Search

Your search keyword '"McCarthy, Mark I [0000-0002-4393-0510]"' showing total 6 results
Start Over Author "McCarthy, Mark I [0000-0002-4393-0510]" Topic male
6 results on '"McCarthy, Mark I [0000-0002-4393-0510]"'

1. Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts

Author

Atabaki-Pasdar, N, Ohlsson, M, Vinuela, A, Frau, F, Pomares-Millan, H, Haid, M, Jones, AG, Thomas, EL, Koivula, RW, Kurbasic, A, Mutie, PM, Fitipaldi, H, Fernandez, J, Dawed, AY, Giordano, GN, Forgie, IM, McDonald, TJ, Rutters, F, Cederberg, H, Chabanova, E, Dale, M, Masi, FD, Thomas, CE, Allin, KH, Hansen, TH, Heggie, A, Hong, M-G, Elders, PJM, Kennedy, G, Kokkola, T, Pedersen, HK, Mahajan, A, McEvoy, D, Pattou, F, Raverdy, V, Haussler, RS, Sharma, S, Thomsen, HS, Vangipurapu, J, Vestergaard, H, 't Hart, LM, Adamski, J, Musholt, PB, Brage, S, Brunak, S, Dermitzakis, E, Frost, G, Hansen, T, Laakso, M, Pedersen, O, Ridderstrale, M, Ruetten, H, Hattersley, AT, Walker, M, Beulens, JWJ, Mari, A, Schwenk, JM, Gupta, R, McCarthy, MI, Pearson, ER, Bell, JD, Pavo, I, Franks, PW, Epidemiology and Data Science, General practice, APH - Health Behaviors & Chronic Diseases, Amsterdam Reproduction & Development (AR&D), ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, APH - Aging & Later Life, Atabaki-Pasdar, Naeimeh [0000-0001-7229-1888], Ohlsson, Mattias [0000-0003-1145-4297], Viñuela, Ana [0000-0003-3771-8537], Pomares-Millan, Hugo [0000-0001-9245-4576], Haid, Mark [0000-0001-6118-1333], Jones, Angus G. [0000-0002-0883-7599], Thomas, E. Louise [0000-0003-4235-4694], Koivula, Robert W. [0000-0002-1646-4163], Kurbasic, Azra [0000-0002-1910-2619], Fitipaldi, Hugo [0000-0001-5352-2134], Dawed, Adem Y. [0000-0003-0224-2428], Forgie, Ian M. [0000-0002-8800-6145], Cederberg, Henna [0000-0003-2901-9373], Dale, Matilda [0000-0002-5788-7744], Masi, Federico De [0000-0003-4859-4170], Thomas, Cecilia Engel [0000-0001-6201-6380], Allin, Kristine H. [0000-0002-6880-5759], Hansen, Tue H. [0000-0001-5948-8993], Elders, Petra J. M. [0000-0002-5907-7219], Kennedy, Gwen [0000-0002-9856-3236], Kokkola, Tarja [0000-0002-3303-3912], Pedersen, Helle Krogh [0000-0001-9609-7377], Mahajan, Anubha [0000-0001-5585-3420], McEvoy, Donna [0000-0003-1546-5567], Häussler, Ragna S. [0000-0003-1664-8875], Vangipurapu, Jagadish [0000-0001-6657-2659], Vestergaard, Henrik [0000-0003-3090-269X], ‘t Hart, Leen M. [0000-0003-4401-2938], Brage, Soren [0000-0002-1265-7355], Frost, Gary [0000-0003-0529-6325], Hansen, Torben [0000-0001-8748-3831], Hattersley, Andrew T. [0000-0001-5620-473X], Mari, Andrea [0000-0002-1436-5591], Schwenk, Jochen M. [0000-0001-8141-8449], Gupta, Ramneek [0000-0001-6841-6676], McCarthy, Mark I. [0000-0002-4393-0510], Pearson, Ewan R. [0000-0001-9237-8585], Bell, Jimmy D. [0000-0003-3804-1281], Franks, Paul W. [0000-0002-0520-7604], Apollo - University of Cambridge Repository, HUS Abdominal Center, Clinicum, Department of Medicine, Endokrinologian yksikkö, Jones, Angus G [0000-0002-0883-7599], Thomas, E Louise [0000-0003-4235-4694], Koivula, Robert W [0000-0002-1646-4163], Dawed, Adem Y [0000-0003-0224-2428], Forgie, Ian M [0000-0002-8800-6145], Allin, Kristine H [0000-0002-6880-5759], Hansen, Tue H [0000-0001-5948-8993], Elders, Petra JM [0000-0002-5907-7219], Häussler, Ragna S [0000-0003-1664-8875], 't Hart, Leen M [0000-0003-4401-2938], Hattersley, Andrew T [0000-0001-5620-473X], Schwenk, Jochen M [0000-0001-8141-8449], McCarthy, Mark I [0000-0002-4393-0510], Pearson, Ewan R [0000-0001-9237-8585], Bell, Jimmy D [0000-0003-3804-1281], Franks, Paul W [0000-0002-0520-7604], and IMI

Subjects
Male, Proteomics, Oral Glucose Suppression Test, Biochemistry, Machine Learning, Fats, Database and Informatics Methods, Endocrinology, Medicine and Health Sciences, Insulin, Prospective Studies, 11 Medical and Health Sciences, GLOBAL EPIDEMIOLOGY, INSULIN SENSITIVITY, Proteomic Databases, Liver Diseases, Middle Aged, Lipids, Medicine, Female, Life Sciences & Biomedicine, Research Article, Computer and Information Sciences, Endocrine Disorders, BIOMARKERS, Gastroenterology and Hepatology, Research and Analysis Methods, Risk Assessment, Diabetes Complications, Medicine, General & Internal, SDG 3 - Good Health and Well-being, Artificial Intelligence, General & Internal Medicine, NAFLD, Diabetes Mellitus, Humans, Metabolomics, Diabetic Endocrinology, Pharmacology, Science & Technology, Models, Statistical, Reproducibility of Results, Biology and Life Sciences, ALCOHOLIC STEATOHEPATITIS, Hormones, Pharmacologic-Based Diagnostics, Fatty Liver, Metabolism, Biological Databases, 3121 General medicine, internal medicine and other clinical medicine, Metabolic Disorders
Abstract

