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101. Lipolysis defect in people with obesity who undergo metabolic surgery

Author

Rydén, Mikael, Andersson, Daniel P., Kotopouli, Maria I., Stenberg, Erik, Näslund, Erik, Thorell, Anders, Sørensen, Thorkild I. A., Arner, Peter, Rydén, Mikael, Andersson, Daniel P., Kotopouli, Maria I., Stenberg, Erik, Näslund, Erik, Thorell, Anders, Sørensen, Thorkild I. A., and Arner, Peter

Abstract

OBJECTIVE: Cross-sectional studies demonstrate that catecholamine stimulation of fat cell lipolysis is blunted in obesity. We investigated whether this defect persists after substantial weight loss has been induced by metabolic surgery, and whether it is related to the outcome. DESIGN/METHODS: Patients with obesity not able to successfully reduce body weight by conventional means (n = 126) were investigated before and 5 years after Roux-en-Y gastric bypass surgery (RYGB). They were compared with propensity-score matched subjects selected from a control group (n = 1017), and with the entire group after adjustment for age, sex, body mass index (BMI), fat cell volume and other clinical parameters. Catecholamine-stimulated lipolysis (glycerol release) was investigated in isolated fat cells using noradrenaline (natural hormone) or isoprenaline (synthetic beta-adrenoceptor agonist). RESULTS: Following RYGB, BMI was reduced from 39.9 (37.5-43.5) (median and interquartile range) to 29.5 (26.7-31.9) kg/m2 (p < 0.0001). The post-RYGB patients had about 50% lower lipolysis rates compared with the matched and total series of controls (p < 0.0005). Nordrenaline activation of lipolysis at baseline was associated with the RYGB effect; those with high lipolysis activation (upper tertile) lost 30%-45% more in body weight, BMI or fat mass than those with low (bottom tertile) initial lipolysis activation (p < 0.0007). CONCLUSION: Patients with obesity requiring metabolic surgery have impaired ability of catecholamines to stimulate lipolysis, which remains despite long-term normalization of body weight by RYGB. Furthermore, preoperative variations in the ability of catecholamines to activate lipolysis may predict the long-term reduction in body weight and fat mass., Funding agencies:Strategic Diabetes Research Program at Karolinska InstitutetTripartite Immuno-metabolism Consortium NNF15CC0018486 NNF15SA0018346 0064142Erling-Persson Family Foundation

Published
2022
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103. Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

Author

Sharp, Gemma C, Salas, Lucas A, Monnereau, Claire, Allard, Catherine, Yousefi, Paul, Everson, Todd M, Bohlin, Jon, Xu, Zongli, Huang, Rae-Chi, Reese, Sarah E, Xu, Cheng-Jian, Baïz, Nour, Hoyo, Cathrine, Agha, Golareh, Roy, Ritu, Holloway, John W, Ghantous, Akram, Merid, Simon K, Bakulski, Kelly M, Küpers, Leanne K, Zhang, Hongmei, Richmond, Rebecca C, Page, Christian M, Duijts, Liesbeth, Lie, Rolv T, Melton, Phillip E, Vonk, Judith M, Nohr, Ellen A, Williams-DeVane, ClarLynda, Huen, Karen, Rifas-Shiman, Sheryl L, Ruiz-Arenas, Carlos, Gonseth, Semira, Rezwan, Faisal I, Herceg, Zdenko, Ekström, Sandra, Croen, Lisa, Falahi, Fahimeh, Perron, Patrice, Karagas, Margaret R, Quraishi, Bilal M, Suderman, Matthew, Magnus, Maria C, Jaddoe, Vincent W V, Taylor, Jack A, Anderson, Denise, Zhao, Shanshan, Smit, Henriette A, Josey, Michele J, Bradman, Asa, Baccarelli, Andrea A, Bustamante, Mariona, Håberg, Siri E, Pershagen, Göran, Hertz-Picciotto, Irva, Newschaffer, Craig, Corpeleijn, Eva, Bouchard, Luigi, Lawlor, Debbie A, Maguire, Rachel L, Barcellos, Lisa F, Davey Smith, George, Eskenazi, Brenda, Karmaus, Wilfried, Marsit, Carmen J, Hivert, Marie-France, Snieder, Harold, Fallin, Daniele M, Melén, Erik, Munthe-Kaas, Monica C, Arshad, Hasan, Wiemels, Joseph L, Annesi-Maesano, Isabella, Vrijheid, Martine, Oken, Emily, Holland, Nina, Murphy, Susan K, Sørensen, Thorkild I A, Koppelman, Gerard H, Newnham, John P, Wilcox, Allen J, Nystad, Wenche, London, Stephanie J, Felix, Janine F, and Relton, Caroline L

Published
2017
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104. Maternal body mass index, gestational weight gain, and the risk of overweight and obesity across childhood: An individual participant data meta-analysis

