daehee Kang, Jie Yao, Hirotsugu Ueshima, Jerome I. Rotter, Xiaobo Yang, Li Ching Chang, Keizo Ohnaka, Huaixing Li, Bok Ghee Han, Yuan-Tsong Chen, Jirong Long, Xiuqing Guo, Dongfeng Gu, Yasuharu Tabara, Bong Jo Kim, Yiqin Wang, Chen Wu, Yasuyuki Nakamura, Xiao-Ou Shu, Wanqing Wen, Yu Tang Gao, and Fumihiko Takeuchi

Subjects
Male, 0301 basic medicine, Genome-wide association study, 030105 genetics & heredity, Cardiovascular, Waist–hip ratio, 2.1 Biological and endogenous factors, Aetiology, 10. No inequality, Abdominal obesity, 2. Zero hunger, Genetics, Multidisciplinary, Public Health, Global Health, Social Medicine and Epidemiology, Single Nucleotide, Other Physical Sciences, Female, Waist Circumference, medicine.symptom, Asian Continental Ancestry Group, Asia, Waist, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, abdominal obesity, Quantitative Trait, 03 medical and health sciences, Quantitative Trait, Heritable, Sex Factors, Asian People, Clinical Research, medicine, Humans, Genetic Predisposition to Disease, Obesity, Polymorphism, Heritable, Waist-Hip Ratio, nutritional and metabolic diseases, genetic loci, medicine.disease, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 030104 developmental biology, Biochemistry and Cell Biology, Body mass index, Genome-Wide Association Study
Abstract

Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2 and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI and three loci near the CEP120, TSC22D2 and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.

Published
2016

34. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author

Timo A. Lakka, Kathleen Stirrups, Jean Ferrières, Ying Wu, Gulum Kosova, Toby Johnson, Heather M. Stringham, Bruce M. Psaty, Bruna Gigante, Göran Hallmans, Cornelia M. van Duijn, Kae Woei Liang, Niclas Eriksson, N. William Rayner, Lynda M. Rose, Stavroula Kanoni, Xueling Sim, Evangelos Evangelou, Philippe Froguel, Michel Burnier, Andrew P. Morris, Olle Melander, Martin Farrall, Albert V. Smith, Brendan J. Keating, Thomas Illig, Johan Sundström, Dorret I. Boomsma, Kate Witkowska, Ellen M. Schmidt, Aki S. Havulinna, Ann-Kristin Petersen, Paul F. O'Reilly, Young Jin Kim, Kari Kuulasmaa, Tom Wilsgaard, John D. Eicher, Marcus E. Kleber, Francis S. Collins, Rona J. Strawbridge, Ronald M. Krauss, Fotios Drenos, Stuart K. Kim, Ken K. Ong, Pascal Bovet, Danish Saleheen, Jaspal S. Kooner, Karl-Heinz Herzig, Tien Yin Wong, Benjamin F. Voight, Stefania Bandinelli, Stéphane Lobbens, Colin A. McKenzie, Jing Hua Zhao, Terrence Forrester, Louise A. Donnelly, Alice Stanton, Jean Dallongeville, Kirill V. Tarasov, Narisu Narisu, Jürgen Gräßler, Luigi Ferrucci, Peter S. Sever, Paul Elliott, Tune H. Pers, Andrew J. Smith, Tomas Axelsson, Young Ah Shin, Nora Franceschini, James F. Wilson, Vilmundur Gudnason, Kati Kristiansson, Andrew A. Hicks, Kent D. Taylor, Genovefa Kolovou, Andrew D. Morris, André G. Uitterlinden, Serena Sanna, Xiuqing Guo, Honghuang Lin, Aravinda Chakravarti, Wayne Huey-Herng Sheu, Panos Deloukas, Linda S. Adair, Diana Kuh, Murielle Bochud, Eric Boerwinkle, Inger Njølstad, Meena Kumari, Norman Klopp, Leo-Pekka Lyytikäinen, Steven C. Hunt, Weihua Zhang, Tõnu Esko, Pierre Meneton, Markus Perola, Erik P A Van Iperen, Georg Ehret, Veikko Salomaa, Lars Lind, Zoltán Kutalik, Cristiano Fava, Caroline Hayward, Hugh S. Markus, Teresa Ferreira, Stefan R. Bornstein, Vasyl Pihur, Patricia B. Munroe, Anne U. Jackson, Eirini Marouli, Gabriele Müller, Damiano Baldassarre, Jacques E. Rossouw, Dan E. Arking, Maija Hassinen, Nicholas J. Wareham, Robert Roberts, Daniel I. Chasman, I. Shou Chang, Sylvain Sebert, Tove Fall, Roby Joehanes, Patrik K. E. Magnusson, John C. Chambers, Peter Vollenweider, Wen Jane Lee, Dmitry Shungin, Mathias Gorski, Christopher Newton-Cheh, Anders Franco-Cereceda, Ching-Yu Cheng, Yun Kyoung Kim, Ruth J. F. Loos, Lude Franke, Karen L. Mohlke, Yii-Der Ida Chen, Carlos Iribarren, Martina Müller-Nurasyid, Alexander Teumer, Andrew D. Johnson, Antonella Mulas, Ulf Gyllensten, Martin D. Tobin, George Dedoussis, Rainford J. Wilks, Joshua C. Bis, Beverley Balkau, Jie Yao, Frida Renström, Themistocles L. Assimes, Morris Brown, Inês Barroso, Hyun Min Kang, Loic Yengo, Mika Kähönen, Christopher J. Groves, Kirsti Kvaløy, Rainer Rauramaa, Heribert Schunkert, Satu Männistö, Marjo-Riitta Järvelin, Nancy L. Pedersen, Karl Gertow, Rick Jansen, Thomas Quertermous, Jarmo Virtamo, Lazaros Lataniotis, Serge Hercberg, Paul M. Ridker, Osorio Meirelles, Jostein Holmen, Phil Howard, G. Kees Hovingh, Jeanette Erdmann, Jong-Young Lee, Peter Schwarz, Ramaiah Nagaraja, Elizabeth Theusch, Wei Zhao, Sonia Shah, Chao A. Hsiung, Santhi K. Ganesh, Richard S. Cooper, John M. C. Connell, Jian'an Luan, Graciela E. Delgado, Eric Kim, Daniel Levy, Li Lin, Jerome I. Rotter, Andres Metspalu, Nabila Bouatia-Naji, Christopher J. O'Donnell, Roberto Elosua, Andrew Wong, Alanna C. Morrison, Juha Saltevo, Michael R. Barnes, Alan B. Weder, Kay-Tee Khaw, Leena Moilanen, Peter S. Chines, Claudia Langenberg, Marika Kaakinen, Asif Rasheed, Annette Peters, Angela Döring, Alena Stančáková, Richard A. Jensen, Jaana Lindström, Alison H. Goodall, Toshiko Tanaka, Loukianos S. Rallidis, Dabeeru C. Rao, Ann-Christine Syvänen, Alun Evans, Brenda W.J.H. Penninx, Sarah Edkins, Xiaohui Li, Neil Poulter, Jouko Saramies, Ulf de Faire, Walter Palmas, Jaakko Tuomilehto, Louise V. Wain, Cristina Menni, Stephen Bevan, Maria X. Sosa, Nanette R. Lee, Anuj Goel, Germaine C. Verwoert, Kjell Nikus, Helen R. Warren, May E. Montasser, Ren-Hua Chung, Francesco Gianfagna, Kristian Hveem, Rainer Rettig, Unnur Thorsteinsdottir, Lori L. Bonnycastle, Tim D. Spector, Paul W. Franks, Bamidele O. Tayo, Ilja M. Nolte, John Danesh, E. Shyong Tai, Mika Kivimäki, Devin Absher, Oddgeir L. Holmen, Per Eriksson, Pirjo Komulainen, Peter P. Pramstaller, Cameron D. Palmer, He Gao, Elena Tremoli, H.-Erich Wichmann, Myriam Fornage, Gyda Bjornsdottir, Afshin Parsa, Anders Hamsten, Terho Lehtimäki, Lasse Folkersen, Janine F. Felix, Anna F. Dominiczak, Hinco J. Gierman, Edward G. Lakatta, Alex S. F. Doney, Erik Ingelsson, Colin N. A. Palmer, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Vladan Mijatovic, Mark I. McCarthy, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Stefan Enroth, Mark J. Caulfield, Gudmar Thorleifsson, Tsun-Po Yang, François Mach, Cristen J. Willer, Claudia P. Cabrera, Aline Wagner, Michael Boehnke, Elias Salfati, Sekar Kathiresan, Ramachandran S. Vasan, Franco Giulianini, Harm-Jan Westra, Harold Snieder, Mark O. Goodarzi, M. Arfan Ikram, Fred Paccaud, Johannes H. Smit, Anna-Liisa Hartikainen, Xiaofeng Zhu, Markku Laakso, Ahmad Vaez, Albert Hofman, Amy J. Swift, Maria Hughes, I. Te Lee, Aroon D. Hingorani, Matti Uusitupa, Oscar H. Franco, Kenneth Rice, Veronique Vitart, Ross M. Fraser, Jouke-Jan Hottenga, Kari Stefansson, Dhananjay Vaidya, Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Saw Swee Hock School of Public Health, National University of Singapore (NUS), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Michigan System, Department of Computational Medicine and Bioinformatics (DCM&B), Queen Mary University of London (QMUL), GlaxoSmithKline, Glaxo Smith Kline, deCODE genetics [Reykjavik], University of Cambridge [UK] (CAM), University of Dundee, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Karolinska University Hospital [Stockholm], Umea University Hospital, Lund University [Lund], Queen's University [Belfast] (QUB), National Institutes of Health, Department of Genomics of Common Disease, Imperial College London, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), National Institute of Health and Welfare, Institute for Molecular Medicine Finland (FIMM), University College London Hospitals (UCLH), University Hospital of Heidelberg, Harbor UCLA Medical Center [Torrance, Ca.], University of Tampere, University of Verona (UNIVR), Uppsala University Hospital, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Stanford University School of Medicine [CA, USA], Medical School University of Athens, Partenaires INRAE, Children's Hospital Oakland Research Institute, Boston Children's Hospital, Broad Institute of Harvard and MIT, University of Copenhagen = Københavns Universitet (KU), Statens Serum Institut [Copenhagen], Framingham Heart Dis Epidemiol Study, Department of Psychiatry, VU University Medical Center [Amsterdam], National Heart, Lung and Blood Institute, Osong Health Technology Administration Complex, University of Pennsylvania, Department of Genetics, University of North Carolina at Chapel Hill (UNC), Loyola University [Chicago], Centre Hospitalier Universitaire Vaudois (CHUV), Hudson Alpha Institute for Biotechnology, Erasmus University Rotterdam, Department of Medical Sciences, Uppsala University, Università degli Studi di Milano [Milano] (UNIMI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], University of Lincoln, University of Washington [Seattle], Amgen Inc., The University of Texas Health Science Center at Houston (UTHealth), VU University Amsterdam, University of Dresden Medical School, Université de Lausanne (UNIL), Healthcare NHS Trust, National Health Research Institutes, National University Health System [Singapore] (NUHS), Duke-NUS Medical School [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National Human Genome Research Institute (NHGRI), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Radiology and nuclear medicine, EMGO - Mental health, Lin, Li, Mach, François, ProdInra, Migration, University of Oxford, Università degli studi di Verona = University of Verona (UNIVR), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano = University of Milan (UNIMI), Vrije Universiteit Amsterdam [Amsterdam] (VU), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO+ - Lifestyle, Overweight and Diabetes, Biological Psychology, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Danesh, John [0000-0003-1158-6791], Khaw, Kay-Tee [0000-0002-8802-2903], Markus, Hugh [0000-0002-9794-5996], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Medical Microbiology & Infectious Diseases, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Clinical Genetics, Biochemistry, National Institute for Health Research, and Medical Research Council (MRC)

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), CHROMATIN, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Blood Pressure, SUSCEPTIBILITY, Bioinformatics, Cardiovascular, Genome-wide association studies, Medical and Health Sciences, single nucleotide polymorphism, CHARGE-EchoGen consortium, GWAS, 2.1 Biological and endogenous factors, Aetiology, Cells, Cultured, African Continental Ancestry Group, Genetics & Heredity, Genetics, ddc:616, Kidney, Framingham Risk Score, Cultured, COMMON VARIANTS, 11 Medical And Health Sciences, Single Nucleotide, Biological Sciences, African Continental Ancestry Group/genetics, Asian Continental Ancestry Group/genetics, Blood Pressure/genetics, Genome-Wide Association Study, Humans, Hypertension/genetics, Hypertension/pathology, Microarray Analysis, Polymorphism, Single Nucleotide, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hypertension/genetics/pathology, Hypertension, Medical genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, TRAITS, Biotechnology, Asian Continental Ancestry Group, medicine.medical_specialty, CHARGE-EchoGen Consortium, Cells, Black People, BIOLOGY, Single-nucleotide polymorphism, Biology, Blood pressure, hypertension, genetics, single nucleotide polymorphism, GWAS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, CELL-TYPES, METAANALYSIS, Genetic association, Science & Technology, CHARGE-HF consortium, 06 Biological Sciences, Genetic architecture, 030104 developmental biology, Blood pressure, CHARGE-HF Consortium, ARTERIAL-HYPERTENSION, Developmental Biology
Abstract

To dissect the genetic architecture of blood pressure (BP) and assess how its elevation promotes downstream cardiovascular diseases, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry. Genotypes from an additional 140,886 individuals of European ancestry were used as validation for loci reaching genome-wide significance but without prior support in the literature. We identified 66 BP loci, of which 17 were novel and 15 harbored multiple distinct association signals, and which together explain up to 3.5% of BP variation. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in BP control through modulating blood vessel tone and fluid filtration across multiple tissues, not solely the kidney. Importantly, the 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent (South-Asian, East-Asian and African), confirming that these are ancestral physiological effects that arose prior to human migration out of Africa. The 66-SNP BP risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our data expand current knowledge of BP pathways, and also, highlight that BP regulation and its effects may occur in multiple organs and tissues beyond the classic renal system.