Background Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. Methods and findings We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (, In a modelling study, Naeimeh Atabaki-Pasdar and colleagues apply machine learning techniques to develop models to predict non-alcoholic fatty liver disease diagnosis using multi-omic and clinical data from individuals with and without type 2 diabetes in the IMI DIRECT cohorts., Author summary Why was this study done? Globally, about 1 in 4 adults have non-alcoholic fatty liver disease (NAFLD), which adversely affects energy homeostasis (in particular blood glucose concentrations), blood detoxification, drug metabolism, and food digestion. Although numerous noninvasive tests to detect NAFLD exist, these typically include inaccurate blood-marker tests or expensive imaging methods. The purpose of this work was to develop accurate noninvasive methods to aid in the clinical prediction of NAFLD. What did the researchers do and find? The analyses applied machine learning methods to data from the deep-phenotyped IMI DIRECT cohorts (n = 1,514) to identify sets of highly informative variables for the prediction of NAFLD. The criterion measure was liver fat quantified from MRI. We developed a total of 18 prediction models that ranged from very inexpensive models of modest accuracy to more expensive biochemistry- and/or omics-based models with high accuracy. We found that models using measures commonly collected in either clinical settings or research studies proved adequate for the prediction of NAFLD. The addition of detailed omics data significantly improved the predictive utility of these models. We also found that of all omics markers, proteomic markers yielded the highest predictive accuracy when appropriately combined. What do these findings mean? We envisage that these new approaches to predicting fatty liver may be of clinical value when screening at-risk populations for NAFLD. The identification of specific molecular features that underlie the development of NAFLD provides novel insights into the disease’s etiology, which may lead to the development of new treatments.

Published
2020
Full Text
View/download PDF

2. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author

Cuellar-Partida, Gabriel, Tung, Joyce Y, Eriksson, Nicholas, Albrecht, Eva, Aliev, Fazil, Andreassen, Ole A, Barroso, Inês, Beckmann, Jacques S, Boks, Marco P, Boomsma, Dorret I, Boyd, Heather A, Breteler, Monique MB, Campbell, Harry, Chasman, Daniel I, Cherkas, Lynn F, Davies, Gail, de Geus, Eco JC, Deary, Ian J, Deloukas, Panos, Dick, Danielle M, Duffy, David L, Eriksson, Johan G, Esko, Tõnu, Feenstra, Bjarke, Geller, Frank, Gieger, Christian, Giegling, Ina, Gordon, Scott D, Han, Jiali, Hansen, Thomas F, Hartmann, Annette M, Hayward, Caroline, Heikkilä, Kauko, Hicks, Andrew A, Hirschhorn, Joel N, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Liang-Dar, Ikram, M Arfan, Kaprio, Jaakko, Kemp, John P, Khaw, Kay-Tee, Klopp, Norman, Konte, Bettina, Kutalik, Zoltan, Lahti, Jari, Li, Xin, Loos, Ruth JF, Luciano, Michelle, Magnusson, Sigurdur H, Mangino, Massimo, Marques-Vidal, Pedro, Martin, Nicholas G, McArdle, Wendy L, McCarthy, Mark I, Medina-Gomez, Carolina, Melbye, Mads, Melville, Scott A, Metspalu, Andres, Milani, Lili, Mooser, Vincent, Nelis, Mari, Nyholt, Dale R, O'Connell, Kevin S, Ophoff, Roel A, Palmer, Cameron, Palotie, Aarno, Palviainen, Teemu, Pare, Guillaume, Paternoster, Lavinia, Peltonen, Leena, Penninx, Brenda WJH, Polasek, Ozren, Pramstaller, Peter P, Prokopenko, Inga, Raikkonen, Katri, Ripatti, Samuli, Rivadeneira, Fernando, Rudan, Igor, Rujescu, Dan, Smit, Johannes H, Smith, George Davey, Smoller, Jordan W, Soranzo, Nicole, Spector, Tim D, Pourcain, Beate St, Starr, John M, Stefánsson, Hreinn, Steinberg, Stacy, Teder-Laving, Maris, Thorleifsson, Gudmar, Stefánsson, Kári, Timpson, Nicholas J, Uitterlinden, André G, van Duijn, Cornelia M, van Rooij, Frank JA, Vink, Jaqueline M, Vollenweider, Peter, Vuoksimaa, Eero, Waeber, Gérard, Wareham, Nicholas J, Warrington, Nicole, Waterworth, Dawn, Werge, Thomas, Wichmann, H-Erich, Widen, Elisabeth, Willemsen, Gonneke, Wright, Alan F, Wright, Margaret J, Xu, Mousheng, Zhao, Jing Hua, Kraft, Peter, Hinds, David A, Lindgren, Cecilia M, Mägi, Reedik, Neale, Benjamin M, Evans, David M, Medland, Sarah E, Cuellar-Partida, Gabriel [0000-0001-7648-4097], Aliev, Fazil [0000-0001-8357-4699], Andreassen, Ole A [0000-0002-4461-3568], Barroso, Inês [0000-0001-5800-4520], Beckmann, Jacques S [0000-0002-9741-1900], Boks, Marco P [0000-0001-6163-7484], Boomsma, Dorret I [0000-0002-7099-7972], Boyd, Heather A [0000-0001-6849-9985], Breteler, Monique MB [0000-0002-0626-9305], Chasman, Daniel I [0000-0003-3357-0862], de Geus, Eco JC [0000-0001-6022-2666], Deary, Ian J [0000-0002-1733-263X], Deloukas, Panos [0000-0001-9251-070X], Dick, Danielle M [0000-0002-1636-893X], Feenstra, Bjarke [0000-0003-1478-649X], Geller, Frank [0000-0002-9238-3269], Gordon, Scott D [0000-0001-7623-328X], Hansen, Thomas F [0000-0001-6703-7762], Hayward, Caroline [0000-0002-9405-9550], Hicks, Andrew A [0000-0001-6320-0411], Hirschhorn, Joel N [0000-0002-1650-7901], Hottenga, Jouke-Jan [0000-0002-5668-2368], Huffman, Jennifer E [0000-0002-9672-2491], Hwang, Liang-Dar [0000-0002-5535-2199], Ikram, M Arfan [0000-0003-0372-8585], Kaprio, Jaakko [0000-0002-3716-2455], Kemp, John P [0000-0002-9105-2249], Konte, Bettina [0000-0001-5287-308X], Kutalik, Zoltan [0000-0001-8285-7523], Lahti, Jari [0000-0002-4310-5297], Li, Xin [0000-0002-0135-8800], Loos, Ruth JF [0000-0002-8532-5087], Luciano, Michelle [0000-0002-7306-3008], Magnusson, Sigurdur H [0000-0001-6669-3071], Mangino, Massimo [0000-0002-2167-7470], Marques-Vidal, Pedro [0000-0002-4548-8500], Martin, Nicholas G [0000-0003-4069-8020], McArdle, Wendy L [0000-0002-0605-5403], McCarthy, Mark I [0000-0002-4393-0510], Medina-Gomez, Carolina [0000-0001-7999-5538], Melbye, Mads [0000-0001-8264-6785], Metspalu, Andres [0000-0002-3718-796X], Milani, Lili [0000-0002-5323-3102], Nelis, Mari [0000-0001-9748-1020], Nyholt, Dale R [0000-0001-7159-3040], O'Connell, Kevin S [0000-0002-6865-8795], Ophoff, Roel A [0000-0002-8287-6457], Palviainen, Teemu [0000-0002-7847-8384], Pare, Guillaume [0000-0002-6795-4760], Paternoster, Lavinia [0000-0003-2514-0889], Polasek, Ozren [0000-0002-5765-1862], Prokopenko, Inga [0000-0003-1624-7457], Ripatti, Samuli [0000-0002-0504-1202], Rivadeneira, Fernando [0000-0001-9435-9441], Rudan, Igor [0000-0001-6993-6884], Smit, Johannes H [0000-0002-2062-8378], Smith, George Davey [0000-0002-1407-8314], Smoller, Jordan W [0000-0002-0381-6334], Spector, Tim D [0000-0002-9795-0365], Pourcain, Beate St [0000-0002-4680-3517], Stefánsson, Hreinn [0000-0002-9331-6666], Steinberg, Stacy [0000-0001-7726-5152], Teder-Laving, Maris [0000-0002-5872-1850], Stefánsson, Kári [0000-0003-1676-864X], Timpson, Nicholas J [0000-0002-7141-9189], Uitterlinden, André G [0000-0002-7276-3387], van Rooij, Frank JA [0000-0002-8600-9852], Vink, Jaqueline M [0000-0003-3910-3528], Waeber, Gérard [0000-0003-4193-788X], Warrington, Nicole [0000-0003-4195-775X], Werge, Thomas [0000-0003-1829-0766], Wright, Margaret J [0000-0001-7133-4970], Zhao, Jing Hua [0000-0002-1463-5870], Kraft, Peter [0000-0002-4472-8103], Hinds, David A [0000-0002-4911-803X], Lindgren, Cecilia M [0000-0002-4903-9374], Neale, Benjamin M [0000-0003-1513-6077], Evans, David M [0000-0003-0663-4621], Medland, Sarah E [0000-0003-1382-380X], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Genetic Variation, Middle Aged, Polymorphism, Single Nucleotide, Functional Laterality, Linkage Disequilibrium, Quantitative Trait, Heritable, Sex Factors, Gene Frequency, Genetic Loci, Humans, Female, Aged, Genome-Wide Association Study
Abstract