Author

Voerman, Ellis, Santos, Susana, Patro Golab, Bernadeta, Amiano, Pilar, Ballester, Ferran, Barros, Henrique, Bergström, Anna, Charles, Marie-Aline, Chatzi, Leda, Chevrier, Cécile, Chrousos, George P., Corpeleijn, Eva, Costet, Nathalie, Crozier, Sarah, Devereux, Graham, Eggesbø, Merete, Ekström, Sandra, Fantini, Maria Pia, Farchi, Sara, Forastiere, Francesco, Georgiu, Vagelis, Godfrey, Keith M., Gori, Davide, Grote, Veit, Hanke, Wojciech, Hertz-Picciotto, Irva, Heude, Barbara, Hryhorczuk, Daniel, Huang, Rae-Chi, Inskip, Hazel, Iszatt, Nina, Karvonen, Anne M., Kenny, Louise C., Koletzko, Berthold, Küpers, Leanne K., Lagström, Hanna, Lehmann, Irina, Magnus, Per, Majewska, Renata, Mäkelä, Johanna, Manios, Yannis, McAuliffe, Fionnuala M., McDonald, Sheila W., Mehegan, John, Mommers, Monique, Morgen, Camilla S., Mori, Trevor A., Moschonis, George, Murray, Deirdre, Chaoimh, Carol Ní, Nohr, Ellen A., Nybo Andersen, Anne-Marie, Oken, Emily, Oostvogels, Adriëtte J. J. M., Pac, Agnieszka, Papadopoulou, Eleni, Pekkanen, Juha, Pizzi, Costanza, Polanska, Kinga, Porta, Daniela, Richiardi, Lorenzo, Rifas-Shiman, Sheryl L., Ronfani, Luca, Santos, Ana C., Standl, Marie, Stoltenberg, Camilla, Thiering, Elisabeth, Thijs, Carel, Torrent, Maties, Tough, Suzanne C., Trnovec, Tomas, Turner, Steve, van Rossem, Lenie, von Berg, Andrea, Vrijheid, Martine, Vrijkotte, Tanja G. M., West, Jane, Wijga, Alet, Wright, John, Zvinchuk, Oleksandr, Sørensen, Thorkild I. A., Lawlor, Debbie A., Gaillard, Romy, and Jaddoe, Vincent W. V.

Subjects
Childhood obesity -- Risk factors -- Research, Weight gain -- Analysis, Health risk assessment -- Analysis, Body mass index -- Analysis, Pregnancy -- Health aspects, Pregnant women -- Health aspects, Biological sciences
Abstract

Background Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. Methods and findings We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations. Conclusions In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy., Author(s): Ellis Voerman 1,2, Susana Santos 1,2, Bernadeta Patro Golab 1,2,3, Pilar Amiano 4,5,6, Ferran Ballester 6,7, Henrique Barros 8,9, Anna Bergström 10,11, Marie-Aline Charles 12,13, Leda Chatzi 14,15,16, Cécile [...]

Published
2019
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114. Hyperglucagonemia in Pediatric Adiposity Associates With Cardiometabolic Risk Factors but Not Hyperglycemia

Author

Stinson, Sara E, primary, Jonsson, Anna E, additional, de Retana Alzola, Ierai Fernández, additional, Lund, Morten A V, additional, Frithioff-Bøjsøe, Christine, additional, Aas Holm, Louise, additional, Fonvig, Cilius E, additional, Pedersen, Oluf, additional, Ängquist, Lars, additional, Sørensen, Thorkild I A, additional, Holst, Jens J, additional, Christiansen, Michael, additional, Holm, Jens-Christian, additional, Hartmann, Bolette, additional, and Hansen, Torben, additional

Published
2022
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118. Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

Author

Tyrrell, Jessica, Richmond, Rebecca C., Palmer, Tom M., Feenstra, Bjarke, Rangarajan, Janani, Metrustry, Sarah, Cavadino, Alana, Paternoster, Lavinia, Armstrong, Loren L., De Silva, N. Maneka G., Wood, Andrew R., Horikoshi, Momoko, Geller, Frank, Myhre, Ronny, Bradfield, Jonathan P., Kreiner-Møller, Eskil, Huikari, Ville, Painter, Jodie N., Hottenga, Jouke-Jan, Allard, Catherine, Berry, Diane J., Bouchard, Luigi, Das, Shikta, Evans, David M., Hakonarson, Hakon, Hayes, M. Geoffrey, Heikkinen, Jani, Hofman, Albert, Knight, Bridget, Lind, Penelope A., McCarthy, Mark I., McMahon, George, Medland, Sarah E., Melbye, Mads, Morris, Andrew P., Nodzenski, Michael, Reichetzeder, Christoph, Ring, Susan M., Sebert, Sylvain, Sengpiel, Verena, Sørensen, Thorkild I. A., Willemsen, Gonneke, de Geus, Eco J. C., Martin, Nicholas G., Spector, Tim D., Power, Christine, Järvelin, Marjo-Riitta, Bisgaard, Hans, Grant, Struan F. A., Nohr, Ellen A., Jaddoe, Vincent W., Jacobsson, Bo, Murray, Jeffrey C., Hocher, Berthold, Hattersley, Andrew T., Scholtens, Denise M., Davey Smith, George, Hivert, Marie-France, Felix, Janine F., Hyppönen, Elina, Lowe, William L., Jr, Frayling, Timothy M., Lawlor, Debbie A., and Freathy, Rachel M.

Published
2016
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121. Non-linear interaction between physical activity and polygenic risk score of body mass index in Danish and Russian populations

Author

Borisevich, Dmitrii, primary, Schnurr, Theresia M., additional, Engelbrechtsen, Line, additional, Rakitko, Alexander, additional, Ängquist, Lars, additional, Ilinsky, Valery, additional, Aadahl, Mette, additional, Grarup, Niels, additional, Pedersen, Oluf, additional, Sørensen, Thorkild I. A., additional, and Hansen, Torben, additional

Published
2021
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123. Beer, Wine, Spirits and Subjective Health

Author

Grønbæk, Morten, Mortensen, Erik Lykke, Mygind, Karen, Andersen, Anne Torgny, Becker, Ulrik, Gluud, Christian, and Sørensen, Thorkild I. A.