Published
2016

35. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Author

John R. B. Perry, James B. Meigs, José Dupuis, Luigi Ferrucci, Johan G. Eriksson, Vilmundur Gudnason, Eric J.G. Sijbrands, Jeanette S. Andrews, Jonna L. Grimsby, Lawrence F. Bielak, Peter Kovacs, Panos Deloukas, Marijana Peričić, Johannes H. Smit, Ruth J. F. Loos, Gonneke Willemsen, Eric Boerwinkle, Ben A. Oostra, Manuel Serrano-Ríos, Alena Stančáková, Meena Kumari, Antti Jula, Michael Marmot, Caroline S. Fox, Simon Heath, Guo Li, Ola Hansson, Gerard Waeber, Anne U. Jackson, Nicholas L. Smith, Markku Laakso, George Dedoussis, Aarno Palotie, Sara M. Willems, John F. Peden, Elisabeth Widen, Caroline Hayward, Alan F. Wright, Claes Ladenvall, May E. Montasser, María Teresa Martínez-Larrad, Peter Vollenweider, Louis Pérusse, Tamara B. Harris, Wen Hong L. Kao, Danijela Budimir, Denis Rybin, David B. Savage, Michael A. Province, Alisa K. Manning, Bruna Gigante, Najaf Amin, Lenore J. Launer, Naveed Sattar, Lori L. Bonnycastle, Göran Hallmans, Jeffrey R. O'Connell, Stéphane Lobbens, Jacques S. Beckmann, Gemma Cadby, J. Wouter Jukema, Maria Dimitriou, Michael Stumvoll, Max Vikström, Rona J. Strawbridge, Hugh Watkins, Lyle J. Palmer, Johanna Kuusisto, Aimo Ruokonen, Hanieh Yaghootkar, Yan V. Sun, Inês Barroso, Amy J. Swift, Nancy L. Pedersen, Lars Lind, Mladen Boban, Nita G. Forouhi, Ken K. Ong, Ivana Kolcic, Anke Tönjes, Timothy M. Frayling, Paul W. Franks, Narisu Narisu, Karin Leander, Serge Hercberg, Diana Zelenika, Sharon L.R. Kardia, Min A. Jhun, Marjo-Riitta Järvelin, Stella Trompet, Jaakko Kaprio, Toshiko Tanaka, David S. Siscovick, Toby Johnson, Cornelia M. van Duijn, Veikko Salomaa, Jose C. Florez, James F. Wilson, Leena Peltonen, Pilar Galan, Robert Clarke, Andrew A. Hicks, Claudia Langenberg, Anders Hamsten, David Couper, Albert Hofman, Dawn M. Waterworth, John Blangero, James S. Pankow, Nabila Bouatia-Naji, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Valeriya Lyssenko, Leif Groop, Brenda W.J.H. Penninx, Ching-Ti Liu, Anuj Goel, Marina Pehlić, Michael Boehnke, Mika Kivimäki, Maria Sabater-Lleal, Emil Rehnberg, Ingrid B. Borecki, Ozren Polasek, Eco J. C. de Geus, Peter P. Pramstaller, Igor Rudan, Richard M. Watanabe, Pierre Meneton, Iva Miljkovic, Vincent Mooser, G. Mark Lathrop, John Beilby, Laura J. Rasmussen-Torvik, Arturo Corbató-Anchuelo, Yvonne Böttcher, Richard N. Bergman, Daniel R. Barnes, Paul C. D. Johnson, Mustafa Atalay, Aroon D. Hingorani, Olga D. Carlson, Perttu Salo, Jacqueline C.M. Witteman, Udo Seedorf, Timo Saaristo, Jian'an Luan, Nicholas J. Wareham, Gudny Eiriksdottir, Matti Uusitupa, Yongmei Liu, Jaakko Tuomilehto, Yurii S. Aulchenko, Peter Schwarz, Robert A. Scott, Lina Zgaga, Joseph Hung, Reedik Mägi, Maria Grazia Franzosi, Eric J. Brunner, Claude Bouchard, Ian Ford, Francis S. Collins, Ulf de Faire, Benjamin F. Voight, Erik Ingelsson, Mario A. Morken, Stefania Bandinelli, Nicole L. Glazer, Dmitry Shungin, Lars Lannfelt, André G. Uitterlinden, Tatijana Zemunik, Markus Perola, Kenneth Rice, Veronique Vitart, Kerrin S. Small, Jouke-Jan Hottenga, Han Chen, Jerome I. Rotter, Philippe Froguel, Karen L. Mohlke, Marie-Claude Vohl, Dorret I. Boomsma, Harry Campbell, Peter S. Chines, Pau Navarro, Vasiliki Lagou, Albert V. Smith, Kathleen Stirrups, Josephine M. Egan, Alan R. Shuldiner, Katri Räikkönen, Inga Prokopenko, Ping An, Rainer Rauramaa, Beverley Balkau, Thor Aspelund, Eleanor Wheeler, Mariza de Andrade, Richa Saxena, Jari Lahti, Cécile Lecoeur, Timo A. Lakka, Jennie Hui, Michael R. Erdos, Stavroula Kanoni, Kirsten Ohm Kyvik, Bengt Sennblad, Sarah H. Wild, Patricia A. Peyser, Patrik K. E. Magnusson, Claire Bellis, Elodie Eury, Jaana Lindström, Boston University [Boston] (BU), Broad Institute of Harvard and MIT, Partenaires INRAE, Massachusetts General Hospital, Massachusetts General Hospital [Boston], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), Department of Medicine, Université de Sherbrooke (UdeS), Addenbrooke's Hospital, Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Center [Boston] (BIDMC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Université Lille Nord de France (COMUE), Department of Epidemiology, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-Center for Social Epidemiology and Population Health, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], The Wellcome Trust Centre for Human Genetics [Oxford], The Netherlands Cancer Institute, Ontario Institute for Cancer Research, Mount Sinai Hospital [Toronto, Canada] (MSH), VU University Amsterdam, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Michigan System, Queen Mary University of London (QMUL), The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Diabetes Centre, Lund University, University of Helsinki, Wake Forest School of Medicine, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, University of Maryland School of Medicine, University of Maryland System, University of Edinburgh, University of Exeter, Department of Twin Research and Genetic Epidemiology, King's College London, London, Northwestern University [Evanston], National Institute of Health and Welfare, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Lund University Diabetes Centre, Umeå University, National Institutes of Health, Centre for Medical Systems Biology, Netherlands Genomics Initiative, Washington University in Saint Louis (WUSTL), Department of Health Sciences Research, Mayo Clinic, Wake Forest University, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland, Institute of Biomedicine, Physiology, University of Eastern Finland, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR S 1018, Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Department of Medical Genetics, Université de Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois (CHUV), Queen Elizabeth II Medical Centre, Research Institute, University of Southern California (USC), University of Split, The University of Texas Health Science Center at Houston (UTHealth), Leipzig University, Pennington Biomedical Research Center, Department of Epidemiology & Public Health, University College of London [London] (UCL), San Carlos Clinical Hospital, University of North Carolina, Harokopio University, National Institute on Aging, Folkhälsan Research Centre, Vaasa Central Hospital, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Epidemiology, Immunology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Ophthalmology, Internal Medicine, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA)

Subjects
Blood Glucose, Netherlands Twin Register (NTR), medicine.medical_treatment, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Type 2 diabetes, SUSCEPTIBILITY, Body Mass Index, GLUCOSE, Blood Glucose/metabolism, Cholesterol, HDL/metabolism, Diabetes Mellitus, Type 2/genetics, Genome-Wide Association Study, Humans, Insulin/metabolism, Insulin Resistance/genetics, Polymorphism, Single Nucleotide, 0302 clinical medicine, Insulin, 2. Zero hunger, Genetics, 0303 health sciences, COMMON VARIANTS, 3. Good health, ENVIRONMENT INTERACTION, OBESITY, CORONARY-ARTERY-DISEASE, medicine.medical_specialty, 030209 endocrinology & metabolism, Accounting, Biology, Article, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Internal medicine, Diabetes mellitus, medicine, 030304 developmental biology, Genetic association, Glycemic, loci, SNP, insulin, business.industry, Cholesterol, HDL, medicine.disease, Obesity, POLYMORPHISM, ASSOCIATION ANALYSIS, Endocrinology, Diabetes Mellitus, Type 2, TYPE-2 DIABETES RISK, Insulin Resistance, business
Abstract

Group Authors : DIAGRAM Consortium MUTHER Consortium variants influencing fasting glycemic traits and insulin resistance Seuls les 100 premiers auteurs ont été conservés dans la publication. La liste complète des auteurs et des des affiliations est disponible sur la publication https://www.nature.com/articles/ng.2274.pdf p. 667-669.; International audience; Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Published
2012

36. Large-scale association analysis identifies new risk loci for coronary artery disease

Author

Benjamin F. Voight, Andrew D. Morris, G. Kees Hovingh, Anthony J. Balmforth, Hanneke Basart, Alistair S. Hall, Dominique Gauguier, Bok Ghee Han, Martina Müller-Nurasyid, Sarah Parish, Jarmo Virtamo, Christa Meisinger, Peter Wagner, George Dedoussis, Philipp S. Wild, Kari Stefansson, Jean-Baptiste Cazier, Kathleen Stirrups, Jiyoung Lee, Adrienne Cupples, Stavroula Kanoni, Danish Saleheen, Christian Hengstenberg, Svati H. Shah, Panos Deloukas, Anuj Goel, Stefan Blankenberg, Sian Tsung Tan, Alison H. Goodall, Tõnu Esko, Eric Boerwinkle, Gudmundur Thorgeirsson, Peter S. Braund, Joshua W. Knowles, Olle Melander, C. Ellen van der Schoot, Silke Rosinger, Maria Dimitriou, Wolfgang Koenig, Michael Boehnke, François Cambien, Per Lundmark, Dmitry Shungin, Wolfgang Kratzer, Pierre Zalloua, Reijo Laaksonen, Jean Ferrières, Villi Gudnason, Thorsten Kessler, Daniel J. Rader, Niclas Eriksson, Dominique Arveiler, Natalie R. van Zuydam, Kari Kuulasmaa, N. William Rayner, Sarah E. Hunt, Gudmar Thorleifsson, Jeanette Erdmann, Samuli Ripatti, Tsun-Po Yang, George A. Wells, Terho Lehtimäki, Kjell Nikus, Pierre Fontanillas, Jorg Hager, Martin Farrall, Jemma C. Hopewell, Frank Kee, Juha Sinisalo, Christopher J. O'Donnell, Asif Rasheed, Mika Kähönen, Genovefa Kolovou, Seraya Maouche, Suzanne Rafelt, Cordelia Langford, Winfried März, Leo-Pekka Lyytikäinen, Christina Willenborg, Weihua Zhang, Kati Kristiansson, Hyo-Soo Kim, Weang K. Ho, Jeong E. Park, Mohan U. Sivananthan, Moritz P. Rumpf, Markku Laakso, Klaus Stark, Philippe Amouyel, Paul W. Franks, Andres Metspalu, Anders Franco-Cereceda, Manjinder S. Sandhu, Nour Eddine El Mokhtari, Nicholas J. Wareham, Robert Roberts, Veikko Salomaa, Thomas Illig, Tomi Pastinen, Robert Clarke, Christof Burgdorf, Leif Groop, Devin Absher, Yangsoo Jang, Mark I. McCarthy, Bernhard O. Boehm, Per Eriksson, Nilesh J. Samani, Inke R. König, Stefan Schreiber, Karin Leander, Simone Claudi-Boehm, Ci Song, Benjamin A. Goldstein, Stephen E. Epstein, Andreas Ziegler, Stanley L. Hazen, Arne Schäfer, Elin Grundberg, Sekar Kathiresan, John R. Thompson, Unnur Thorsteinsdottir, Muredach P. Reilly, Heribert Schunkert, Rory Collins, Thomas Quertermous, Jong-Young Lee, John Danesh, John C. Chambers, Marco M Ferrario, Carlos Iribarren, Claudia Langenberg, Hilma Holm, Rona J. Strawbridge, Alan S. Go, Cristen J. Willer, Ron Do, Emmi Tikkanen, Abbas Dehghan, Evelin Mihailov, Lindsay L. Waite, Patrick Diemert, Willem H. Ouwehand, Eric E. Schadt, Diana Rubin, David Altshuler, Marcus E. Kleber, Markus Perola, Alexandre F.R. Stewart, Jaspal S. Kooner, Themistocles L. Assimes, Inês Barroso, Bruna Gigante, Göran Hallmans, Marja-Liisa Lokki, Aki S. Havulinna, Anders Hamsten, Agneta Siegbahn, Lasse Folkersen, Erik Ingelsson, Martina E. Zimmermann, Colin N. A. Palmer, Paolo Brambilla, Ann-Christine Syvänen, Alun Evans, Åsa Johansson, John F. Peden, Alex S. F. Doney, Hugh Watkins, Johanna Kuusisto, Anders Lundmark, David G. Cox, Hyun Min Kang, Lars Lind, Krista Fischer, Markku S. Nieminen, Annette Peters, Norman Klopp, Stefan Gustafsson, Lars Wallentin, Nancy L. Pedersen, David-Alexandre Trégouët, Ulf de Faire, Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, B, Stirrups, K, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Willer, C, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shungin, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Hunt, S, Kang, H, Illig, T, Kessler, T, Knowles, J, Kolovou, J, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Salomaa, V, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Wareham, N, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Franks, P, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Boehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Schunkert, H, Samani, N, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine

Subjects
Adult, Asian Continental Ancestry Group, Male, Candidate gene, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Population, European Continental Ancestry Group, Quantitative Trait Loci, CAD, Genome-wide association study, Single-nucleotide polymorphism, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Bioinformatics, Polymorphism, Single Nucleotide, Article, White People, coronary artery disease, risk loci, Cell Line, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Asian People, Risk Factors, medicine, Humans, genetics, Gene Regulatory Networks, Genetic Predisposition to Disease, cardiovascular diseases, Polymorphism, education, 030304 developmental biology, Genetic association, Aged, Genetics, 0303 health sciences, education.field_of_study, Adult, Aged, Asian Continental Ancestry Group, Cell Line, Coronary Artery Disease, genetics, European Continental Ancestry Group, genetics, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Single Nucleotide, Middle Aged, medicine.disease, 3. Good health, Female, Genome-Wide Association Study
Abstract

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r 2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways. © 2013 Nature America, Inc. All rights reserved.

Published
2012
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37. The interplay of lifestyle and genetic susceptibility in Type 2 diabetes risk

Author

Dmitry Shungin and Paul W. Franks

Subjects
Gerontology, medicine.medical_specialty, business.industry, Psychological intervention, Dietary factors, Type 2 diabetes, Patient exposure, medicine.disease, Obesity, Diabetes mellitus, Genetic predisposition, medicine, Genetic risk, Intensive care medicine, business
Abstract

SUMMARY Type 2 diabetes results from the complex interplay of adverse lifestyle exposures and genetic predisposition. Accordingly, genetic information might one day facilitate personalized medical interventions for diabetes prevention, thus minimizing treatment costs, reducing patient exposure to ineffective therapies and improving patient adherence to treatment recommendations and their prognosis. Here, we briefly overview the roles that obesity, physical activity and dietary factors play in Type 2 diabetes; define common approaches used to discover genetic risk factors and gene–lifestyle interactions; provide relevant examples of gene–lifestyle interactions; and speculate on the application of genetics to the prediction, prevention and treatment of diabetes.

Published
2011

38. Genetic Predisposition to Long-Term Nondiabetic Deteriorations in Glucose Homeostasis

Author

Göran Hallmans, Dmitry Shungin, Frank B. Hu, Ingegerd Johansson, Frida Renström, Jose C. Florez, and Paul W. Franks

Subjects
Blood Glucose, Male, medicine.medical_specialty, Time Factors, Glucose control, Endocrinology, Diabetes and Metabolism, Early detection, 030209 endocrinology & metabolism, Blood Pressure, Type 2 diabetes, Bioinformatics, Polymorphism, Single Nucleotide, Risk Assessment, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Reference Values, Internal Medicine, Genetic predisposition, Genetics, Medicine, Glucose homeostasis, Homeostasis, Humans, Genetic Predisposition to Disease, Triglycerides, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, business.industry, Gene Expression Profiling, Chromosome Mapping, Fasting, Middle Aged, medicine.disease, Glucose, Diabetes Mellitus, Type 2, Hyperglycemia, Medical genetics, Female, business, Follow-Up Studies
Abstract

OBJECTIVE To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits. RESEARCH DESIGN AND METHODS Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk (GLACIER) Study, a population-based prospective cohort study from northern Sweden. Genotypes were tested for association with baseline fasting and 2-h postchallenge glycemia (N = 16,330), and for changes in these glycemic traits during a 10-year follow-up period (N = 4,059). RESULTS Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12 of 16 variants; 10 variants were also associated with impaired fasting glucose (IFG) and 7 were independently associated with 2-h postchallenge glucose concentrations. In prospective analyses, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, and G6PC2 rs560887) were nominally associated with worsening fasting glucose concentrations during 10-years of follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on postchallenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-h glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80th vs. 20th centiles) was associated with a 0.16 mmol/l (P = 2.4 × 10−6) greater elevation in fasting glucose and a 64% (95% CI: 33–201%) higher risk of developing IFG during 10 years of follow-up. CONCLUSIONS Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant.

Published
2010

39. Eating out, weight and weight gain. A cross-sectional and prospective analysis in the context of the EPIC-PANACEA study

Author

Sabina Sieri, M-J Sanchez, Elisabet Wirfält, M. C. Boutron-Ruault, Guy Fagherazzi, Guri Skeie, Kim Overvad, Giovanna Masala, Jytte Halkjær, H. B. Bueno-De-Mesquita, M-D Chirlaque, Michail Katsoulis, Philippos Orfanos, Vardis Dilis, Miren Dorronsoro, Heinz Freisling, L. Rodríguez, Nadia Slimani, Aurelio Barricarte, Dagrun Engeset, Anne M. May, A. Mattiello, Carlotta Sacerdote, Silke Hermann, Eleni Oikonomou, Annika Steffen, F. Clavel-Chapelon, Dora Romaguera, Rosario Tumino, Nicholas J. Wareham, Andreani D. Odysseos, S. Rohrmann, Androniki Naska, K-T Khaw, Antonia Trichopoulou, A. C. Vergnaud, Dmitry Shungin, Marianne Uhre Jakobsen, Jonas Manjer, Elizabeth A Spencer, Veronica Hellstrom, Antonio Agudo, Anne Tjønneland, T Mouw, Petra H.M. Peeters, and J. Haubrock

Subjects
Adult, Male, medicine.medical_specialty, Restaurants, 030309 nutrition & dietetics, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), 030209 endocrinology & metabolism, Context (language use), Weight Gain, Body Mass Index, Panacea (medicine), Eating, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Risk Factors, Environmental health, Internal medicine, medicine, Humans, Obesity, Prospective Studies, Workplace, Prospective cohort study, Aged, 2. Zero hunger, 0303 health sciences, Nutrition and Dietetics, Anthropometry, business.industry, Body Weight, digestive, oral, and skin physiology, Middle Aged, medicine.disease, 3. Good health, Europe, Cross-Sectional Studies, Endocrinology, Female, medicine.symptom, Energy Intake, business, Weight gain, Body mass index
Abstract

Udgivelsesdato: 2010-Jul-27 Objective:The aim of this study was to examine the association of body mass index (BMI) and weight gain with eating at restaurants and similar establishments or eating at work among 10 European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Subjects:This study included a representative sample of 24 310 randomly selected EPIC participants.Methods:Single 24-h dietary recalls with information on the place of consumption were collected using standardized procedures between 1995 and 2000. Eating at restaurants was defined to include all eating and drinking occasions at restaurants, cafeterias, bars and fast food outlets. Eating at work included all eating and drinking occasions at the workplace. Associations between eating at restaurants or eating at work and BMI or annual weight changes were assessed using sex-specific linear mixed-effects models, controlling for potential confounders.Results:In southern Europe energy intake at restaurants was higher than intake at work, whereas in northern Europe eating at work appeared to contribute more to the mean daily intake than eating at restaurants. Cross-sectionally, eating at restaurants was found to be positively associated with BMI only among men (beta=+0.24, P=0.003). Essentially no association was found between BMI and eating at work among both genders. In a prospective analysis among men, eating at restaurants was found to be positively, albeit nonsignificantly, associated with weight gain (beta=+0.05, P=0.368). No association was detected between energy intake at restaurants and weight changes, controlling for total energy intake.Conclusion:Among men, eating at restaurants and similar establishments was associated with higher BMI and possibly weight gain.International Journal of Obesity advance online publication, 27 July 2010; doi:10.1038/ijo.2010.142.