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P

Published
2021

3. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author

David Torrents, Thorkild I. A. Sørensen, André G. Uitterlinden, Dorret I. Boomsma, Harry Campbell, Vasiliki Lagou, Joachim Heinrich, Anna Murray, Nicholas J. Timpson, George Dedoussis, Beverley M. Shields, Timo A. Lakka, Lawrence J. Beilin, Carmen J. Marsit, Katharina E. Schraut, Marie Standl, Torben Hansen, James F. Wilson, Jonas Bacelis, Allan Vaag, Louis J. Muglia, Wei Ang, Josep M. Mercader, Ruifang Li-Gao, Ying Wu, Jessica Tyrrell, Pål R. Njølstad, Mohammad Hadi Zafarmand, Marie-France Hivert, Ioanna Ntalla, Debbie A Lawlor, Martina Müller-Nurasyid, Alana Cavadino, Natalia Vilor-Tejedor, Andrew R. Wood, Zoltán Kutalik, Jodie N. Painter, Tanja G. M. Vrijkotte, Kyle J. Gaulton, Xavier Estivill, George Davey Smith, Christine Power, Andrew T. Hattersley, Berthold Hocher, Gibran Hemani, Sheila J. Barton, Aino-Maija Eloranta, Kathryn L. Lunetta, Kim F. Michaelsen, Frank Geller, Bjarke Feenstra, Carol A. Wang, Peter Vollenweider, Wieland Kiess, Anubha Mahajan, Elina Hyppönen, Elisabeth M. van Leeuwen, Felix R. Day, Natalie R. van Zuydam, Leda Chatzi, Bo L. Chawes, Antje Körner, Dennis O. Mook-Kanamori, Ken K. Ong, Joanne M. Murabito, David M. Hougaard, Jian'an Luan, Letizia Marullo, Catharina E. M. van Beijsterveldt, Yik Ying Teo, Andrew P. Morris, Sarah E. Medland, Juan Fernández-Tajes, Jouke-Jan Hottenga, Frits R. Rosendaal, Inga Prokopenko, Katja Pahkala, Struan F.A. Grant, Sylvain Sebert, Judith B. Borja, Camilla Schmidt Morgen, Charlotta Pisinger, Jia Chen, Øyvind Helgeland, Christian Theil Have, Vincent W. V. Jaddoe, Marjolein N. Kooijman, Mika Kähönen, Timothy M. Frayling, Diana L. Cousminer, Bo Jacobsson, Antoine H. C. van Kampen, Eco J. C. de Geus, Manolis Kogevinas, Rico Rueedi, Grant W. Montgomery, Raimo Joro, Craig E. Pennell, Jonathan P. Bradfield, Janine F. Felix, Ge Zhang, Loreto Santa-Marina, Kalliope Panoutsopoulou, John R. B. Perry, Jeff Murray, Albert Hofman, Terho Lehtimäki, John W. Holloway, Barbera D. C. van Schaik, Pedro Marques-Vidal, Ronny Myhre, Haja N. Kadarmideen, Robert A. Scott, Frank D. Mentch, Katherine S. Ruth, Hans Bisgaard, Marjo-Riitta Järvelin, Catherine Allard, Rachel M. Freathy, Julie A. Marsh, Mariona Bustamante, Elisabeth Thiering, Cæcilie Trier, Marcus A. Tuke, William L. Lowe, Elisabeth Widen, Caroline L Relton, Christoph Reichetzeder, Penelope A. Lind, M. Geoffrey Hayes, Charles Laurin, Tarunveer S. Ahluwalia, Meike Bartels, Mads Melbye, Claudia Langenberg, Ke Hao, Shouneng Peng, Nicholas J. Wareham, Susan M. Ring, Hamdi Mbarek, Mario Murcia, Jing Hua Zhao, Michael Nodzenski, Cornelia M. van Duijn, Hakon Hakonarson, Hanieh Yaghootkar, Po-Ru Loh, Linda S. Adair, Sílvia Bonàs-Guarch, Eleftheria Zeggini, Sarah Metrustry, Shikta Das, Gonneke Willemsen, Ana Espinosa, Lavinia Paternoster, Marc Vaudel, Theresia M. Schnurr, Michael Stumvoll, David M. Evans, Bridget A. Knight, Luigi Bouchard, Robin N Beaumont, Mustafa Atalay, Zhen Qiao, Denise M. Scholtens, Klaus Bønnelykke, Samuel E. Jones, Peter K. Joshi, Oluf Pedersen, Jin-Fang Chai, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Rebecca K. Vinding, Hazel Inskip, Sara M. Willems, Cilius Esmann Fonvig, Momoko Horikoshi, Ellen A. Nohr, Jani Heikkinen, Emil V. R. Appel, Niels Grarup, Michael N. Weedon, Rebecca C Richmond, Peter Kovacs, Jorma Viikari, Amanda J. Bennett, Jens-Christian Holm, Carolina Medina-Gomez, Nicole M. Warrington, Anke Tönjes, Jakob Stokholm, Hugoline G. de Haan, Seang-Mei Saw, Ville Huikari, N. William Rayner, Johan G. Eriksson, Niina Pitkänen, Allan Linneberg, Gunn-Helen Moen, Olli T. Raitakari, Martine Vrijheid, Neil Robertson, Stefan Johansson, Tim D. Spector, Friman Sánchez, Mark I. McCarthy, Harri Niinikoski, Karen L. Mohlke, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Hypponen, E, Freathy, RM, EGG consortium, Medical and Clinical Psychology, University of Helsinki, Johan Eriksson / Principal Investigator, University of Helsinki, Institute for Molecular Medicine Finland, Warrington, Nicole M [0000-0003-4195-775X], Beaumont, Robin N [0000-0003-0750-8248], Day, Felix R [0000-0003-3789-7651], Helgeland, Øyvind [0000-0002-5612-2985], Laurin, Charles [0000-0003-2439-9004], Bacelis, Jonas [0000-0002-2450-732X], Feenstra, Bjarke [0000-0003-1478-649X], Mahajan, Anubha [0000-0001-5585-3420], Moen, Gunn-Helen [0000-0002-8768-0904], Schnurr, Theresia M [0000-0002-6573-4959], Grarup, Niels [0000-0001-5526-1070], Paternoster, Lavinia [0000-0003-2514-0889], Rueedi, Rico [0000-0002-6713-2214], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Metrustry, Sarah [0000-0003-2028-7486], Wang, Carol