Published
1999

124. Directional dominance on stature and cognition in diverse human populations

Author

Joshi, Peter K., Esko, Tonu, Mattsson, Hannele, Eklund, Niina, Gandin, Ilaria, Nutile, Teresa, Jackson, Anne U., Schurmann, Claudia, Smith, Albert V., Zhang, Weihua, Okada, Yukinori, Stančáková, Alena, Faul, Jessica D., Zhao, Wei, Bartz, Traci M., Concas, Maria Pina, Franceschini, Nora, Enroth, Stefan, Vitart, Veronique, Trompet, Stella, Guo, Xiuqing, Chasman, Daniel I., OʼConnel, Jeffrey R., Corre, Tanguy, Nongmaithem, Suraj S., Chen, Yuning, Mangino, Massimo, Ruggiero, Daniela, Traglia, Michela, Farmaki, Aliki-Eleni, Kacprowski, Tim, Bjonnes, Andrew, van der Spek, Ashley, Wu, Ying, Giri, Anil K., Yanek, Lisa R., Wang, Lihua, Hofer, Edith, Rietveld, Cornelius A., McLeod, Olga, Cornelis, Marilyn C., Pattaro, Cristian, Verweij, Niek, Baumbach, Clemens, Abdellaoui, Abdel, Warren, Helen R., Vuckovic, Dragana, Mei, Hao, Bouchard, Claude, Perry, John R. B., Cappellani, Stefania, Mirza, Saira S., Benton, Miles C., Broeckel, Ulrich, Medland, Sarah E., Lind, Penelope A., Malerba, Giovanni, Drong, Alexander, Yengo, Loic, Bielak, Lawrence F., Zhi, Degui, van der Most, Peter J., Shriner, Daniel, Mägi, Reedik, Hemani, Gibran, Karaderi, Tugce, Wang, Zhaoming, Liu, Tian, Demuth, Ilja, Zhao, Jing Hua, Meng, Weihua, Lataniotis, Lazaros, van der Laan, Sander W., Bradfield, Jonathan P., Wood, Andrew R., Bonnefond, Amelie, Ahluwalia, Tarunveer S., Hall, Leanne M., Salvi, Erika, Yazar, Seyhan, Carstensen, Lisbeth, de Haan, Hugoline G., Abney, Mark, Afzal, Uzma, Allison, Matthew A., Amin, Najaf, Asselbergs, Folkert W., Bakker, Stephan J. L., Barr, Graham R., Baumeister, Sebastian E., Benjamin, Daniel J., Bergmann, Sven, Boerwinkle, Eric, Bottinger, Erwin P., Campbell, Archie, Chakravarti, Aravinda, Chan, Yingleong, Chanock, Stephen J., Chen, Constance, Chen, Ida Y.-D., Collins, Francis S., Connell, John, Correa, Adolfo, Cupples, Adrienne L., Smith, George Davey, Davies, Gail, Dörr, Marcus, Ehret, Georg, Ellis, Stephen B., Feenstra, Bjarke, Feitosa, Mary F., Ford, Ian, Fox, Caroline S., Frayling, Timothy M., Friedrich, Nele, Geller, Frank, Scotland, Generation, Gillham-Nasenya, Irina, Gottesman, Omri, Graff, Misa, Grodstein, Francine, Gu, Charles, Haley, Chris, Hammond, Christopher J., Harris, Sarah E., Harris, Tamara B., Hastie, Nicholas D., Heard-Costa, Nancy L., Heikkilä, Kauko, Hocking, Lynne J., Homuth, Georg, Hottenga, Jouke-Jan, Huang, Jinyan, Huffman, Jennifer E., Hysi, Pirro G., Ikram, Arfan M., Ingelsson, Erik, Joensuu, Anni, Johansson, Åsa, Jousilahti, Pekka, Jukema, Wouter J., Kähönen, Mika, Kamatani, Yoichiro, Kanoni, Stavroula, Kerr, Shona M., Khan, Nazir M., Koellinger, Philipp, Koistinen, Heikki A., Kooner, Manraj K., Kubo, Michiaki, Kuusisto, Johanna, Lahti, Jari, Launer, Lenore J., Lea, Rodney A., Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C.M., Lind, Lars, Loh, Marie, Lokki, Marja-Liisa, London, Stephanie J., Loomis, Stephanie J., Loukola, Anu, Lu, Yingchang, Lumley, Thomas, Lundqvist, Annamari, Männistö, Satu, Marques-Vidal, Pedro, Masciullo, Corrado, Matchan, Angela, Mathias, Rasika A., Matsuda, Koichi, Meigs, James B., Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Mentch, Frank D., Mihailov, Evelin, Milani, Lili, Montasser, May E., Montgomery, Grant W., Morrison, Alanna, Myers, Richard H., Nadukuru, Rajiv, Navarro, Pau, Nelis, Mari, Nieminen, Markku S., Nolte, Ilja M., OʼConnor, George T., Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmas, Walter R., Pankow, James S., Patarcic, Inga, Pavani, Francesca, Peyser, Patricia A., Pietilainen, Kirsi, Poulter, Neil, Prokopenko, Inga, Ralhan, Sarju, Redmond, Paul, Rich, Stephen S., Rissanen, Harri, Robino, Antonietta, Rose, Lynda M., Rose, Richard, Sala, Cinzia, Salako, Babatunde, Salomaa, Veikko, Sarin, Antti-Pekka, Saxena, Richa, Schmidt, Helena, Scott, Laura J., Scott, William R., Sennblad, Bengt, Seshadri, Sudha, Sever, Peter, Shrestha, Smeeta, Smith, Blair H., Smith, Jennifer A., Soranzo, Nicole, Sotoodehnia, Nona, Southam, Lorraine, Stanton, Alice V., Stathopoulou, Maria G., Strauch, Konstantin, Strawbridge, Rona J., Suderman, Matthew J., Tandon, Nikhil, Tang, Sian-Tsun, Taylor, Kent D., Tayo, Bamidele O., Töglhofer, Anna Maria, Tomaszewski, Maciej, Tšernikova, Natalia, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vaidya, Dhananjay, van Hylckama Vlieg, Astrid, van Setten, Jessica, Vasankari, Tuula, Vedantam, Sailaja, Vlachopoulou, Efthymia, Vozzi, Diego, Vuoksimaa, Eero, Waldenberger, Melanie, Ware, Erin B., Wentworth-Shields, William, Whitfield, John B., Wild, Sarah, Willemsen, Gonneke, Yajnik, Chittaranjan S., Yao, Jie, Zaza, Gianluigi, Zhu, Xiaofeng, Salem, Rany M., Melbye, Mads, Bisgaard, Hans, Samani, Nilesh J., Cusi, Daniele, Mackey, David A., Cooper, Richard S., Froguel, Philippe, Pasterkamp, Gerard, Grant, Struan F.A., Hakonarson, Hakon, Ferrucci, Luigi, Scott, Robert A., Morris, Andrew D., Palmer, Colin N. A., Dedoussis, George, Deloukas, Panos, Bertram, Lars, Lindenberger, Ulman, Berndt, Sonja I., Lindgren, Cecilia M., Timpson, Nicholas J., Tönjes, Anke, Munroe, Patricia B., Sørensen, Thorkild I. A., Rotimi, Charles N., Arnett, Donna K., Oldehinkel, Albertine J., Kardia, Sharon L. R., Balkau, Beverley, Gambaro, Giovanni, Morris, Andrew P., Eriksson, Johan G., Wright, Margie J., Martin, Nicholas G., Hunt, Steven C., Starr, John M., Deary, Ian J., Griffiths, Lyn R., Tiemeier, Henning, Pirastu, Nicola, Kaprio, Jaakko, Wareham, Nicholas J., Pérusse, Louis, Wilson, James G., Girotto, Giorgia, Caulfield, Mark J., Raitakari, Olli, Boomsma, Dorret I., Gieger, Christian, van der Harst, Pim, Hicks, Andrew A., Kraft, Peter, Sinisalo, Juha, Knekt, Paul, Johannesson, Magnus, Magnusson, Patrik K. E., Hamsten, Anders, Schmidt, Reinhold, Borecki, Ingrid B., Vartiainen, Erkki, Becker, Diane M., Bharadwaj, Dwaipayan, Mohlke, Karen L., Boehnke, Michael, van Duijn, Cornelia M., Sanghera, Dharambir K., Teumer, Alexander, Zeggini, Eleftheria, Metspalu, Andres, Gasparini, Paolo, Ulivi, Sheila, Ober, Carole, Toniolo, Daniela, Rudan, Igor, Porteous, David J., Ciullo, Marina, Spector, Tim D., Hayward, Caroline, Dupuis, Josée, Loos, Ruth J. F., Wright, Alan F., Chandak, Giriraj R., Vollenweider, Peter, Shuldiner, Alan R., Ridker, Paul M., Rotter, Jerome I., Sattar, Naveed, Gyllensten, Ulf, North, Kari E., Pirastu, Mario, Psaty, Bruce M., Weir, David R., Laakso, Markku, Gudnason, Vilmundur, Takahashi, Atsushi, Chambers, John C., Kooner, Jaspal S., Strachan, David P., Campbell, Harry, Hirschhorn, Joel N., Perola, Markus, Polašek, Ozren, and Wilson, James F.