Published
2010

40. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Philippe Froguel, Pekka Jousilahti, Harry Campbell, Ellen M. Schmidt, Vasiliki Lagou, John Andrew Pospisilik, Ivana Kolcic, Igor Rudan, Mark A. Sarzynski, Brigitte Kühnel, Robin Haring, Paul Knekt, Christian Gieger, Eero Kajantie, Jian Yang, Tuomas O. Kilpeläinen, Hans L. Hillege, Niek Verweij, Sarah H Wild, Torben Hansen, Leena Taittonen, Michael Boehnke, Mark I. McCarthy, Joel N. Hirschhorn, Åsa K. Hedman, D. Timothy Bishop, James F. Wilson, Jian'an Luan, Leo-Pekka Lyytikäinen, Nita G. Forouhi, Mark Walker, Elodie Eury, Konstantin Strauch, Aroon D. Hingorani, Nam H. Cho, Peter Vollenweider, Erkki Vartiainen, Jong-Young Lee, Fredrik Karpe, Jiali Han, Joanne M. Jordan, Chen Lu, Henri Wallaschofski, Anna A. E. Vinkhuyzen, Alan R. Shuldiner, David J. Hunter, Mario Falchi, Aron S. Buchman, Caroline S. Fox, Robert A. Scott, Chan Soo Shin, Fernando Rivadeneira, Zari Dastani, Veikko Salomaa, Weihua Zhang, Rui Li, John C. Chambers, Thorkild I. A. Sørensen, André G. Uitterlinden, David A. Bennett, Marianna Sanna, Claire Bellis, Lars Bertram, Karl Michaëlsson, Yingchang Lu, Marie Loh, Loic Yengo, Bok-Ghee Han, Priya Srikanth, Laura Pascoe, Peter Wagner, Philip L. De Jager, Oscar H. Franco, Yongmei Liu, Stavroula Kanoni, Simone Gärtner, Ruth J. F. Loos, Eric E. Schadt, Claes Ohlsson, Cornelia M. van Duijn, Jorma S. A. Viikari, Stephan J. L. Bakker, Tamara B. Harris, Pirro G. Hysi, Samuli Ripatti, John R. B. Perry, Stefan A. Czerwinski, Tune H. Pers, Angela Döring, Ghazaleh Fatemifar, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Carrie M. Nielson, Claudia Langenberg, Carolina Medina-Gomez, Mike A. Nalls, Erik Ingelsson, Barbara McKnight, Niels Grarup, L. Adrienne Cupples, Torben Jørgensen, Satu Männistö, Jianbo Na, Cristen J. Willer, Tuomo Rankinen, Irene Mateo Leach, Cecilia M. Lindgren, Marie-Claude Vohl, Ryan W. Walker, Yun Ju Sung, Joanne M. Murabito, Natasja M. van Schoor, Mika Kivimäki, Nicholas J. Wareham, Lei Yu, Markku Laakso, Julia A. Newton Bishop, Pim van der Harst, Qibin Qi, Veronique Bataille, Clive Osmond, Alan F. Wright, Audrey C. Choh, Charles C. White, Felix R. Day, Ron T. Gansevoort, Tiina Laatikainen, Ozren Polasek, Johan G. Eriksson, Mark M. Iles, Dena G. Hernandez, Meena Kumari, Dmitry Shungin, Jeffrey R. O'Connell, Joseph M. Zmuda, Antti Jula, Hyung Jin Choi, Albert Hofman, Steven R. Cummings, Youfang Liu, Vilmundur Gudnason, J. Brent Richards, Michael Stumvoll, Ayse Demirkan, Teresa Ferreira, Rosalie A. M. Dhonukshe-Rutten, Rahel Eckardt, Lude Franke, Karen L. Mohlke, Uzma Afzal, Kijoung Song, Till Ittermann, Janina S. Ried, Allan Linneberg, Nicholas D. Hastie, Laticia Oozageer, Johanna Kuusisto, John Blangero, Amélie Bonnefond, Panos Deloukas, Andrew P. Morris, Oluf Pedersen, Adam E. Locke, Emmi Tikkanen, Veronique Vitart, Aki S. Havulinna, Olli T. Raitakari, Inga Prokopenko, Peter Lichtner, Harm-Jan Westra, Katja Borodulin, Teemu Kuulasmaa, Lars Lind, Bradford Towne, Christine G. Lee, Mika Kähönen, Anke W. Enneman, Terrence S. Furey, Treva Rice, Abbas Dehghan, Jaspal S. Kooner, Dabeeru C. Rao, Terrence Forrester, Jing Hua Zhao, Xin Li, Mary F. Feitosa, Melissa E. Garcia, Tian Liu, Aarno Palotie, Eric S. Orwoll, Reedik Mägi, Daniel S. Evans, Elisabeth Widen, Tim D. Spector, Caroline Hayward, Annette Peters, Markku Heliövaara, Harald Grallert, Niina Eklund, Robert C. Kaplan, Ilja Demuth, Luigi Ferrucci, Kati Kristiansson, Amy Luke, Tõnu Esko, Ken K. Ong, Gregory J. Tranah, Angelo Tremblay, Ben A. Oostra, Stefan Gustafsson, Zhihong Zhu, Nina Smolej Narančić, Cameron D. Palmer, William R. Scott, Alexander Teumer, Anne U. Jackson, Markus Perola, Toshiko Tanaka, Lavinia Paternoster, Henry Völzke, Terho Lehtimäki, Dominik Spira, Karin M. A. Swart, Louis Pérusse, Matthias Blüher, Jari Lahti, M. Carola Zillikens, Kari E. North, Yvonne Boettcher, Douglas P. Kiel, Bamidele O. Tayo, Elisabeth Steinhagen-Thiessen, Diana L. Cousminer, Joanne E. Curran, Peter Kovacs, David M. Evans, Claude Bouchard, Alena Stančáková, Seppo Koskinen, Jack W. Kent, Alexander W. Drong, Massimo Mangino, Frédéric Fumeron, Richard S. Cooper, Juha Karjalainen, Nathalie van der Velde, Martin L. Buchkovich, Stéphane Lobbens, Cristina Menni, Anubha Mahajan, Nele Friedrich, Anke Tönjes, Colin A. McKenzie, Tom Forsén, Anne E. Justice, Lisette C. P. G. M. de Groot, Ingrid B. Borecki, Mingfeng Zhang, Tommy Cederholm, IOO, Internal medicine, Epidemiology and Data Science, EMGO - Musculoskeletal health, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, Internal Medicine, Erasmus MC other, Epidemiology, Clinical Genetics, Institute for Molecular Medicine Finland, Clinicum, Department of General Practice and Primary Health Care, Behavioural Sciences, Samuli Olli Ripatti / Principal Investigator, Department of Public Health, Aarno Palotie / Principal Investigator, Johan Eriksson / Principal Investigator, Children's Hospital, Lastentautien yksikkö, University of Helsinki, Elisabeth Ingrid Maria Widen / Principal Investigator, Biostatistics Helsinki, Quantitative Genetics, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
0301 basic medicine, Medicin och hälsovetenskap, Drosophila melanogaster/genetics, Nutrition and Disease, General Physics and Astronomy, Genome-wide association study, Medical and Health Sciences, Body fat percentage, Voeding en Ziekte, CUTANEOUS NEVI, Mass index, Human Nutrition & Health, Adiposity, INSULIN-RESISTANCE, Multidisciplinary, body fat, cardiometabolic traits, genome-wide association study, meta-analysis, biology, Disease genetics, Leptin, Humane Voeding & Gezondheid, COMMON VARIANTS, Public Health, Global Health, Social Medicine and Epidemiology, 3. Good health, Biological sciences, Cardiovascular diseases, Drosophila melanogaster, Gene Knockdown Techniques, ENERGY-BALANCE, Medical Genetics, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Heart Diseases, 515 Psychology, Science, Quantitative Trait Loci, PROVIDES INSIGHTS, Quantitative trait locus, General Biochemistry, Genetics and Molecular Biology, Article, GENETIC ARCHITECTURE, 03 medical and health sciences, MASS INDEX, Insulin resistance, Internal medicine, MD Multidisciplinary, Genetics, medicine, Life Science, Animals, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Medicinsk genetik, VLAG, Global Nutrition, Wereldvoeding, Gene Expression Regulation/physiology, C-reactive protein, Metabolic diseases, General Chemistry, ta3121, medicine.disease, Onderwijsinstituut, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Adiposity/genetics, Drosophila melanogaster/metabolism, Genome-Wide Association Study, Heart Diseases/genetics, Quantitative Trait Loci/genetics, 030104 developmental biology, Endocrinology, Gene Expression Regulation, 3121 General medicine, internal medicine and other clinical medicine, biology.protein, Lean body mass, IDENTIFIES COMMON
Abstract

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P, A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Published
2015

41. Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium

Author

Peter Kraft, Peter M. Nilsson, Kaumudi Joshipura, Robert J. Weyant, Nicholas J. Timpson, Eric Boerwinkle, Göran Hallmans, Tom Palmer, John R. Shaffer, Mary L. Marazita, Olle Melander, Silvana P. Barros, Paul W. Franks, Pernilla Lundberg, Paul M. Ridker, Gull Rukh, Birte Holtfreter, Alexander Teumer, Dmitry Shungin, Frank B. Hu, Eric B. Rimm, George Davey Smith, Reiner Biffar, Kimon Divaris, Lynda M. Rose, Patrik K. E. Magnusson, Daniel I. Chasman, Marju Orho-Melander, Nancy L. Pedersen, Ingegerd Johansson, Steven Offenbacher, Kevin Moss, Richard J. Crout, Yau Hua Yu, Andrea Ganna, Kari E. North, George Hindy, Thomas Kocher, Daniel W. McNeil, Marilyn C. Cornelis, and James D. Beck

Subjects
Gerontology, Adult, Male, Genotype, Epidemiology, Mendelian Randomization Causal Analysis, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Bioinformatics, Polymorphism, Single Nucleotide, Body Mass Index, Cohort Studies, Young Adult, Age Distribution, Mendelian randomization, medicine, Humans, Obesity, Periodontitis, Life Style, Adiposity, Aged, business.industry, Confounding, Membrane Proteins, Proteins, Mendelian Randomization Analysis, General Medicine, Middle Aged, medicine.disease, Causal inference, Meta-analysis, Receptor, Melanocortin, Type 4, Observational study, Female, business, Body mass index
Abstract

Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI).Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis.Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data.Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.

Published
2015

42. A novel interaction between the FLJ33534 locus and smoking in obesity: a genome-wide study of 14 131 Pakistani adults

Author

Dmitry Shungin, Syed Zahed Rasheed, Wei Zhao, Mozzam Zaidi, Shahana Urooj Kazmi, Faisal Ahmed, M. Ishaq, Frida Renström, Nadeem Hayyat Mallick, Danish Saleheen, Muhammad Shakir Lakhani, Panagiotis Deloukas, M Samuel, Nabi Shah, Bashir Hanif, Paul W. Franks, Adil Rasheed, Khan Shah Zaman, Shafqat Ahmad, Philippe M. Frossard, and F-U-R Memon

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Locus (genetics), Genome-wide association study, Receptors, Nicotinic, Genome, Polymorphism, Single Nucleotide, Body Mass Index, 03 medical and health sciences, Asian People, Internal medicine, medicine, Global health, Humans, Genetic Predisposition to Disease, Pakistan, Obesity, Life Style, Genetics, Nutrition and Dietetics, business.industry, Public health, Smoking, medicine.disease, 030104 developmental biology, Endocrinology, Cross-Sectional Studies, Female, business, Body mass index, Genome-Wide Association Study
Abstract

Obesity is a complex disease caused by the interplay of genetic and lifestyle factors, but identification of gene-lifestyle interactions in obesity has remained challenging. Few large-scale studies have reported use of genome-wide approaches to investigate gene-lifestyle interactions in obesity.In the Pakistan Risk of Myocardial Infraction Study, a cross-sectional study based in Pakistan, we calculated body mass index (BMI) variance estimates (square of the residual of inverse-normal transformed BMI z-score) in 14 131 participants and conducted genome-wide heterogeneity of variance analyses (GWHVA) for this outcome. All analyses were adjusted for age, age(2), sex and genetic ancestry.The GWHVA analyses identified an intronic variant, rs140133294, in the FLJ33544 gene in association with BMI variance (P-value=3.1 × 10(-8)). In explicit tests of gene × lifestyle interaction, smoking was found to significantly modify the effect of rs140133294 on BMI (Pinteraction=0.0005), whereby the minor allele (T) was associated with lower BMI in current smokers, while positively associated with BMI in never smokers. Analyses of ENCODE data at the FLJ33534 locus revealed features indicative of open chromatin and high confidence DNA-binding motifs for several transcription factors, providing suggestive biological support for a mechanism of interaction.In summary, we have identified a novel interaction between smoking and variation at the FLJ33534 locus in relation to BMI in people from Pakistan.

Published
2015

43. Coronary calcification with no flow limiting lesions : a potential cause for ischaemic dysfunction in syndrome X patients

Author

Michael Y. Henein, Sergio Mondillo, Elisabetta Palmerini, Henrik Antti, Dmitry Shungin, and Stefan Söderberg

Subjects
lcsh:Diseases of the circulatory (Cardiovascular) system, medicine.medical_specialty, Cardiac & Cardiovascular Systems, Stress echo, Article, Coronary calcification, Angina, Internal medicine, medicine, In patient, Cardiac and Cardiovascular Systems, cardiovascular diseases, Coronary flow, Kardiologi, business.industry, CACS, Limiting, medicine.disease, X syndrome, lcsh:RC666-701, Stress Echo, Coronary artery calcification, Cardiology, Cardiology and Cardiovascular Medicine, business, Syndrome x
Abstract

Aim Exertional angina in patients with no coronary flow limiting lesions remains a clinical puzzle. We aimed to assess the extent of coronary artery calcification (CAC) and its relationship to ventricular wall motion function using stress echocardiography in a group of patients limited by exertional angina, but no obstructive lesions. Methods We compared CT coronary calcium score (CACS) and dobutamine stress echocardiography in 55 patients (age 64.7 ± 7.7 years), divided into Group 1 (CACS ≤ 100) and Group 2 (CACS > 100). No patient had LV ejection fraction-EF

Published
2015

44. Genetic Determinants of Long-Term Changes in Blood Lipid Concentrations: 10-Year Follow-Up of the GLACIER Study

Author

Paul W. Franks, Emily Sonestedt, Peter M. Nilsson, Robert W. Koivula, Göran Hallmans, Inês Barroso, Stefan A. Escher, Frida Renström, Tibor V. Varga, Olle Melander, Dmitry Shungin, and Marju Orho-Melander

Subjects
Apolipoprotein E, Male, Cancer Research, Health Screening, Heredity, Apolipoprotein B, Epidemiology, Genome-wide association study, 030204 cardiovascular system & hematology, Vascular Medicine, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Surveys and Questionnaires, Medicine and Health Sciences, Clinical Epidemiology, Public and Occupational Health, Longitudinal Studies, Prospective Studies, Prospective cohort study, Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, biology, Trait Loci, Intracellular Signaling Peptides and Proteins, Middle Aged, Cholesterol, Genetic Epidemiology, Female, Anatomy, Medical Genetics, Research Article, medicine.medical_specialty, lcsh:QH426-470, Genotype, Population, Cardiology, Single-nucleotide polymorphism, Endocrinology and Diabetes, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, 03 medical and health sciences, Apolipoproteins E, Internal medicine, medicine, Humans, Allele, education, Molecular Biology, Life Style, Ecology, Evolution, Behavior and Systematics, Cardiovascular Disease Epidemiology, Triglycerides, 030304 developmental biology, Medicinsk genetik, Aged, Sweden, Evolutionary Biology, Quantitative Traits, Apolipoprotein A-I, Complex Traits, Biology and Life Sciences, Atherosclerosis, lcsh:Genetics, Biomarker Epidemiology, Endocrinology, Cross-Sectional Studies, chemistry, Genetics of Disease, biology.protein, Cardiovascular Anatomy, Genetic Polymorphism, Population Genetics, Genome-Wide Association Study
Abstract

Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (β = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0×10−11 for TC; β = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0×10−5 for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (β = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0×10−5), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (β = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1×10−4) and apolipoprotein A-I (APOA1) rs6589564 (β = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4×10−8), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P≤0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels., Author Summary Although large cross-sectional studies have proven highly successful in identifying gene variants related to lipid levels and other cardiometabolic traits, very few examples of well-designed longitudinal studies exist where associations between genotypes and long-term changes in lipids have been assessed. Here we undertook analyses in the GLACIER Study to determine whether the 157 previously identified lipid-associated genes variants associate with changes in blood lipid levels over 10-yr follow-up. We identified a variant in APOE that is robustly associated with total cholesterol change and two variants in TRIB1 and APOA1 respectively that are robustly associated with triglyceride change. We replicated these findings in a second Swedish cohort (the MDC Study). The identified genes had previously been associated with cardiovascular traits such as myocardial infarction or coronary heart disease; hence, these novel lipid associations provide additional insight into the pathogenesis of atherosclerotic heart and large vessel disease. By incorporating all 157 established variants into gene scores, we also observed strong associations with 10-yr lipid changes, illustrating the polygenic nature of blood lipid deterioration.