A [0000-0002-4301-3974], Joshi, Peter K [0000-0002-6361-5059], Pitkänen, Niina [0000-0001-7383-4987], Richmond, Rebecca C [0000-0003-0574-5071], Inskip, Hazel M [0000-0001-8897-1749], Holloway, John W [0000-0001-9998-0464], Estivill, Xavier [0000-0002-0723-2256], Hocher, Berthold [0000-0001-8143-0579], Lunetta, Kathryn L [0000-0002-9268-810X], Allard, Catherine [0000-0002-8829-4984], Muglia, Louis J [0000-0002-0301-8770], van Kampen, Antoine HC [0000-0003-1025-7232], van Schaik, Barbera DC [0000-0002-5568-8127], Langenberg, Claudia [0000-0002-5017-7344], Hemani, Gibran [0000-0003-0920-1055], Gaulton, Kyle J [0000-0003-1318-7161], Medina-Gomez, Carolina [0000-0001-7999-5538], Kutalik, Zoltán [0000-0001-8285-7523], Marques-Vidal, Pedro [0000-0002-4548-8500], Mbarek, Hamdi [0000-0002-1108-0371], Müller-Nurasyid, Martina [0000-0003-3793-5910], Appel, Emil VR [0000-0001-7704-6611], Fonvig, Cilius E [0000-0002-5031-0125], Hougaard, David M [0000-0001-5928-3517], Mercader, Josep M [0000-0001-8494-3660], Linneberg, Allan [0000-0002-0994-0184], Lind, Penelope A [0000-0002-3887-2598], Medland, Sarah E [0000-0003-1382-380X], Bartels, Meike [0000-0002-9667-7555], Stokholm, Jakob [0000-0003-4989-9769], Chawes, Bo L [0000-0001-6846-6243], Kovacs, Peter [0000-0002-0290-5423], Prokopenko, Inga [0000-0003-1624-7457], Tuke, Marcus A [0000-0003-0008-9263], Ruth, Katherine S [0000-0003-4966-9170], Jones, Samuel E [0000-0003-0153-922X], Zeggini, Eleftheria [0000-0003-4238-659X], Wilson, James F [0000-0001-5751-9178], Vrijkotte, Tanja GM [0000-0003-3641-4048], de Geus, Eco JCN [0000-0001-6022-2666], Kadarmideen, Haja N [0000-0001-6294-382X], Mohlke, Karen L [0000-0001-6721-153X], Sørensen, Thorkild IA [0000-0003-4821-430X], Bisgaard, Hans [0000-0003-4131-7592], Bønnelykke, Klaus [0000-0003-2003-1018], Melbye, Mads [0000-0001-8264-6785], Rivadeneira, Fernando [0000-0001-9435-9441], Felix, Janine F [0000-0002-9801-5774], Jaddoe, Vincent WV [0000-0003-2939-0041], Hansen, Torben [0000-0001-8748-3831], Hyppönen, Elina [0000-0003-3670-9399], Davey Smith, George [0000-0002-1407-8314], Morris, Andrew P [0000-0002-6805-6014], Hakonarson, Hakon [0000-0003-2814-7461], Grant, Struan FA [0000-0003-2025-5302], Lawlor, Debbie A [0000-0002-6793-2262], Njølstad, Pål R [0000-0003-0304-6728], Ong, Ken K [0000-0003-4689-7530], McCarthy, Mark I [0000-0002-4393-0510], Evans, David M [0000-0003-0663-4621], Freathy, Rachel M [0000-0003-4152-2238], Apollo - University of Cambridge Repository, Department of Medical and Clinical Genetics, Institute for Molecular Medicine Finland, Neuroscience Center, Doctoral Programme Brain & Mind, Ecology and Evolutionary Biology, University of Helsinki, Research Groups, Department of General Practice and Primary Health Care, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Doctoral Programme in Clinical Research, Doctoral Programme in Oral Sciences, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, University Management, Epidemiology, Erasmus MC other, Internal Medicine, Pediatrics, Epidemiology and Data Science, APH - Global Health, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, ARD - Amsterdam Reproduction and Development, Experimental Immunology, Public and occupational health, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Male, Netherlands Twin Register (NTR), LD SCORE REGRESSION, Birth Weight/genetics, Physiology, Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, Type 2 diabetes, DISEASE, Fetal Development, 0302 clinical medicine, Models, Pregnancy, Risk Factors, Genotype, Birth Weight, maternal genetic, 030212 general & internal medicine, Maternal-Fetal Exchange, 0303 health sciences, Body Height/genetics, 1184 Genetics, developmental biology, physiology, Heart Diseases/etiology, Single Nucleotide, ASSOCIATION, Metabolic Diseases/etiology, 3. Good health, Type 2/etiology, MENDELIAN RANDOMIZATION, GROWTH, Female, Maternal Inheritance, Maternal Inheritance/genetics, Adult, Blood Pressure/genetics, Heart Diseases, Offspring, Birth weight, cardio-metabolic health outcomes, Biology, Diabetes Mellitus, Type 2/etiology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic, Metabolic Diseases, SDG 3 - Good Health and Well-being, Diabetes mellitus, Mendelian randomization, Genetics, medicine, Diabetes Mellitus, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Glycemic, Fetus, IDENTIFICATION, Models, Genetic, Infant, Newborn, Infant, birth weight, DIABETES-MELLITUS, medicine.disease, Newborn, Fetal Development/genetics, Body Height, Maternal-Fetal Exchange/genetics, LIFE, Blood pressure, Diabetes Mellitus, Type 2, ORIGINS, Institut für Ernährungswissenschaft, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