Published
2015
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125. Alcohol Intake and Cancer of the Upper Digestive Tract

Author

La Vecchia, Carlo, Franceschi, Silvia, Favero, Adriano, Talamini, Renato, Negri, Eva, Cheng, K. K., Cummins, C., Maric, R., Reed, Vaughan, Fitzgerald, Rebecca, Caygill, Christine, Grønbæk, Morten, and Sørensen, Thorkild I. A.

Published
1999

127. Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids

Author

Orešič, Matej, Hyötyläinen, Tuulia, Kotronen, Anna, Gopalacharyulu, Peddinti, Nygren, Heli, Arola, Johanna, Castillo, Sandra, Mattila, Ismo, Hakkarainen, Antti, Borra, Ronald J. H., Honka, Miikka-Juhani, Verrijken, An, Francque, Sven, Iozzo, Patricia, Leivonen, Marja, Jaser, Nabil, Juuti, Anne, Sørensen, Thorkild I. A., Nuutila, Pirjo, Van Gaal, Luc, and Yki-Järvinen, Hannele

Published
2013
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129. The trans-ancestral genomic architecture of glycemic traits

Author

Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian'an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, Waage, Johannes, Li-Gao, Ruifang, Chan, Kei Hang Katie, Yao, Jie, Anasanti, Mila D., Chu, Audrey Y., Claringbould, Annique, Heikkinen, Jani, Hong, Jaeyoung, Hottenga, Jouke-Jan, Huo, Shaofeng, Kaakinen, Marika A., Louie, Tin, März, Winfried, Moreno-Macias, Hortensia, Ndungu, Anne, Nelson, Sarah C., Nolte, Ilja M., North, Kari E., Raulerson, Chelsea K., Ray, Debashree, Rohde, Rebecca, Rybin, Denis, Schurmann, Claudia, Sim, Xueling, Southam, Lorraine, Stewart, Isobel D., Wang, Carol A., Wang, Yujie, Wu, Peitao, Zhang, Weihua, Ahluwalia, Tarunveer S., Appel, Emil V R, Bielak, Lawrence F., Brody, Jennifer A., Burtt, Noël P, Cabrera, Claudia P., Cade, Brian E., Chai, Jin Fang, Chai, Xiaoran, Chang, Li-Ching, Chen, Chien-Hsiun, Chen, Brian H., Chitrala, Kumaraswamy Naidu, Chiu, Yen-Feng, de Haan, Hugoline G., Delgado, Graciela E., Demirkan, Ayse, Duan, Qing, Engmann, Jorgen, Fatumo, Segun A., Gayán, Javier, Giulianini, Franco, Gong, Jung Ho, Gustafsson, Stefan, Hai, Yang, Hartwig, Fernando P., He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Hwang, Mi Yeong, Jensen, Richard A., Kawaguchi, Takahisa, Kentistou, Katherine A., Kim, Young Jin, Kleber, Marcus E., Kooner, Ishminder K., Lai, Shuiqing, Lange, Leslie A., Langefeld, Carl D., Lauzon, Marie, Li, Man, Ligthart, Symen, Liu, Jun, Loh, Marie, Long, Jirong, Lyssenko, Valeriya, Mangino, Massimo, Marzi, Carola, Montasser, May E., Nag, Abhishek, Nakatochi, Masahiro, Noce, Damia, Noordam, Raymond, Pistis, Giorgio, Preuss, Michael, Raffield, Laura, Rasmussen-Torvik, Laura J., Rich, Stephen S., Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Sanna, Serena, Saxena, Richa, Schraut, Katharina E., Sennblad, Bengt, Setoh, Kazuya, Smith, Albert V., Sparsø, Thomas, Strawbridge, Rona J., Takeuchi, Fumihiko, Tan, Jingyi, Trompet, Stella, van den Akker, Erik, van der Most, Peter J., Verweij, Niek, Vogel, Mandy, Wang, Heming, Wang, Chaolong, Wang, Nan, Warren, Helen R., Wen, Wanqing, Wilsgaard, Tom, Wong, Andrew, Wood, Andrew R., Xie, Tian, Zafarmand, Mohammad Hadi, Zhao, Jing-Hua, Zhao, Wei, Amin, Najaf, Arzumanyan, Zorayr, Astrup, Arne, Bakker, Stephan J L, Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bertoni, Alain, Blüher, Matthias, Bonnycastle, Lori L., Bornstein, Stefan R., Bowden, Donald W., Cai, Qiuyin, Campbell, Archie, Campbell, Harry, Chang, Yi Cheng, de Geus, Eco J C, Dehghan, Abbas, Du, Shufa, Eiriksdottir, Gudny, Farmaki, Aliki Eleni, Frånberg, Mattias, Fuchsberger, Christian, Gao, Yutang, Gjesing, Anette P., Goel, Anuj, Han, Sohee, Hartman, Catharina A., Herder, Christian, Hicks, Andrew A., Hsieh, Chang-Hsun, Hsueh, Willa A., Ichihara, Sahoko, Igase, Michiya, Ikram, M Arfan, Johnson, W