Published
2014

45. Supplementary Material 1

Author

Henry Völzke, Tõnu Esko, Ken K. Ong, Aldi T. Kraja, Anne U. Jackson, Meena Kumari, Eva Albrecht, Rona J. Strawbridge, Antti Jula, Mark J. Caulfield, Alistair S. Hall, Karol Estrada, Jennifer L. Bolton, Teresa Ferreira, Inger Njølstad, Thomas W. Winkler, Ross M. Fraser, Daniel I. Chasman, Maris Teder-Laving, Yii-Der Ida Chen, Claudia Langenberg, Kevin B. Jacobs, Jennifer G. Sambrook, Evelin Mihailov, Peter Kovacs, Susanne Moebus, Jouke-Jan Hottenga, George Dedoussis, Gudmar Thorleifsson, Sirkka M. Keinanen Kiukaanniemi, Matti Uusitupa, Denise Anderson, Lindsay L. Waite, Johan G. Eriksson, Mustafa Atalay, Kari Stefansson, Amélie Bonnefond, Gerry Fowkes, Tove Fall, Dmitry Shungin, Stephan J. L. Bakker, Tamara B. Harris, Thomas Illig, Wolfgang Koenig, Heribert Schunkert, Caroline S. Fox, Gabrielle Boucher, Sonja I. Berndt, Timo Saaristo, Maria Dimitriou, Pim van der Harst, Christina Loley, John Yarnell, Rainer Rauramaa, Sarah Edkins, Jaakko Tuomilehto, Karen L. Mohlke, Damien C. Croteau Chonka, Reedik Mägi, Olli T. Raitakari, Kathleen Stirrups, Aroon D. Hingorani, Inga Prokopenko, Henrik Grönberg, Marcus E. Kleber, Massimo Mangino, Michael A. Province, Markus M. Nöthen, Patricia B. Munroe, Francis S. Collins, Jeanette Erdmann, Mattias Lorentzon, Lynda M. Rose, Jon P. Krohn, Paul M. Ridker, M. Carola Zillikens, Jouko Saramies, Andrew Wong, Anuj Goel, Christa Buechler, Chris Power, Iain Mathieson, Bernhard O. Boehm, Jonathan Tyrer, Fredrik Karpe, Lu Qi, Nicholas G. Martin, Kristian Hveem, Jackie F. Price, Martin Farrall, Albert V. Smith, Mary F. Feitosa, Caroline Hayward, Juha Sinisalo, Stavroula Kanoni, Elina Hyppönen, Christian Hengstenberg, Lori L. Bonnycastle, Ilja M. Nolte, Sonali Pechlivanis, Barbara Thorand, Patrik K. E. Magnusson, Cristina Barlassina, Andrew A. Hicks, Genovefa Kolovou, Melanie M. van der Klauw, Markus Perola, Tsegaselassie Workalemahu, Ida Surakka, Veikko Salomaa, Andrea Ganna, Timothy M. Frayling, Iris M. Heid, Brenda W.J.H. Penninx, Stephen J. Chanock, Jeffrey R. O'Connell, Tom Wilsgaard, Alan R. Shuldiner, David J. Hunter, Deborah J. Clegg, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, David P. Strachan, Lyle J. Palmer, Alexander Teumer, Kari E. North, L. Adrienne Cupples, Carlos Iribarren, Anna-Liisa Hartikainen, Andrew R. Wood, Lambertus A. Kiemeney, Ulf Gyllensten, Jennie Hui, Tim D. Spector, Paul W. Franks, Andrew D. Morris, Ruth J. F. Loos, George Nicholson, Felix R. Day, Kati Kristiansson, Talin Haritunians, Martina Müller-Nurasyid, Sailaja Vedantam, Pablo V. Gejman, Martin den Heijer, Andrea Maschio, Anke Tönjes, Kari Kuulasmaa, Raimund Erbel, Markku Laakso, Devin Absher, Narisu Narisu, Zhaoming Wang, Jing Hua Zhao, Thomas N. Person, Irene Mateo Leach, Mark I. McCarthy, Albert Hofman, Joel N. Hirschhorn, H.-Erich Wichmann, Nicholas J. Wareham, André Scherag, Jarmo Virtamo, James F. Wilson, Gonçalo R. Abecasis, Winfried März, Nilesh J. Samani, Timo A. Lakka, Jacques S. Beckmann, Harold Snieder, Adam E. Locke, Hanneke Basart, Grant W. Montgomery, Robert C. Kaplan, Claudia Lamina, Sekar Kathiresan, Mika Kivimäki, Leif Groop, Emil Rehnberg, Jana V. Van Vliet Ostaptchouk, Ingrid B. Borecki, Sabrina Bauer, Terho Lehtimäki, Steve E. Humphries, Zoltán Kutalik, Kees Hovingh, Carolina Medina-Gomez, Panos Deloukas, Antony P. Attwood, Kay-Tee Khaw, Per Hall, Jaakko Kaprio, Jian Yang, Tuomas O. Kilpeläinen, Andres Metspalu, Igor Rudan, Michael Boehnke, Ben A. Oostra, Jaana Lindström, André G. Uitterlinden, Peter Schwarz, Keri L. Monda, John Beilby, Fernando Rivadeneira, Emmanouil T. Dermitzakis, Dominique Arveiler, Valgerdur Steinthorsdottir, Jian'an Luan, Cecilia M. Lindgren, Guo Li, Bruna Gigante, Göran Hallmans, Liming Liang, Peter S. Chines, Sarah E. Medland, Joseph Hung, Peter P. Pramstaller, Ulf de Faire, Joshua C. Randall, Nancy L. Pedersen, Wendy L. McArdle, Unnur Thorsteinsdottir, Bernhard R. Winkelmann, Kaarel KrjutÅ¡kov, Philippe Froguel, Harry Campbell, Dorret I. Boomsma, Harald Grallert, Nancy L. Heard Costa, Shengxu Li, Amy J. Swift, Diana Kuh, Gerjan Navis, Christian Gieger, Heikki V. Huikuri, Niina Eklund, Anders Hamsten, Elizabeth K. Speliotes, Josine L. Min, Hendrik B. Sager, Stefan Gustafsson, Antigone S. Dimas, Elena Tremoli, Carlo Rivolta, Jianxin Shi, Najaf Amin, Claes Ohlsson, Johanna Kuusisto, Giancarlo Cesana, Lars Lind, Stefan R. Bornstein, Erik Ingelsson, Colin N. A. Palmer, Marjo-Riitta Järvelin, Krista Fischer, Annette Peters, David Schlessinger, Themistocles L. Assimes, Inês Barroso, Kristina Eisinger, Marja-Liisa Lokki, Jennifer Jolley, and Åsa Johansson

Subjects
Cultural Studies, Archeology, History, Chemistry, Cystolith, medicine, Magnesium ammonium phosphate, Bladder stones, medicine.disease, Nuclear chemistry
Published
2013

46. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Author

Zhaoming Wang, André Scherag, James F. Wilson, Nancy L. Heard-Costa, Ingrid B. Borecki, Sang Hong Lee, Veronique Vitart, Zoltán Kutalik, Jeffrey R. O'Connell, Mieke D. Trip, Lu Qi, Peter Vollenweider, Jennifer L. Bragg-Gresham, Davide Gentilini, Kees Hovingh, Lynda M. Rose, Carolin Pütter, Martin Farrall, Albert V. Smith, Nicholas G. Martin, Tõnu Esko, David J. Hunter, Georg Homuth, Liming Liang, Yudi Pawitan, Winfried März, George Dedoussis, Irene Mateo Leach, Nicholas J. Wareham, Lars Lind, Thomas Illig, Andrew P. Morris, Daniele Cusi, Jouke-Jan Hottenga, Tove Fall, Themistocles L. Assimes, Massimo Mangino, Dmitry Shungin, Kari Stefansson, Anne U. Jackson, Inês Barroso, Sarah E. Medland, Lude Franke, Karen L. Mohlke, Folkert W. Asselbergs, Sarah E. Hunt, Gudmar Thorleifsson, Pablo V. Gejman, Serena Sanna, Mark I. McCarthy, David M. Evans, Joel N. Hirschhorn, Alan F. Wright, Sarah H. Wild, Patricia B. Munroe, Marcel Bruinenberg, Gonneke Willemsen, Ulf de Faire, Markku Laakso, Marja-Liisa Lokki, Andrew C. Heath, Jing Hua Zhao, Lavinia Paternoster, Jana V. van Vliet-Ostaptchouk, Sailaja Vedantam, Danyu Lin, Eric E. Schadt, Stefano Signorini, Harald Grallert, Tsegaselassie Workalemahu, Jonathan Tyrer, Albert Hofman, George Nicholson, Patrik K. E. Magnusson, Arthur W. Musk, Jian Yang, Vilmundur Gudnason, Robert C. Kaplan, Panos Deloukas, Nilesh J. Samani, Inke R. König, Frank B. Hu, Paul M. Ridker, Tamara B. Harris, Bruce H. R. Wolffenbuttel, Ellen A. Nohr, Sarah Edkins, Lambertus A. Kiemeney, Anke Hinney, Eric Boerwinkle, Klaus Stark, Ben A. Oostra, Barbara Thorand, Unnur Thorsteinsdottir, Meena Kumari, Evelin Mihailov, Caroline S. Fox, Michael Boehnke, Aroon D. Hingorani, Jonathan Stephens, Kathleen Stirrups, Inga Prokopenko, Anke Tönjes, Lili Milani, John Beilby, Carlos Iribarren, Kari E. North, Cécile Lecoeur, So-Youn Shin, Marjo-Riitta Järvelin, Matti Uusitupa, Åsa Johansson, Nancy L. Pedersen, Krista Fischer, Fernando Rivadeneira, Wolfgang Koenig, Fredrik Karpe, Antti Jula, Lindsay L. Waite, Gérard Waeber, Mustafa Atalay, Heribert Schunkert, Narisu Narisu, Sita H. Vermeulen, Bernhard R. Winkelmann, Guo Li, Anders Hamsten, Elizabeth K. Speliotes, Ivonne Jarick, Sirkka Keinänen-Kiukaanniemi, L. Adrienne Cupples, Ruth J. F. Loos, Martina Müller-Nurasyid, David-Alexandre Trégouët, Claudia Langenberg, Willem H. Ouwehand, Julius S. Ngwa, Jennifer E. Huffman, H-Erich Wichmann, Amy J. Swift, Marco M Ferrario, Leif Groop, Henrik Grönberg, Peter M. Visscher, Claes Ohlsson, Markku S. Nieminen, Aparna Radhakrishnan, Harold Snieder, Devin Absher, Albertine J. Oldehinkel, Erik Ingelsson, Anna Maria Di Blasio, M. Carola Zillikens, Veikko Salomaa, Colin N. A. Palmer, Lori L. Bonnycastle, Teresa Ferreira, Ronald P. Stolk, Annette Peters, Philippe Froguel, Michael Stumvoll, David Schlessinger, Maria Dimitriou, Timo Saaristo, Cristen J. Willer, Jarmo Virtamo, Jorma Viikari, Alena Stančáková, Mika Kivimäki, Paolo Brambilla, Jaakko Tuomilehto, Dorret I. Boomsma, Harry Campbell, Jianjun Liu, Daniel I. Chasman, Gonçalo R. Abecasis, Ilja M. Nolte, Karl-Heinz Jöckel, Reedik Mägi, Pamela A. F. Madden, Jaana Laitinen, Sonja I. Berndt, Frank Kee, Marcus E. Kleber, Jacqueline C.M. Witteman, Jouko Saramies, Francis S. Collins, Johan G. Eriksson, Melanie M. van der Klauw, Yi-Juan Hu, John F. Peden, Markus Perola, Henri Wallaschofski, Jean Ferrières, Elena Tremoli, Marjolein J. Peters, Olli T. Raitakari, Claudia Lamina, Sekar Kathiresan, Mary F. Feitosa, Diana Kuh, Tim D. Spector, Paul W. Franks, Gerjan Navis, Martin den Heijer, Christian Gieger, Kevin B. Jacobs, Andrea Ganna, Timothy M. Frayling, Iris M. Heid, Bernhard O. Boehm, Eleanor Wheeler, Sonali Pechlivanis, Miriam F. Moffatt, Brenda W.J.H. Penninx, Anna-Liisa Hartikainen, Augusto Rendon, Stefan Schreiber, Stephen J. Chanock, Andrew R. Wood, Jianxin Shi, Najaf Amin, Lenore J. Launer, Michael A. Province, Jeanette Erdmann, Mattias Lorentzon, Hugh Watkins, Johanna Kuusisto, John-Olov Jansson, David P. Strachan, Anne E. Justice, Toby Johnson, Cornelia M. van Duijn, Niina Eklund, Samuli Ripatti, Aarno Palotie, Aldi T. Kraja, Michael Preuss, Rona J. Strawbridge, Ozren Polasek, Elisabeth Widen, Barbara McKnight, Mariano Dei, Vincent Mooser, Josine L. Min, Caroline Hayward, Mika Kähönen, Peter P. Pramstaller, Femmie de Vegt, Rainer Rauramaa, Douglas F. Levinson, Diana Marek, Antonio Liuzzi, Stefan Gustafsson, Andrew A. Hicks, Gemma Cadby, Damien C. Croteau-Chonka, Mark J. Caulfield, Boris Skrobek, Lyle J. Palmer, Alexander Teumer, Ken K. Ong, Ulf Gyllensten, Anneli Pouta, Anuj Goel, Eva Albrecht, Kristian Hveem, Inger Njølstad, David Meyre, Ida Surakka, Francesca Frau, Paolo Manunta, Sabine Schipf, Carolina Medina-Gomez, Kay-Tee Khaw, Alan R. Sanders, Thorkild I. A. Sørensen, André G. Uitterlinden, Alistair S. Hall, Felix R. Day, Karol Estrada, Jennifer G. Sambrook, Eirini V. Theodoraki, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Talin Haritunian, Benjamin M. Neale, Juha Sinisalo, Kati Kristiansson, Thomas W. Winkler, Pim van der Harst, Peter S. Chines, Joyce B. J. van Meurs, Wendy L. McArdle, Andrew Wong, Grant W. Montgomery, Terho Lehtimäki, Igor Rudan, Keri L. Monda, John M. C. Connell, Jian'an Luan, Per Hall, Joshua C. Randall, Anthony J. Balmforth, Chris Power, Philippe Amouyel, Andres Metspalu, Johannes Hebebrand, Andrew D. Morris, Jaana Lindström, Liesbeth Vandenput, William O.C.M. Cookson, Hanneke Basart, Stavroula Kanoni, Elina Hyppönen, Christian Hengstenberg, Thomas W. Mühleisen, Kari Kuulasmaa, Timo A. Lakka, Nicole Soranzo, Bruce M. Psaty, Antony P. Attwood, Epidemiology, Clinical Genetics, Surgery, Erasmus School of Social and Behavioural Sciences, Public Health, Internal Medicine, Immunology, Child and Adolescent Psychiatry / Psychology, Internal medicine, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Other departments, Vascular Medicine, Biological Psychology, Cognitive Psychology, AIMMS, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Esko, T, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Luan, J, Randall, J, Vedantam, S, Willer, C, Winkler, T, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Huffman, J, Jarick, I, Johansson, Å, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mangino, M, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Teumer, A, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Zhao, J, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, Brambilla, P, Bruinenberg, M, Campbell, H, Chasman, D, Chines, P, Collins, F, Connell, J, Cookson, W, De, F, U, D, Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Evans, D, Farrall, M, Ferrario, M, Ferrières, J, Franke, L, Frau, F, Gejman, P, Grallert, H, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, Homuth, G, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimäki, M, Koenig, W, Kraja, A, Kumari, M, Kuulasmaa, K, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Mateo Leach, I, Mcknight, B, Medland, S, Mihailov, E, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Navis, G, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palmer, C, Palotie, A, Peden, J, Pedersen, N, Peters, A, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stančáková, A, Stark, K, Stephens, J, Stirrups, K, Stolk, R, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widén, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wolffenbuttel, B, Wong, A, Wright, A, Zillikens, M, Amouyel, P, Boehm, B, Boerwinkle, E, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Cusi, D, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Metspalu, A, Morris, A, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Snieder, H, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, van der Harst, P, Vollenweider, P, Wallaschofski, H, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Heid, I, Hunter, D, Kaplan, R, Karpe, F, Moffatt, M, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, Van, D, Cm, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Scherag, A, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Medical Research Council (MRC), Berndt, Sonja I, Gustafsson, Stefan, Mägi, Reedik, Ganna, Andrea, Lee, Sang Hong, Hyppönen, Elina Tuulikki, Ingelsson, Erik, Berndt, Si, Feitosa, Mf, Justice, Ae, Monda, Kl, CROTEAU CHONKA, Dc, Day, Fr, Jackson, Au, Randall, Jc, Willer, Cj, Winkler, Tw, Wood, Ar, Hu, Yj, Lee, Sh, Lin, Dy, Min, Jl, Neale, Bm, BRAGG GRESHAM, Jl, DEN HEIJER, M, Hottenga, Jj, Huffman, Je, Johansson, A, Kleber, Me, König, Ir, Mcardle, Wl, MEDINA GOMEZ, C, MÜLLER NURASYID, M, Nolte, Im, Peters, Mj, Rose, Lm, Smith, Av, Strawbridge, Rj, Trip, Md, VAN VLIET OSTAPTCHOUK, Jv, Waite, Ll, Zhao, Jh, Asselbergs, Fw, Attwood, Ap, Balmforth, Aj, Bonnycastle, Ll, Chasman, Di, Connell, Jm, Cookson, Wo, DE FAIRE, U, DE VEGT, F, Evans, Dm, Ferrario, Mm, Gejman, Pv, Hartikainen, Al, HEARD COSTA, Nl, Heath, Ac, Hu, Fb, Hunt, Se, Jacobs, Kb, Jansson, Jo, Khaw, Kt, Kraja, At, Laitinen, Jh, Lakka, Ta, Launer, Lj, Lokki, Ml, Madden, Pa, Magnusson, Pk, Manunta, Paolo, MATEO LEACH, I, Medland, Se, Montgomery, Gw, Mühleisen, Tw, Munroe, Pb, Musk, Aw, Nohr, Ea, Ong, Kk, Oostra, Ba, Palmer, Cn, Peden, Jf, Pramstaller, Pp, Saaristo, Te, Sambrook, Jg, Sanders, Ar, Shin, Sy, Stephens, Jc, Stolk, Rp, Swift, Aj, Theodoraki, Ev, Tregouet, Da, VAN DER KLAUW, Mm, VAN MEURS, Jb, Vermeulen, Sh, Wild, Sh, Winkelmann, Br, Witteman, Jc, Wolffenbuttel, Bh, Wright, Af, Zillikens, Mc, Boehm, Bo, Boomsma, Di, Caulfield, Mj, Chanock, Sj, Cupples, La, Dedoussis, Gv, Eriksson, Jg, Franks, Pw, Harris, Tb, Hicks, Aa, Hovingh, Kg, Jarvelin, Mr, Jöckel, Kh, KEINANEN KIUKAANNIEMI, Sm, Kiemeney, La, Levinson, Df, Martin, Ng, Morris, Ad, Oldehinkel, Aj, Ouwehand, Wh, Palmer, Lj, Province, Ma, Psaty, Bm, Ridker, Pm, Samani, Nj, Sørensen, Ti, Spector, Td, Uitterlinden, Ag, VAN DER HARST, P, Wareham, Nj, Wichmann, He, Wilson, Jf, Abecasis, Gr, Assimes, Tl, Borecki, Ib, Groop, Lc, Heid, Im, Kaplan, Rc, Moffatt, Mf, Mohlke, Kl, O'Connell, Jr, Schadt, Ee, Strachan, Dp, VAN DUIJN, Cm, Visscher, Pm, DI BLASIO, Am, Hirschhorn, Jn, Lindgren, Cm, Morris, Ap, Mccarthy, Mi, Speliotes, Ek, North, Ke, Loos, Rj, and Ingelsson, E.

Subjects
Netherlands Twin Register (NTR), Linkage disequilibrium, SORTILIN, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Medizin, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], polymorphism, Body Mass Index, 0302 clinical medicine, Missing heritability problem, MISSING HERITABILITY, EXTREME OBESITY, CONFER RISK, POPULATION, Genetics & Heredity, 2. Zero hunger, Genetics, Medical And Health Sciences, 0303 health sciences, education.field_of_study, Anthropometry, COMMON VARIANTS, Single Nucleotide, ASSOCIATION, Biological Sciences, Anthropometry, Body Height, genetics, Body Mass Index, Case-Control Studies, European Continental Ancestry Group, genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity, genetics, Phenotype, Polymorphism, genetics, Quantitative Trait Loci, Waist-Hip Ratio, Phenotype, Life Sciences & Biomedicine, EXPRESSION, Genotype, Missing heritabillity, Population, European Continental Ancestry Group, Quantitative Trait Loci, EARLY-ONSET, Genomics, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Obesity, body height/genetics, Polymorphism, Allele, Genetik, education, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Science & Technology, Waist-Hip Ratio, BMI, height, WHR, obesity, GWS, ta3121, Genetic architecture, Body Height, BODY-MASS INDEX, Case-Control Studies, gene, stature, height, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. © 2013 Nature America, Inc. All rights reserved.