Published
2019
Full Text
View/download PDF

4. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Couto Alves, Alexessander, De Silva, N Maneka G, Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H Rob, Warrington, Nicole M, Lewin, Alexandra M, Kaakinen, Marika, Cousminer, Diana L, Thiering, Elisabeth, Timpson, Nicholas J, Bond, Tom A, Lowry, Estelle, Brown, Christopher D, Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P, Geller, Frank, Speed, Doug, Coin, Lachlan J M, Loh, Marie, Barton, Sheila J, Beilin, Lawrence J, Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J, Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique A J, Van Duijn, Cornelia M, Moltchanova, Elena, Eriksson, Johan G, Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M, Freathy, Rachel M, Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T, Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W, Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M, Hedman, Asa K, Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A, Lawlor, Debbie A, Melbye, Mads, Ahluwalia, Tarunveer S, Marinelli, Marcella, Millwood, Iona Y, Palmer, Lyle J, Pennell, Craig E, Perry, John R, Ring, Susan M, Savolainen, Markku J, Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M T, Uitterlinden, Andre G, Schierding, William, O'Sullivan, Justin M, Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F, Buxton, Jessica L, Blakemore, Alexandra I F, Ong, Ken K, Jaddoe, Vincent W V, Grant, Struan F A, Sebert, Sylvain, McCarthy, Mark I, Järvelin, Marjo-Riitta, Erasmus MC other, Epidemiology, Internal Medicine, Pediatrics, Medical Research Council (MRC), Sovio, Ulla [0000-0002-0799-1105], Perry, John [0000-0001-6483-3771], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Warrington, Nicole M [0000-0003-4195-775X], Lewin, Alexandra M [0000-0003-0081-7582], Kaakinen, Marika [0000-0002-9228-0462], Cousminer, Diana L [0000-0001-8864-7893], Timpson, Nicholas J [0000-0002-7141-9189], Lowry, Estelle [0000-0002-4655-416X], Brown, Christopher D [0000-0002-3785-5008], Estivill, Xavier [0000-0002-0723-2256], Geller, Frank [0000-0002-9238-3269], Speed, Doug [0000-0002-0096-9765], Coin, Lachlan J M [0000-0002-4300-455X], Loh, Marie [0000-0003-3626-8466], Barton, Sheila J [0000-0003-4963-4242], Alili, Rohia [0000-0002-0158-4250], Schramm, Katharina [0000-0002-8809-3170], Charles, Marie-Aline [0000-0003-4025-4390], Claringbould, Annique A J [0000-0002-9201-6557], van Duijn, Cornelia M [0000-0002-2374-9204], Feenstra, Bjarke [0000-0003-1478-649X], Frayling, Timothy M [0000-0001-8362-2603], Freathy, Rachel M [0000-0003-4152-2238], Widén, Elisabeth [0000-0001-7108-2806], Hakonarson, Hakon [0000-0003-2814-7461], Rodriguez, Alina [0000-0003-1209-8802], Heude, Barbara [0000-0002-1565-1629], Holloway, John W [0000-0001-9998-0464], Hofman, Albert [0000-0002-9865-121X], Hyppönen, Elina [0000-0003-3670-9399], Inskip, Hazel [0000-0001-8897-1749], Kaplan, Lee M [0000-0002-6301-2696], Prokisch, Holger [0000-0003-2379-6286], Lakka, Timo A [0000-0002-9199-2871], Lawlor, Debbie A [0000-0002-6793-2262], Melbye, Mads [0000-0001-8264-6785], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Marinelli, Marcella [0000-0002-5450-3960], Palmer, Lyle J [0000-0002-1628-3055], Pennell, Craig E [0000-0002-0937-6165], Perry, John R [0000-0001-6483-3771], Ring, Susan M [0000-0003-3103-9330], Savolainen, Markku J [0000-0002-2557-6423], Rivadeneira, Fernando [0000-0001-9435-9441], Sunyer, Jordi [0000-0002-2602-4110], Schierding, William [0000-0001-5659-2701], O'Sullivan, Justin M [0000-0003-2927-450X], Prokopenko, Inga [0000-0003-1624-7457], Smith, George Davey [0000-0002-1407-8314], Felix, Janine F [0000-0002-9801-5774], Ong, Ken K [0000-0003-4689-7530], Jaddoe, Vincent W V [0000-0003-2939-0041], Sebert, Sylvain [0000-0001-6681-6983], McCarthy, Mark I [0000-0002-4393-0510], and Järvelin, Marjo-Riitta [0000-0002-2149-0630]