Craig, Jørgensen, Marit E., Joshi, Peter K., Kalyani, Rita R., Kandeel, Fouad R., Katsuya, Tomohiro, Khor, Chiea Chuen, Kiess, Wieland, Kolcic, Ivana, Kuulasmaa, Teemu, Kuusisto, Johanna, Läll, Kristi, Lam, Kelvin, Lawlor, Deborah A., Lee, Nanette R., Lemaitre, Rozenn N., Li, Honglan, Lin, Shih-Yi, Lindström, Jaana, Linneberg, Allan, Liu, Jianjun, Lorenzo, Carlos, Matsubara, Tatsuaki, Matsuda, Fumihiko, Mingrone, Geltrude, Mooijaart, Simon, Moon, Sanghoon, Nabika, Toru, Nadkarni, Girish N., Nadler, Jerry L., Nelis, Mari, Neville, Matt J., Norris, Jill M., Ohyagi, Yasumasa, Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Qi, Qibin, Raven, Dennis, Reilly, Dermot F., Reiner, Alex, Rivideneira, Fernando, Roll, Kathryn, Rudan, Igor, Sabanayagam, Charumathi, Sandow, Kevin, Sattar, Naveed, Schürmann, Annette, Shi, Jinxiu, Stringham, Heather M., Taylor, Kent D., Teslovich, Tanya M., Thuesen, Betina, Timmers, Paul R H J, Tremoli, Elena, Tsai, Michael Y., Uitterlinden, Andre, van Dam, Rob M., van Heemst, Diana, van Hylckama Vlieg, Astrid, van Vliet-Ostaptchouk, Jana V., Vangipurapu, Jagadish, Vestergaard, Henrik, Wang, Tao, Willems van Dijk, Ko, Zemunik, Tatijana, Abecasis, Gonçalo R, Adair, Linda S., Aguilar-Salinas, Carlos Alberto, Alarcón-Riquelme, Marta E., An, Ping, Aviles-Santa, Larissa, Becker, Diane M., Beilin, Lawrence J., Bergmann, Sven, Bisgaard, Hans, Black, Corri, Boehnke, Michael, Boerwinkle, Eric, Böhm, Bernhard O., Bønnelykke, Klaus, Boomsma, D.I., Bottinger, Erwin P., Buchanan, Thomas A., Canouil, Mickaël, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Cheng, Ching-Yu, Collins, Francis S., Correa, Adolfo, Cucca, Francesco, de Silva, H Janaka, Dedoussis, George, Elmståhl, Sölve, Evans, Michele K., Ferrannini, Ele, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Frayling, Timothy M., Froguel, Philippe, Gigante, Bruna, Goodarzi, Mark O., Gordon-Larsen, Penny, Grallert, Harald, Grarup, Niels, Grimsgaard, Sameline, Groop, Leif, Gudnason, Vilmundur, Guo, Xiuqing, Hamsten, Anders, Hansen, Torben, Hayward, Caroline, Heckbert, Susan R., Horta, Bernardo L., Huang, Wei, Ingelsson, Erik, James, Pankow S., Jarvelin, Marjo-Ritta, Jonas, Jost B., Jukema, J Wouter, Kaleebu, Pontiano, Kaplan, Robert, Kardia, Sharon L R, Kato, Norihiro, Keinanen-Kiukaanniemi, Sirkka M., Kim, Bong-Jo, Kivimaki, Mika, Koistinen, Heikki A., Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kuh, Diana, Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lakka, Timo A., Launer, Lenore J., Leander, Karin, Li, Huaixing, Lin, Xu, Lind, Lars, Lindgren, Cecilia, Liu, Simin, Loos, Ruth J F, Magnusson, Patrik K E, Mahajan, Anubha, Metspalu, Andres, Mook-Kanamori, Dennis O., Mori, Trevor A., Munroe, Patricia B., Njølstad, Inger, O'Connell, Jeffrey R., Oldehinkel, Albertine J., Ong, Ken K., Padmanabhan, Sandosh, Palmer, Colin N A, Palmer, Nicholette D., Pedersen, Oluf, Pennell, Craig E., Porteous, David J., Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Qi, Lu, Raffel, Leslie J., Rauramaa, Rainer, Redline, Susan, Ridker, Paul M., Rosendaal, Frits R., Saaristo, Timo E., Sandhu, Manjinder, Saramies, Jouko, Schneiderman, Neil, Schwarz, Peter, Scott, Laura J., Selvin, Elizabeth, Sever, Peter, Shu, Xiao-Ou, Slagboom, P Eline, Small, Kerrin S., Smith, Blair H., Snieder, Harold, Sofer, Tamar, Sørensen, Thorkild I A, Spector, Tim D., Stanton, Alice, Steves, Claire J., Stumvoll, Michael, Sun, Liang, Tabara, Yasuharu, Tai, E Shyong, Timpson, Nicholas J., Tönjes, Anke, Tuomilehto, Jaakko, Tusie, Teresa, Uusitupa, Matti, van der Harst, Pim, van Duijn, Cornelia, Vitart, Veronique, Vollenweider, Peter, Vrijkotte, Tanja G M, Wagenknecht, Lynne E., Walker, Mark, Wang, Ya X., Wareham, Nick J., Watanabe, Richard M., Watkins, Hugh, Wei, Wen