Published
2013

47. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Author

Andrew A. Hicks, Han Chen, Anders Franco-Cereceda, Vilmundur Gudnason, David M. Evans, May E. Montasser, Ulf de Faire, Jeanette S. Andrews, Rainer Rauramaa, Ching-Ti Liu, Michael Boehnke, Panos Deloukas, Naveed Sattar, Jacques S. Beckmann, Marcus E. Kleber, Hanneke Basart, Bruna Gigante, Göran Hallmans, Francis S. Collins, Toshiko Tanaka, Stella Trompet, Kathleen Stirrups, Jula Antti, Ryan P. Welch, Sirkka Keinänen-Kiukaanniemi, Jaakko Kaprio, T. Saaristo, Jeffrey R. O'Connell, Bernhard O. Boehm, Eleanor Wheeler, Kijoung Song, John Beilby, Michael A. Province, Inga Prokopenko, Ping An, Dawn M. Waterworth, Nita G. Forouhi, Nicholas J. Timpson, George Dedoussis, Fernando Rivadeneira, Winfried Maerz, Anneli Pouta, Anuj Goel, Jackie F. Price, Sarah Edkins, Markus Perola, Inês Barroso, Albertine J. Oldehinkel, Igor Rudan, Peter Vollenweider, Philippe Froguel, Richard M. Watanabe, Kari E. North, Dorret I. Boomsma, Harry Campbell, G. Kees Hovingh, Paul C. D. Johnson, Cécile Lecoeur, Vasiliki Lagou, Denis Rybin, Pierre Meneton, Soumya Raychaudhuri, Jian'an Luan, Neil Robertson, Andrew P. Morris, Veikko Salomaa, Anubha Mahajan, Beate St Pourcain, Robert A. Scott, Evelin Mihailov, Gerard R Fowkes, Nancy L. Pedersen, Susan Campbell, Sonia Shah, Veronique Vitart, Mustafa Atalay, Richard N. Bergman, Ross M. Fraser, Anders Hamsten, Benjamin F. Voight, Wolfgang Rathmann, Christian Gieger, James F. Wilson, Wieland Kiess, Marcel Bruinenberg, Serge Hercberg, Ian Ford, James B. Meigs, Tibor V. Varga, George Davey Smith, Josée Dupuis, Stefania Bandinelli, John F. Peden, Mika Kivimäki, J. Wouter Jukema, Michael Stumvoll, Caroline Hayward, Emil Rehnberg, Ozren Polasek, Letizia Marullo, Andrew D. Morris, Brenda W.J.H. Penninx, Lori L. Bonnycastle, Jouke-Jan Hottenga, Martin Farrall, Albert V. Smith, Rona J. Strawbridge, Ingrid B. Borecki, Kari Stefansson, Kirsten Ohm Kyvik, Harald Grallert, Alan James, Tim D. Spector, Paul W. Franks, Lasse Folkersen, Sara M. Willems, Stephan J. L. Bakker, Iva Miljkovic, Nigel W. Rayner, Tamara B. Harris, Momoko Horikoshi, Linda S. Adair, Christian Herder, Tõnu Esko, Thomas Illig, Alan R. Shuldiner, Ruth J. F. Loos, Serena Sanna, Massimo Mangino, Alex S. F. Doney, Hugh Watkins, Erik Ingelsson, Colin N. A. Palmer, Pau Navarro, Claudia Langenberg, Mark I. McCarthy, Johanna Kuusisto, Anne U. Jackson, Martina Müller-Nurasyid, Perttu Salo, Ying Wu, Alan F. Wright, Lars Lind, Johannes H. Smit, Gonneke Willemsen, Stefan R. Bornstein, Jennie Hui, Peter Schwarz, Anke Toenjes, Albert Hofman, Markku Laakso, Maria Dimitriou, Marjo-Riitta Järvelin, Aaron Isaacs, Hyun Min Kang, James S. Pankow, Annette Peters, André G. Uitterlinden, Loic Yengo, Beverley Balkau, Augustine Kong, Toby Johnson, Cornelia M. van Duijn, Luigi Ferrucci, Samuli Ripatti, Mulas Antonella, Aroon D. Hingorani, Meena Kumari, Nicholas J. Wareham, Sarah H. Wild, Patricia B. Munroe, Nicholas D. Hastie, Stefan Gustafsson, Kerrin S. Small, Cecilia M. Lindgren, Jennifer L. Bolton, Matti Uusitupa, Peter P. Pramstaller, Tove Fall, Patricia A. Peyser, Dmitry Shungin, Yongmei Liu, Patrik K. E. Magnusson, Jaakko Tuomilehto, Francesco Cucca, Reedik Mägi, Karen L. Mohlke, Gudmar Thorleifsson, Hanneke Jansen, Mark J. Caulfield, Tanya M. Teslovich, Timo A. Lakka, Heather M. Stringham, Bruce M. Psaty, Niek Verweij, Heikki Oksa, Wei Zhao, Andres Metspalu, Jaana Lindström, Stavroula Kanoni, Bengt Sennblad, Carlo Sidore, Eco J. C. de Geus, Ben A. Oostra, Lawrence F. Bielak, Peter Kovacs, Laura J. Rasmussen-Torvik, Tatijana Zemunik, Jose C. Florez, Antje Körner, Pim van der Harst, Ramaiah Nagaraja, Peter S. Chines, Nabila Bouatia-Naji, Addenbrooke's Hospital, Wellcome Trust Ctr Human Genet, University of Oxford [Oxford], Michigan State University [East Lansing], Michigan State University System, Wellcome Trust Sanger Inst, Partenaires INRAE, University of Maryland [College Park], University of Maryland System, University of Tartu, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], The Wellcome Trust Sanger Institute [Cambridge], Northwestern University [Evanston], Université Lille Nord de France (COMUE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Lund University [Lund], Umeå University, Consiglio Nazionale delle Ricerche (CNR), Istituto di Virologia Vegetale, Università degli studi di Torino (UNITO), Università degli Studi di Sassari, University of Glasgow, Netherlands Heart Institute, Leiden University, Queen Mary University of London (QMUL), University of Groningen, deCODE genetics [Reykjavik], Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), (IGE3 Inst Genet & Genom Geneva), University College of London [London] (UCL), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Natl Inst Hlth & Welf, University of Helsinki, University of Bristol [Bristol], North Carolina State University, Center for High Performance Simulation and Department of Chemical and Biomolecular Engineering, Wake Forest School of Medicine, Sir Charles Gairdner Hospital, University of Western Australia, PathW Lab Med WA, University of Edinburgh, Centre for Medical Systems Biology, Erasmus University Rotterdam, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Pennyslvania, Brigham and Women's Hospital, Boston University [Boston] (BU), Dept Med Genet, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire Vaudois (CHUV), National Human Genome Research Institute (NHGRI), GlaxoSmithKline, National Institute on Aging, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), National Institutes of Health [N01-AG-1-2100], National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), Althingi (the Icelandic Parliament), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Medical Research Council (MRC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Chemistry, Child and Adolescent Psychiatry / Psychology, Dermatology, Internal Medicine, Clinical Genetics, and VU University Amsterdam

Subjects
Netherlands Twin Register (NTR), Blood Glucose, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Genome-wide association study, Type 2 diabetes, Fasting/blood, Mice, 0302 clinical medicine, DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, Gene Frequency, Insulin, GENETICS & HEREDITY, Genetics, 0303 health sciences, INSULIN-RESISTANCE, Metabolic Networks and Pathways/genetics, gene, glucose, glycemic, GLUCOSE-METABOLISM, 11 Medical And Health Sciences, Fasting, CARDIOVASCULAR-DISEASE, SKELETAL-MUSCLE, Female, Life Sciences & Biomedicine, Metabolic Networks and Pathways, Adult, SUSCEPTIBILITY LOCI, Quantitative Trait Loci, 030209 endocrinology & metabolism, Blood Glucose/genetics, KAPPA-B, Quantitative trait locus, Biology, Article, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Genome-Wide Association Study/statistics & numerical data, Quantitative Trait Loci/physiology, KLOTHO GENE POLYMORPHISMS, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, Allele frequency, 030304 developmental biology, Glycemic, Science & Technology, Osmolar Concentration, 06 Biological Sciences, medicine.disease, BODY-MASS INDEX, BINDING-PROTEIN-ALPHA, Insulin/blood, Developmental Biology, Genome-Wide Association Study
Abstract

Seuls les auteurs INRA et les 100 premiers auteurs figurent sur la notice. Group Authors : DIAbet Genetics Replication traits and provide insight into the underlying biological pathways La liste complète des auteurs et de leurs affiliations des auteurs est disponible sur la publication, p. 1004-1005, à l'adresse suivante : https://www.nature.com/articles/ng.2385.pdf; International audience; Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Published
2012

48. No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels

Author

Daniel R. Witte, Han Chen, Lori L. Bonnycastle, Mette Aadahl, Olga D. Carlson, Josée Dupuis, Yii-Der Ida Chen, Tanya M. Teslovich, Richard M. Watanabe, Frida Renström, John W. Holloway, Meena Kumari, Michael Boehnke, Audrey Y. Chu, Robert A. Scott, Alisa K. Manning, Ajay Yesupriya, Anke Tönjes, Niels Grarup, Ingegerd Johansson, Nita G. Forouhi, Inês Barroso, Aroon D. Hingorani, Dmitry Shungin, Mika Kivimäki, Weijia Xie, David Couper, Diana Marek, Peter Schwarz, Torben Hansen, Jose C. Florez, Camilla H. Sandholt, Philippe Froguel, Leif Groop, Vasiliki Lagou, Johanna Kuusisto, W. H. Linda Kao, Suzannah Bumpstead, Nabila Bouatia-Naji, Inga Prokopenko, Peter Kovacs, Zoltán Kutalik, Eric Boerwinkle, Kenneth Rice, Michael R. Erdos, Gabriele Müller, Claire Levy-Marchal, Alena Stančáková, Jürgen Grässler, Erik Ingelsson, Mario A. Morken, Gerard Waeber, Eric J. Brunner, Ulf Ekelund, Luigi Ferrucci, Francis S. Collins, Mark Walker, Laura J. Rasmussen-Torvik, Markku Laakso, Stefan Gustafsson, Stefan R. Bornstein, Guo Li, Dan E. Arking, Torben Jørgensen, Peter Vollenweider, Peter Shrader, Michael Stumvoll, Mark O. Goodarzi, Oluf Pedersen, Avan Aihie Sayer, Heather M. Stringham, Bruce M. Psaty, Claudia Langenberg, Soren Brage, Ruth J. F. Loos, David S. Siscovick, Denis Rybin, Gordon H. Williams, Caroline S. Fox, Sven Bergmann, Felicity Payne, James B. Meigs, Marie-France Hivert, Nicole L. Glazer, Jerome I. Rotter, Elaine M. Dennison, Andrew R. Wood, Göran Hallmans, Nicole F. Dowling, Peter S. Chines, Cyrus Cooper, Josephine S. Egan, Paul W. Franks, Frank B. Hu, Michael Marmot, Pedro Marques-Vidal, Kari E. North, James S. Pankow, Valeri Lyssenko, Cécile Lecoeur, Toshiko Tanaka, Daniel R. Barnes, Nicholas J. Wareham, Anna Jonsson, Bo Isomaa, Anne U. Jackson, Karen A. Jameson, Barnes, Daniel [0000-0002-3781-7570], Brage, Soren [0000-0002-1265-7355], Forouhi, Nita [0000-0002-5041-248X], Barroso, Ines [0000-0001-5800-4520], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)

Subjects
Blood Glucose, medicine.medical_specialty, DIABETES PREVENTION PROGRAM, ENDOCRINOLOGY & METABOLISM, Genotype, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Physical exercise, Single-nucleotide polymorphism, PROGRESSION, Type 2 diabetes, Biology, Motor Activity, Polymorphism, Single Nucleotide, Body Mass Index, Epigenesis, Genetic, 03 medical and health sciences, TYPE-2, MELLITUS, 0302 clinical medicine, Polymorphism (computer science), Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Allele, Life Style, POLYMORPHISMS, 030304 developmental biology, Genetic association, RISK, 0303 health sciences, ENVIRONMENT, Science & Technology, COMMON VARIANTS, Genetics/Genomes/Proteomics/Metabolomics, 11 Medical And Health Sciences, medicine.disease, Endocrinology, Gene Expression Regulation, LIFE-STYLE INTERVENTION, Body mass index, Life Sciences & Biomedicine, TRAITS
Abstract

Gene–lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13–0.31], P = 1.63 × 10−6). All SNPs were associated with 2-h glucose (β = 0.06–0.12 mmol/allele, P ≤ 1.53 × 10−7), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene–lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