Subjects
Adult, Male, Pharmacogenomic Variants, Quantitative Trait Loci, BLOOD-PRESSURE, 030209 endocrinology & metabolism, Polymorphism, Single Nucleotide, Body Mass Index, EARLY-LIFE, 03 medical and health sciences, AGE, Quantitative Trait, Heritable, 0302 clinical medicine, Humans, Genetic Predisposition to Disease, Longitudinal Studies, 030212 general & internal medicine, GENOME-WIDE ASSOCIATION, METABOLIC RISK, Growth Charts, FTO GENE, Child, Research Articles, Genetic Association Studies, Adaptor Proteins, Signal Transducing, 2. Zero hunger, Science & Technology, BIRTH COHORT, Intracellular Signaling Peptides and Proteins, nutritional and metabolic diseases, SciAdv r-articles, Infant, Human Genetics, Genomics, 3. Good health, Multidisciplinary Sciences, BODY-MASS INDEX, OBESITY, Science & Technology - Other Topics, Receptors, Leptin, ADIPOSITY, Female, biological, Research Article, Genome-Wide Association Study
Abstract

Longitudinal data find a new variant controlling BMI in infancy and reveal genetic differences between infant and adult BMI., Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

5. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Author

George Dedoussis, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Gudmar Thorleifsson, Oscar H. Franco, Xueling Sim, Philippe Froguel, Symen Ligthart, Ellen M. Schmidt, Jason M. Torres, Karen L. Mohlke, Markku Laakso, Barbara Thorand, Erwin P. Bottinger, Matthias Thurner, Torben Hansen, Jerome I. Rotter, Weihua Zhang, Ching-Ti Liu, Michael Boehnke, Kristi Läll, Konstantin Strauch, Kent D. Taylor, Andrew D. Morris, Daniel R. Witte, Anna L. Gloyn, Jonathan Marchini, Andres Metspalu, Florian Kronenberg, Anubha Mahajan, Claudia Schurmann, Jennifer Kriebel, James S. Pankow, Matthias Wuttke, Valeriya Lyssenko, Jose C. Florez, Josée Dupuis, Patricia A. Peyser, Leif Groop, John C. Chambers, Torben Jørgensen, Timothy M. Frayling, Lawrence F. Bielak, Nicholas J. Wareham, Thomas Meitinger, Alena Stančáková, Vasiliki Mamakou, Cramer Christensen, Michael Preuss, Bram P. Prins, Niels Grarup, Amanda J. Bennett, Vilmantas Giedraitis, Jian'an Luan, Young-Jin Kim, Mickaël Canouil, Robert A. Scott, Kari Stefansson, Jana Nano, Donald W. Bowden, Oluf Pedersen, Cécile Lecoeur, Anna Köttgen, Jette Bork-Jensen, Francis S. Collins, Unnur Thorsteinsdottir, Naveed Sattar, Stella Trompet, Martin Ingelsson, Maggie C.Y. Ng, Jaakko Tuomilehto, Reedik Mägi, James B. Meigs, Lauren E. Petty, J. Wouter Jukema, Andrew T. Hattersley, Claudia Langenberg, Harald Grallert, Christian Gieger, Chad M. Brummett, Ian Ford, Andrew P. Morris, James P. Cook, Vibe Nylander, Sebastian Schönherr, Daniel Taliun, Xiuqing Guo, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Jennifer E. Below, Eleftheria Zeggini, Anthony Payne, Loic Yengo, Sharon L.R. Kardia, Neil R. Robertson, Abbas Dehghan, Ivan Brandslund, Erik Ingelsson, Colin N. A. Palmer, Ruth J. F. Loos, Girish N. Nadkarni, Gonçalo R. Abecasis, Adam E. Locke, Johanna Kuusisto, Lars Lind, Krista Fischer, Annette Peters, Kai-Uwe Ec Kardt, Ioanna Ntalla, Chloé Sarnowski, Mark I. McCarthy, N. William Rayner, Allan Linneberg, Sophie Hackinger, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, University of Helsinki, HUS Abdominal Center, Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Boehnke, Michael [0000-0002-6442-7754], McCarthy, Mark I [0000-0002-4393-0510], Apollo - University of Cambridge Repository, Lee Kong Chian School of Medicine (LKCMedicine), and Epidemiology