B., Wickremasinghe, Ananda R., Willemsen, Gonneke, Wilson, James F., Wong, Tien-Yin, Wu, Jer-Yuarn, Xiang, Anny H., Yanek, Lisa R., Yengo, Loïc, Yokota, Mitsuhiro, Zeggini, Eleftheria, Zheng, Wei, Zonderman, Alan B., Rotter, Jerome I., Gloyn, Anna L., McCarthy, Mark I., Dupuis, Josée, Meigs, James B., Scott, Robert A., Prokopenko, Inga, Leong, Aaron, Liu, Ching-Ti, Parker, Stephen C J, Mohlke, Karen L., Langenberg, Claudia, Wheeler, Eleanor, Morris, Andrew P., Barroso, Inês, Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian'an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, Waage, Johannes, Li-Gao, Ruifang, Chan, Kei Hang Katie, Yao, Jie, Anasanti, Mila D., Chu, Audrey Y., Claringbould, Annique, Heikkinen, Jani, Hong, Jaeyoung, Hottenga, Jouke-Jan, Huo, Shaofeng, Kaakinen, Marika A., Louie, Tin, März, Winfried, Moreno-Macias, Hortensia, Ndungu, Anne, Nelson, Sarah C., Nolte, Ilja M., North, Kari E., Raulerson, Chelsea K., Ray, Debashree, Rohde, Rebecca, Rybin, Denis, Schurmann, Claudia, Sim, Xueling, Southam, Lorraine, Stewart, Isobel D., Wang, Carol A., Wang, Yujie, Wu, Peitao, Zhang, Weihua, Ahluwalia, Tarunveer S., Appel, Emil V R, Bielak, Lawrence F., Brody, Jennifer A., Burtt, Noël P, Cabrera, Claudia P., Cade, Brian E., Chai, Jin Fang, Chai, Xiaoran, Chang, Li-Ching, Chen, Chien-Hsiun, Chen, Brian H., Chitrala, Kumaraswamy Naidu, Chiu, Yen-Feng, de Haan, Hugoline G., Delgado, Graciela E., Demirkan, Ayse, Duan, Qing, Engmann, Jorgen, Fatumo, Segun A., Gayán, Javier, Giulianini, Franco, Gong, Jung Ho, Gustafsson, Stefan, Hai, Yang, Hartwig, Fernando P., He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Hwang, Mi Yeong, Jensen, Richard A., Kawaguchi, Takahisa, Kentistou, Katherine A., Kim, Young Jin, Kleber, Marcus E., Kooner, Ishminder K., Lai, Shuiqing, Lange, Leslie A., Langefeld, Carl D., Lauzon, Marie, Li, Man, Ligthart, Symen, Liu, Jun, Loh, Marie, Long, Jirong, Lyssenko, Valeriya, Mangino, Massimo, Marzi, Carola, Montasser, May E., Nag, Abhishek, Nakatochi, Masahiro, Noce, Damia, Noordam, Raymond, Pistis, Giorgio, Preuss, Michael, Raffield, Laura, Rasmussen-Torvik, Laura J., Rich, Stephen S., Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Sanna, Serena, Saxena, Richa, Schraut, Katharina E., Sennblad, Bengt, Setoh, Kazuya, Smith, Albert V., Sparsø, Thomas, Strawbridge, Rona J., Takeuchi, Fumihiko, Tan, Jingyi, Trompet, Stella, van den Akker, Erik, van der Most, Peter J., Verweij, Niek, Vogel, Mandy, Wang, Heming, Wang, Chaolong, Wang, Nan, Warren, Helen R., Wen, Wanqing, Wilsgaard, Tom, Wong, Andrew, Wood, Andrew R., Xie, Tian, Zafarmand, Mohammad Hadi, Zhao, Jing-Hua, Zhao, Wei, Amin, Najaf, Arzumanyan, Zorayr, Astrup, Arne, Bakker, Stephan J L, Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bertoni, Alain, Blüher, Matthias, Bonnycastle, Lori L., Bornstein, Stefan R., Bowden, Donald W., Cai, Qiuyin, Campbell, Archie, Campbell, Harry, Chang, Yi Cheng, de Geus, Eco J C, Dehghan, Abbas, Du, Shufa, Eiriksdottir, Gudny, Farmaki, Aliki Eleni, Frånberg, Mattias, Fuchsberger, Christian, Gao, Yutang, Gjesing, Anette P., Goel, Anuj, Han, Sohee, Hartman, Catharina A., Herder, Christian, Hicks, Andrew A., Hsieh, Chang-Hsun, Hsueh, Willa A., Ichihara, Sahoko, Igase, Michiya, Ikram, M Arfan, Johnson, W Craig, Jørgensen, Marit E., Joshi, Peter K., Kalyani, Rita R., Kandeel, Fouad R., Katsuya, Tomohiro, Khor, Chiea Chuen, Kiess, Wieland, Kolcic, Ivana, Kuulasmaa, Teemu, Kuusisto, Johanna, Läll, Kristi, Lam, Kelvin, Lawlor, Deborah A., Lee, Nanette R., Lemaitre, Rozenn N., Li, Honglan, Lin, Shih-Yi, Lindström, Jaana, Linneberg, Allan, Liu, Jianjun, Lorenzo, Carlos, Matsubara, Tatsuaki, Matsuda, Fumihiko, Mingrone, Geltrude, Mooijaart, Simon, Moon, Sanghoon, Nabika, Toru, Nadkarni, Girish