Published
2012

49. On the Futility of Screening for Genes That Make You Fat

Author

Terho Lehtimäki, Emily Sonestedt, Göran Hallmans, Andy R Ness, Simin Liu, Tuija Tammelin, John J. Nolan, Massimo Mangino, Nicholas J. Timpson, George Dedoussis, Aline Meirhaeghe, Lu Qi, Pål R. Njølstad, Ruth J. F. Loos, Mustafa Atalay, Mao Fu, Natalia V. Rivera, Marju Orho-Melander, Thorkild I. A. Sørensen, Philippe Froguel, André G. Uitterlinden, Torben Hansen, Debbie A Lawlor, M. Carola Zillikens, Tapani Rönnemaa, Vilmundur Gudnason, Esther Zimmermann, Claes Ohlsson, Cornelia M. van Duijn, Paul M. Ridker, Marjo-Riitta Järvelin, Samia Mora, María Teresa Martínez Larrad, Alena Stančáková, Thomas Illig, Zoltán Kutalik, Sven Bergmann, Jonatan R. Ruiz, Luigi Palla, Kathleen A. Jablonski, Günther Silbernagel, Ulla Sovio, Soren Snitker, Karina Meidtner, Bo Isomaa, Stephen J. Sharp, Jana V. van Vliet-Ostaptchouk, Louis Pérusse, Mika Kähönen, Daniel I. Chasman, Najaf Amin, Johanna Kuusisto, Toshiko Tanaka, Ingrid B. Borecki, John-Olov Jansson, Christine Cavalcanti-Proença, N. Charlotte Onland-Moret, Kay-Tee Khaw, Camilla H. Sandholt, Ulf Ekelund, Luigi Ferrucci, Mark Walker, Yiqing Song, Jose C. Florez, Oluf Pedersen, Leif Groop, Ying Wu, Soren Brage, Tuomas O. Kilpeläinen, Anders Grøntved, Frida Renström, Meena Kumari, Stéphane Cauchi, Michael Boehnke, Tamara B. Harris, Christine S. Autenrieth, Jeffery Metter, Beverley Balkau, Dmitry Shungin, Karen L. Mohlke, Markku Laakso, Matti Uusitupa, Nicholas J. Wareham, Andreas Fritsche, Jaakko Tuomilehto, Albert Hofman, Shah Ebrahim, Mary F. Feitosa, Melissa E. Garcia, Stefan Johansson, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Frank B. Hu, Jonathan T. Tan, Maarit Hakanen, Heiner Boeing, Manuel Serrano Ríos, Olli T. Raitakari, Michael Marmot, Meian He, Jennifer L. Bragg-Gresham, Claude Bouchard, Tariq Ahmad, Ellen W. Demerath, Keri L. Monda, Robert A. Scott, Marika Kaakinen, Chris Power, Stefania Bandinelli, Christina Holzapfel, Timo A. Lakka, Heather M. Stringham, Stavroula Kanoni, Elina Hyppönen, Pamela L. Lutsey, Internal Medicine, Medical Microbiology & Infectious Diseases, Epidemiology, Urology, Institute of Metabolic Science, MRC, Departments of Epidemiology and Nutrition, Harvard School of Public Health, Department of Clinical Sciences, Lund University Diabetes Centre-Lund University [Lund], Division of Epidemiology and Community Health, University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Division of Cardiology, Duke University Medical Center, Brigham and Women's Hospital [Boston], Institute of Health Sciences and Biocenter Oulu, University of Oulu, Hagedorn Research Institute, Else Kroener Fresenius Centre - Zentralinstitut für Ernährungs und Lebensmittelfors (ZIEL), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Department of Population Health Sciences, University of Wisconsin-Madison, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre for Paediatric Epidemiology and Biostatistics, University College of London [London] (UCL), MRC Centre for Epidemiology of Child Health, UCL Institute of Child Health, Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Genetics, Université de Lausanne (UNIL), Department of Epidemiology and Public Health, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Department of Epidemiology, Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association-Leibniz Association, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National University of Singapore (NUS)-Yong Loo Lin School of Medicine, King‘s College London, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, Division of Preventive Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), The Biostatistics Center, The George Washington University (GW), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Mental Health Sciences Unit, Department of Clinical Medicine, University of Bergen (UiB), Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Genetics, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Complex Genetics Section, University Medical Center [Utrecht], Julius Center for Health Sciences and Primary Care, Institute of Preventive Medicine, Copenhagen University Hospital, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Genetic Epidemiology Unit, Medstar Research Institute, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Department of Nutrition-Dietetics, Harokopio University of Athens, Division of Statistical Genomics, Washington University School of Medicine, University of Maryland School of Medicine, University of Maryland System, Unit for Preventive Nutrition, Karolinska Institutet [Stockholm], Department of Physical Education and Sport, University of Granada [Granada], Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Hospital Clínico San Carlos, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Institute of Sport Science and Clinical Biomechanics, University of Southern Denmark (SDU), Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU)-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Clinical Physiology, University of Tampere [Finland]-Tampere University Hospital, Steno Diabetes Centre, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health Sciences, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Odontology, Department of Medical Statistics, London School of Hygiene and Tropical Medicine (LSHTM), LIKES Research Center for Sport and Health Sciences, Finnish Institute of Occupational Health, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Human Genomics Laboratory, Pennington Biomedical Research Center, Louisiana State University (LSU)-Louisiana State University (LSU), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Division of Endocrinology, Diabetes and Nutrition, University of Maryland System-University of Maryland System, Institute of Cell and Molecular Biosciences, Newcastle University [Newcastle], Centre for Bone and Arthritis Research, Institute of Medicine-University of Gothenburg (GU), Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Centre for Medical Systems Biology, Faculty of Epidemiology and Population Health [London], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Department of Clinical Chemistry, Turku University Hospital (TYKS), Folkhälsan Research Centre, Department of Pediatrics, Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB), Center for Human Genetic Research and Diabetes Research Center, Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Program for Medical and Population Genetics, Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT)-Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Center for Metabolic Disease Prevention, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, School of Oral and Dental Sciences, University of Bristol [Bristol], National University of Singapore (NUS), Department of Genomics of Common Disease, Imperial College London, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Department of Epidemiology and Biostatistics, Department of Life Course and Services, National Institute for Health and Welfare [Helsinki], Autard, Delphine, Lund University [Lund], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Universidad de Granada = University of Granada (UGR), University of Gothenburg (GU)-Institute of Medicine, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), Medical Research Council (MRC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Brage, Soren [0000-0002-1265-7355], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Khaw, Kay-Tee [0000-0002-8802-2903], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Hjelt Institute (-2014), Harvard University-Massachusetts Institute of Technology (MIT)-Harvard University-Massachusetts Institute of Technology (MIT), Kilpeläinen, Tuomas O, Qi, Lu, Brage, Soren, Sharp, Stephen J, Hypponen, Elina, and Loos, Ruth JF

Subjects
Male, Heredity, endocrine system diseases, Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714 [VDP], Epidemiology, Social and Behavioral Sciences, no keywords, MESH: Genotype, 0302 clinical medicine, MESH: Child, GENETIC-VARIANTS, MESH: Proteins, 10. No inequality, Child, 0303 health sciences, Anthropometry, MESH: Polymorphism, Single Nucleotide, General Medicine, 11 Medical And Health Sciences, Genomics, MESH: Motor Activity, Adipose Tissue, Perspective, Medicine, Public Health, WAIST CIRCUMFERENCE, MESH: Adipose Tissue, medicine.medical_specialty, Genotype, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Endocrinology and Diabetes, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genomic Medicine, Genetics, Humans, Genetic Testing, Gene Prediction, Biology, Adipose Tissue/metabolism, Adolescent, Adult, Aged, Female, Genetic Predisposition to Disease, Motor Activity, Obesity/genetics, Obesity/metabolism, Polymorphism, Single Nucleotide, Proteins/genetics, Risk Factors, MESH: Adolescent, Science & Technology, MESH: Humans, Computational Biology, nutritional and metabolic diseases, Proteins, MESH: Adult, Odds ratio, medicine.disease, Obesity, RS9939609 POLYMORPHISM, Endocrinology, Anthropology, Physiological Processes, Body mass index, MESH: Female, Population Genetics, obesity, Genetic Screens, Anatomy and Physiology, FTO gene, IDENTICAL-TWINS, MESH: Risk Factors, MESH: Obesity, adolescents, 030212 general & internal medicine, MESH: Aged, MESH: Genetic Predisposition to Disease, 3142 Public health care science, environmental and occupational health, ENVIRONMENT INTERACTION, Genetic Epidemiology, childhood obesity, Life Sciences & Biomedicine, Research Article, Clinical Research Design, UNITED-STATES, WEIGHT-LOSS, Childhood obesity, body weight, Medicine, General & Internal, Genome Analysis Tools, Internal medicine, General & Internal Medicine, medicine, Allele, Sports and Exercise Medicine, Genetic Association Studies, 030304 developmental biology, Nutrition, Clinical Genetics, Population Biology, business.industry, Human Genetics, MESH: Male, COMMON VARIANT, meta-analysis, Minor allele frequency, BODY-MASS INDEX, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Genetics of Disease, Genetic Polymorphism, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Meta-Analyses, business, Energy Metabolism, genetic predisposition, DIABETES PREVENTION
Abstract

Ruth Loos and colleagues report findings from a meta-analysis of multiple studies examining the extent to which physical activity attenuates effects of a specific gene variant, FTO, on obesity in adults and children. They report a fairly substantial attenuation by physical activity on the effects of this genetic variant on the risk of obesity in adults., Background The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings All studies identified to have data on the FTO rs9939609 variant (or any proxy [r 2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (p interaction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents. Conclusions The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors' Summary, Editors’ Summary Background Two in three Americans are overweight, of whom half are obese, and the trend towards increasing obesity is now seen across developed and developing countries. There has long been interest in understanding the impact of genes and environment when it comes to apportioning responsibility for obesity. Carrying a change in the FTO gene is common (found in three-quarters of Europeans and North Americans) and is associated with a 20%–30% increased risk of obesity. Some overweight or obese individuals may feel that the dice are loaded and there is little point in fighting the fat; it has been reported that those made aware of their genetic susceptibility to obesity may still choose a poor diet. A similar fatalism may occur when overweight and obese people consider physical activity. But disentangling the influence of physical activity on those genetically susceptible to obesity from other factors that might impact weight is not straightforward, as it requires large sample sizes, could be subject to publication bias, and may rely on less than ideal self-reporting methods. Why Was This Study Done? The public health ramifications of understanding the interaction between genetic susceptibility to obesity and physical activity are considerable. Tackling the rising prevalence of obesity will inevitably include interventions principally aimed at changing dietary intake and/or increasing physical activity, but the evidence for these with regards to those genetically susceptible has been lacking to date. The authors of this paper set out to explore the interaction between the commonest genetic susceptibility trait and physical activity using a rigorous meta-analysis of a large number of studies. What Did the Researchers Do and Find? The authors were concerned that a meta-analysis of published studies would be limited both by the data available to them and by possible bias. Instead of this more widely used approach, they took the literature search as their starting point, identified other studies through their collaborators’ network, and then undertook a meta-analysis of all available studies using a new and standardized analysis plan. This entailed an extremely large number of authors mining their data afresh to extract the relevant data points to enable such a meta-analysis. Physical activity was identified in the original studies in many different ways, including by self-report or by using an external measure of activity or heart rate. In order to perform the meta-analysis, participants were labeled as physically active or inactive in each study. For studies that had used a continuous scale, the authors decided that the bottom 20% of the participants were inactive (10% for children and adolescents). Using data from over 218,000 adults, the authors found that carrying a copy of the susceptibility gene increased the odds of obesity by 1.23-fold. But the size of this influence was 27% less in the genetically susceptible adults who were physically active (1.22-fold) compared to those who were physically inactive (1.30-fold). In a smaller study of about 19,000 children, no such effect of physical activity was seen. What Do these Findings Mean? This study demonstrates that people who carry the susceptibility gene for obesity can benefit from physical activity. This should inform health care professionals and the wider public that the view of genetically determined obesity not being amenable to exercise is incorrect and should be challenged. Dissemination, implementation, and ensuring uptake of effective physical activity programs remains a challenge and deserves further consideration. That the researchers treated “physically active” as a yes/no category, and how they categorized individuals, could be criticized, but this was done for pragmatic reasons, as a variety of means of assessing physical activity were used across the studies. It is unlikely that the findings would have changed if the authors had used a different method of defining physically active. Most of the studies included in the meta-analysis looked at one time point only; information about the influence of physical activity on weight changes over time in genetically susceptible individuals is only beginning to emerge. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001116. This study is further discussed in a PLoS Medicine Perspective by Lennert Veerman The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States A more worldwide view is given by the World Health Organization The UK National Health Service website gives information on physical activity guidelines for different age groups, while similar information can also be found from US sources

Published
2011

50. Orthodontic treatment-related white spot lesions: a 14-year prospective quantitative follow-up, including bonding material assessment

Author

Alexandra Ioannidis Olsson, Maurits Persson, and Dmitry Shungin

Subjects
Male, Adolescent, Abrasion (medical), Treatment outcome, Acrylic Resins, Dentistry, Orthodontics, macromolecular substances, Dental Debonding, Dental Caries, Orthodontics, Corrective, Statistics, Nonparametric, Young Adult, Orthodontic Appliances, medicine, Humans, Fluorides, Topical, Prospective Studies, Prospective cohort study, Dental Enamel, Tooth Demineralization, business.industry, Follow up studies, Dental Bonding, medicine.disease, Cariostatic Agents, Treatment Outcome, Glass Ionomer Cements, White Spots, Female, business, Follow-Up Studies
Abstract

White spots (WS) related to orthodontic treatment are severe cariologic and cosmetic complications, but they are shown to be partially reduced by remineralization or abrasion in short-term follow-ups. In this prospective study, we quantitatively analyzed changes in WS in general and in treatment-related white spot lesions (WSL) during orthodontic treatment and at a 12-year follow-up after treatment. In addition, we quantitatively compared the effects of an acrylic bonding material vs a glass ionomer cement (GIC) on WSL.Sum areas of WS and WSL were calculated on scans of standardized photos of the vestibular surfaces of 4 teeth in consecutive orthodontic patients (median treatment time, 1.7 years) bonded with the 2 materials in a split-mouth design. Comparisons were made in 59 patients before treatment (BF), at debonding (T0), at 1 year (T1), and at 2 years (T2), and in 30 patients at a 12-year follow-up (T3) with the Friedman test followed by pairwise comparisons with the Wilcoxon matched-pairs signed rank test. Differences of the effects of acrylic vs GIC on the sum areas of WSL were tested for each observation period with the Mann-Whitney U test.Increases in the sum areas of WS and WSL from BF to T0 (P0.001) were followed by significant decreases at T1 (P0.001) and T2 (P0.01 for WS; P0.001 for WSL). Significant changes were also found in the sum areas for WS at T3 compared with T2 (P0.01), but not for WSL (P = 0.328). The sum areas of WS and WSL at T3 did not return to BF levels (P0.001). Sum areas of WSL were higher for surfaces bonded with acrylic compared with GIC for each observation period from BF to T2 (P0.001), and from T2 to T3 (P0.05).Although significantly reduced during the 12-year follow-up and significantly lower with the GIC than the acrylic material at bonding, WSL are a cariologic and cosmetic problem for many orthodontic patients.

Published
2009

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