Subjects
0301 basic medicine, Male, Linkage disequilibrium, endocrine system diseases, Genome-wide association study, DISEASE, Linkage Disequilibrium, Body Mass Index, Epigenesis, Genetic, 0302 clinical medicine, Gene Frequency, High-Throughput Screening Assays/methods, European Continental Ancestry Group/genetics, Genetics & Heredity, 0303 health sciences, Chromosome Mapping, 11 Medical And Health Sciences, Functional Genomics, 3. Good health, Genetic Loci/genetics, Medical genetics, Female, Islets of Langerhans/metabolism, Life Sciences & Biomedicine, TRAITS, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Genomics, 030209 endocrinology & metabolism, PHENOTYPES, Computational biology, Biology, Polymorphism, Single Nucleotide, White People, Article, GENETIC ARCHITECTURE, Islets of Langerhans, 03 medical and health sciences, Sex Factors, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, SCORE, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, Genotyping, Allele frequency, METAANALYSIS, 030304 developmental biology, Science & Technology, IDENTIFICATION, Genome, Human, Haplotype, 06 Biological Sciences, Human genetics, Genetic architecture, High-Throughput Screening Assays, Minor allele frequency, 030104 developmental biology, Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 2/epidemiology, Sample size determination, Genetic Loci, Case-Control Studies, Genome, Human/genetics, Genome-wide Association Studies, 3111 Biomedicine, Chromosome Mapping/methods, 030217 neurology & neurosurgery, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract

We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of >30,000 sequenced haplotypes. Analysis of ˜27M variants (˜21M with minor allele frequency [MAF]p−8; MAF 0.02%-50%; odds ratio [OR] 1.04-8.05), 135 not previously-implicated in T2D-predisposition. Conditional analyses revealed 160 additional distinct association signals (p−5) within the identified loci. The combined set of 403 T2D-risk signals includes 56 low-frequency (0.5%≤MAF2. Forty-one of the signals displayed effect-size heterogeneity between BMI-unadjusted and adjusted analyses. Increased sample size and improved imputation led to substantially more precise localisation of causal variants than previously attained: at 51 signals, the lead variant after fine-mapping accounted for >80% posterior probability of association (PPA) and at 18 of these, PPA exceeded 99%. Integration with islet regulatory annotations enriched for T2D association further reduced median credible set size (from 42 variants to 32) and extended the number of index variants with PPA>80% to 73. Although most signals mapped to regulatory sequence, we identified 18 genes as human validated therapeutic targets through coding variants that are causal for disease. Genome wide chip heritability accounted for 18% of T2D-risk, and individuals in the 2.5% extremes of a polygenic risk score generated from the GWAS data differed >9-fold in risk. Our observations highlight how increases in sample size and variant diversity deliver enhanced discovery and single-variant resolution of causal T2D-risk alleles, and the consequent impact on mechanistic insights and clinical translation.