N., Nadler, Jerry L., Nelis, Mari, Neville, Matt J., Norris, Jill M., Ohyagi, Yasumasa, Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Qi, Qibin, Raven, Dennis, Reilly, Dermot F., Reiner, Alex, Rivideneira, Fernando, Roll, Kathryn, Rudan, Igor, Sabanayagam, Charumathi, Sandow, Kevin, Sattar, Naveed, Schürmann, Annette, Shi, Jinxiu, Stringham, Heather M., Taylor, Kent D., Teslovich, Tanya M., Thuesen, Betina, Timmers, Paul R H J, Tremoli, Elena, Tsai, Michael Y., Uitterlinden, Andre, van Dam, Rob M., van Heemst, Diana, van Hylckama Vlieg, Astrid, van Vliet-Ostaptchouk, Jana V., Vangipurapu, Jagadish, Vestergaard, Henrik, Wang, Tao, Willems van Dijk, Ko, Zemunik, Tatijana, Abecasis, Gonçalo R, Adair, Linda S., Aguilar-Salinas, Carlos Alberto, Alarcón-Riquelme, Marta E., An, Ping, Aviles-Santa, Larissa, Becker, Diane M., Beilin, Lawrence J., Bergmann, Sven, Bisgaard, Hans, Black, Corri, Boehnke, Michael, Boerwinkle, Eric, Böhm, Bernhard O., Bønnelykke, Klaus, Boomsma, D.I., Bottinger, Erwin P., Buchanan, Thomas A., Canouil, Mickaël, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Cheng, Ching-Yu, Collins, Francis S., Correa, Adolfo, Cucca, Francesco, de Silva, H Janaka, Dedoussis, George, Elmståhl, Sölve, Evans, Michele K., Ferrannini, Ele, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Frayling, Timothy M., Froguel, Philippe, Gigante, Bruna, Goodarzi, Mark O., Gordon-Larsen, Penny, Grallert, Harald, Grarup, Niels, Grimsgaard, Sameline, Groop, Leif, Gudnason, Vilmundur, Guo, Xiuqing, Hamsten, Anders, Hansen, Torben, Hayward, Caroline, Heckbert, Susan R., Horta, Bernardo L., Huang, Wei, Ingelsson, Erik, James, Pankow S., Jarvelin, Marjo-Ritta, Jonas, Jost B., Jukema, J Wouter, Kaleebu, Pontiano, Kaplan, Robert, Kardia, Sharon L R, Kato, Norihiro, Keinanen-Kiukaanniemi, Sirkka M., Kim, Bong-Jo, Kivimaki, Mika, Koistinen, Heikki A., Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kuh, Diana, Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lakka, Timo A., Launer, Lenore J., Leander, Karin, Li, Huaixing, Lin, Xu, Lind, Lars, Lindgren, Cecilia, Liu, Simin, Loos, Ruth J F, Magnusson, Patrik K E, Mahajan, Anubha, Metspalu, Andres, Mook-Kanamori, Dennis O., Mori, Trevor A., Munroe, Patricia B., Njølstad, Inger, O'Connell, Jeffrey R., Oldehinkel, Albertine J., Ong, Ken K., Padmanabhan, Sandosh, Palmer, Colin N A, Palmer, Nicholette D., Pedersen, Oluf, Pennell, Craig E., Porteous, David J., Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Qi, Lu, Raffel, Leslie J., Rauramaa, Rainer, Redline, Susan, Ridker, Paul M., Rosendaal, Frits R., Saaristo, Timo E., Sandhu, Manjinder, Saramies, Jouko, Schneiderman, Neil, Schwarz, Peter, Scott, Laura J., Selvin, Elizabeth, Sever, Peter, Shu, Xiao-Ou, Slagboom, P Eline, Small, Kerrin S., Smith, Blair H., Snieder, Harold, Sofer, Tamar, Sørensen, Thorkild I A, Spector, Tim D., Stanton, Alice, Steves, Claire J., Stumvoll, Michael, Sun, Liang, Tabara, Yasuharu, Tai, E Shyong, Timpson, Nicholas J., Tönjes, Anke, Tuomilehto, Jaakko, Tusie, Teresa, Uusitupa, Matti, van der Harst, Pim, van Duijn, Cornelia, Vitart, Veronique, Vollenweider, Peter, Vrijkotte, Tanja G M, Wagenknecht, Lynne E., Walker, Mark, Wang, Ya X., Wareham, Nick J., Watanabe, Richard M., Watkins, Hugh, Wei, Wen B., Wickremasinghe, Ananda R., Willemsen, Gonneke, Wilson, James F., Wong, Tien-Yin, Wu, Jer-Yuarn, Xiang, Anny H., Yanek, Lisa R., Yengo, Loïc, Yokota, Mitsuhiro, Zeggini, Eleftheria, Zheng, Wei, Zonderman, Alan B., Rotter, Jerome I., Gloyn, Anna L., McCarthy, Mark I., Dupuis, Josée, Meigs, James B., Scott, Robert A., Prokopenko, Inga, Leong, Aaron, Liu, Ching-Ti, Parker, Stephen C J, Mohlke, Karen L., Langenberg, Claudia, Wheeler, Eleanor, Morris, Andrew P., and Barroso, Inês