Published
2018
Full Text
View/download PDF

6. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Author

Justice, Anne E, Karaderi, Tugce, Highland, Heather M, Young, Kristin L, Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L, Fine, Rebecca S, Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W, Locke, Adam E, Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Angelantonio, Emanuele Di, Dörr, Marcus, Drenos, Fotios, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Fornage, Myriam, Fox, Caroline S, Franks, Paul W, Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T, Hayward, Caroline, Heid, Iris M, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jarvik, Gail P, Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M, Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kovacs, Peter, Krämer, Bernhard K, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas GD, McCarthy, Mark I, Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O, Morgan, Anna, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Ntalla, Ioanna, O'Connell, Jeffrey R, Owen, Katharine R, Pedersen, Oluf, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T, Rasheed, Asif, Raulerson, Chelsea K, Rauramaa, Rainer, Reilly, Dermot F, Reiner, Alex P, Ridker, Paul M, Rivas, Manuel A, Robertson, Neil R, Robino, Antonietta, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J, Small, Kerrin S, Smith, Blair H, Smith, Jennifer A, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E, Strauch, Konstantin, Stringham, Heather M, Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin MA, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, van Duijn, Cornelia M, Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Vuckovic, Dragana, Wagenknecht, Lynne E, Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wareham, Nicholas J, Warren, Helen R, Waterworth, Dawn M, Wessel, Jennifer, White, Harvey D, Willer, Cristen J, Wilson, James G, Wood, Andrew R, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M Carola, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CH, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Rivadeneira, Fernando, Borecki, Ingrid B, Pospisilik, J Andrew, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, Mohlke, Karen L, Rotter, Jerome I, Kutalik, Zoltán, Hirschhorn, Joel N, Cupples, L Adrienne, Loos, Ruth JF, North, Kari E, Lindgren, Cecilia M, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Institute for Molecular Medicine Finland, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, Young, Kristin L [0000-0003-0070-6145], Mahajan, Anubha [0000-0001-5585-3420], Winkler, Thomas W [0000-0003-0292-5421], Locke, Adam E [0000-0001-6227-198X], Medina-Gomez, Carolina [0000-0001-7999-5538], Giri, Ayush [0000-0002-7786-4670], Ng, Maggie CY [0000-0002-4133-2007], Heard-Costa, Nancy L [0000-0001-9730-0306], Manning, Alisa K [0000-0003-0247-902X], Alam, Dewan S [0000-0002-2051-3837], Amouyel, Philippe [0000-0001-9088-234X], Bergmann, Sven [0000-0002-6785-9034], Boehnke, Michael [0000-0002-6442-7754], Butterworth, Adam S [0000-0002-6915-9015], Caulfield, Mark J [0000-0001-9295-3594], Collins, Francis S [0000-0002-1023-7410], de Bakker, Paul IW [0000-0001-7735-7858], Dennis, Joe G [0000-0003-4591-1214], Easton, Douglas F [0000-0003-2444-3247], Elliott, Paul [0000-0002-7511-5684], Evangelou, Evangelos [0000-0002-5488-2999], Giedraitis, Vilmantas [0000-0003-3423-2021], Girotto, Giorgia [0000-0003-4507-6589], Grarup, Niels [0000-0001-5526-1070], Gustafsson, Stefan [0000-0001-5894-0351], Hansen, Torben [0000-0001-8748-3831], Hayward, Caroline [0000-0002-9405-9550], Howson, Joanna MM [0000-0001-7618-0050], Ikram, M Arfan [0000-0003-0372-8585], Jackson, Anne U [0000-0002-9672-2547], Justesen, Johanne M [0000-0002-0484-8522], Kovacs, Peter [0000-0002-0290-5423], Kuulasmaa, Kari [0000-0003-2165-1411], Langenberg, Claudia [0000-0002-5017-7344], Lin, Li-An [0000-0003-2731-1346], Linneberg, Allan [0000-0002-0994-0184], Liu, Ching-Ti [0000-0002-0703-0742], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], MacGregor, Stuart [0000-0001-6731-8142], McCarthy, Mark I [0000-0002-4393-0510], Morgan, Anna [0000-0001-6290-445X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Munroe, Patricia B [0000-0002-4176-2947], Narisu, Narisu [0000-0002-8483-1156], Neville, Matt [0000-0002-6004-5433], Reilly, Dermot F [0000-0002-9456-1364], Rudan, Igor [0000-0001-6993-6884], Saleheen, Danish [0000-0001-6193-020X], Salomaa, Veikko [0000-0001-7563-5324], Sim, Xueling [0000-0002-1233-7642], Small, Kerrin S [0000-0003-4566-0005], Smith, Blair H [0000-0002-5362-9430], Smith, Jennifer A [0000-0002-3575-5468], Southam, Lorraine [0000-0002-7546-9650], Stefansson, Kari [0000-0003-1676-864X], Stirrups, Kathleen E [0000-0002-6823-3252], Stringham, Heather M [0000-0002-2991-6392], Teumer, Alexander [0000-0002-8309-094X], Thompson, Deborah J [0000-0003-1465-5799], Vestergaard, Henrik [0000-0003-3090-269X], Vitart, Veronique [0000-0002-4991-3797], Wang, Carol A [0000-0002-4301-3974], Wessel, Jennifer [0000-0002-7031-0085], Willer, Cristen J [0000-0001-5645-4966], Zeggini, Eleftheria [0000-0003-4238-659X], Rivadeneira, Fernando [0000-0001-9435-9441], Pospisilik, J Andrew [0000-0002-9745-0977], Deloukas, Panos [0000-0001-9251-070X], Mohlke, Karen L [0000-0001-6721-153X], Kutalik, Zoltán [0000-0001-8285-7523], Loos, Ruth JF [0000-0002-8532-5087], Lindgren, Cecilia M [0000-0002-4903-9374], Apollo - University of Cambridge Repository, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Medical and Clinical Psychology, Justice, Anne E., Karaderi, Tugce, Highland, Heather M., Young, Kristin L., Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L., Fine, Rebecca S., Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W., Locke, Adam E., Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie C. Y., Heard-Costa, Nancy L., Feitosa, Mary F., Manning, Alisa K., Willems, Sara M., Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S., Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Broer, Linda, Burt, Amber A., Butterworth, Adam S., Caulfield, Mark J., Cesana, Giancarlo, Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Collins, Francis S., Cook, James P., Cox, Amanda J., Crosslin, David S., Danesh, John, de Bakker, Paul I. W., Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele Di, Dörr, Marcu, Drenos, Fotio, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Fornage, Myriam, Fox, Caroline S., Franks, Paul W., Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Girotto, Giorgia, Gorski, Mathia, Grallert, Harald, Grarup, Niel, Grove, Megan L., Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T., Hayward, Caroline, Heid, Iris M., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jarvik, Gail P., Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M., Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kovacs, Peter, Krämer, Bernhard K., Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Luan, Jian’An, Lyytikäinen, Leo-Pekka, Macgregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas G. D., Mccarthy, Mark I., Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Ntalla, Ioanna, O’Connell, Jeffrey R., Owen, Katharine R., Pedersen, Oluf, Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T., Rasheed, Asif, Raulerson, Chelsea K., Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Ridker, Paul M., Rivas, Manuel A., Robertson, Neil R., Robino, Antonietta, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Blair H., Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin M. A., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, van Duijn, Cornelia M., Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M. Carola, Rivadeneira, Fernando, Borecki, Ingrid B., Pospisilik, J. Andrew, Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, Mohlke, Karen L., Rotter, Jerome I., Kutalik, Zoltán, Hirschhorn, Joel N., Cupples, L. Adrienne, Loos, Ruth J. F., North, Kari E., Lindgren, Cecilia M., APH - Societal Participation & Health, APH - Health Behaviors & Chronic Diseases, APH - Aging & Later Life, Epidemiology and Data Science, and VU University medical center

Subjects
Exome/genetics, Male, ReproGen Consortium, Adipose tissue, Genome-wide association study, Type 2 diabetes, White adipose tissue, Body Mass Index, Animals, Body Fat Distribution, Case-Control Studies, Drosophila, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeostasis, Humans, Lipids, Proteins, Risk Factors, Waist-Hip Ratio, 0302 clinical medicine, Hyperlipidemia, Body fat distribution, 2. Zero hunger, Genetics, 0303 health sciences, INSULIN-RESISTANCE, ADIPOCYTE DIFFERENTIATION, CHD Exome+ Consortium, Genetic Predisposition to Disease/genetics, Drosophila/genetics, RS11209026 POLYMORPHISM, KINASE 7, 1184 Genetics, developmental biology, physiology, T2D-Genes Consortium, 11 Medical And Health Sciences, Body Fat Distribution/methods, RECEPTOR ALK7, ADIPOSE-TISSUE, Gene Frequency/genetics, Genetic Variation/genetics, InterAct, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], genetic association study, RNA splicing, Proteins/genetics, Genome-Wide Association Study/methods, Lipid particle, ExomeBP Consortium, WAIST CIRCUMFERENCE, Waist-Hip Ratio/methods, Biology, EPIC-CVD Consortium, Article, MAGIC Investigators, 03 medical and health sciences, Homeostasis/genetics, Lipids/genetics, All institutes and research themes of the Radboud University Medical Center, medicine, Global Lipids Genetic Consortium, Risk factor, GENOME-WIDE ASSOCIATION, ABDOMINAL ADIPOSITY, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Gene, 030304 developmental biology, 06 Biological Sciences, medicine.disease, Minor allele frequency, GoT2D Genes Consortium, genetics research, TYPE-2 DIABETES SUSCEPTIBILITY, 3111 Biomedicine, Body mass index, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Body fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥ 5%) and 9 low frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology, and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants., Editorial summary: A trans-ethnic exome-wide association study for body fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.

Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results