Abstract

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

Published
2021
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130. Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

Author

Ahluwalia, Tarunveer S, Prins, Bram P, Abdollahi, Mohammadreza, Armstrong, Nicola J, Aslibekyan, Stella, Bain, Lisa, Jefferis, Barbara, Baumert, Jens, Beekman, Marian, Ben-Shlomo, Yoav, Bis, Joshua C, Mitchell, Braxton D, de Geus, Eco, Delgado, Graciela E, Marek, Diana, Eriksson, Joel, Kajantie, Eero, Kanoni, Stavroula, Kemp, John P, Lu, Chen, Marioni, Riccardo E, McLachlan, Stela, Milaneschi, Yuri, Nolte, Ilja M, Petrelis, Alexandros M, Porcu, Eleonora, Sabater-Lleal, Maria, Naderi, Elnaz, Seppälä, Ilkka, Shah, Tina, Singhal, Gaurav, Standl, Marie, Teumer, Alexander, Thalamuthu, Anbupalam, Thiering, Elisabeth, Trompet, Stella, Ballantyne, Christie M, Benjamin, Emelia J, Casas, Juan P, Toben, Catherine, Dedoussis, George, Deelen, Joris, Durda, Peter, Engmann, Jorgen, Feitosa, Mary F, Grallert, Harald, Hammarstedt, Ann, Jess, Tine, Rossing, Peter, Sørensen, Thorkild I A, Ahluwalia, Tarunveer S, Prins, Bram P, Abdollahi, Mohammadreza, Armstrong, Nicola J, Aslibekyan, Stella, Bain, Lisa, Jefferis, Barbara, Baumert, Jens, Beekman, Marian, Ben-Shlomo, Yoav, Bis, Joshua C, Mitchell, Braxton D, de Geus, Eco, Delgado, Graciela E, Marek, Diana, Eriksson, Joel, Kajantie, Eero, Kanoni, Stavroula, Kemp, John P, Lu, Chen, Marioni, Riccardo E, McLachlan, Stela, Milaneschi, Yuri, Nolte, Ilja M, Petrelis, Alexandros M, Porcu, Eleonora, Sabater-Lleal, Maria, Naderi, Elnaz, Seppälä, Ilkka, Shah, Tina, Singhal, Gaurav, Standl, Marie, Teumer, Alexander, Thalamuthu, Anbupalam, Thiering, Elisabeth, Trompet, Stella, Ballantyne, Christie M, Benjamin, Emelia J, Casas, Juan P, Toben, Catherine, Dedoussis, George, Deelen, Joris, Durda, Peter, Engmann, Jorgen, Feitosa, Mary F, Grallert, Harald, Hammarstedt, Ann, Jess, Tine, Rossing, Peter, and Sørensen, Thorkild I A

Abstract

Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Published
2021

131. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Author

Merid, Simon Kebede, Novoloaca, Alexei, Sharp, Gemma C, Küpers, Leanne K, Kho, Alvin T, Roy, Ritu, Gao, Lu, Annesi-Maesano, Isabella, Jain, Pooja, Plusquin, Michelle, Kogevinas, Manolis, Allard, Catherine, Vehmeijer, Florianne O, Kazmi, Nabila, Salas, Lucas A, Rezwan, Faisal I, Zhang, Hongmei, Sebert, Sylvain, Czamara, Darina, Rifas-Shiman, Sheryl L, Melton, Phillip E, Lawlor, Debbie A, Pershagen, Göran, Breton, Carrie V, Huen, Karen, Baiz, Nour, Gagliardi, Luigi, Nawrot, Tim S, Corpeleijn, Eva, Perron, Patrice, Duijts, Liesbeth, Nohr, Ellen Aagaard, Bustamante, Mariona, Ewart, Susan L, Karmaus, Wilfried, Zhao, Shanshan, Page, Christian M, Herceg, Zdenko, Jarvelin, Marjo-Riitta, Lahti, Jari, Baccarelli, Andrea A, Anderson, Denise, Kachroo, Priyadarshini, Relton, Caroline L, Bergström, Anna, Eskenazi, Brenda, Soomro, Munawar Hussain, Vineis, Paolo, Snieder, Harold, Bouchard, Luigi, Jaddoe, Vincent W, Sørensen, Thorkild I A, Vrijheid, Martine, Arshad, S Hasan, Holloway, John W, Håberg, Siri E, Magnus, Per, Dwyer, Terence, Binder, Elisabeth B, DeMeo, Dawn L, Vonk, Judith M, Newnham, John, Tantisira, Kelan G, Kull, Inger, Wiemels, Joseph L, Heude, Barbara, Sunyer, Jordi, Nystad, Wenche, Munthe-Kaas, Monica C, Räikkönen, Katri, Oken, Emily, Huang, Rae-Chi, Weiss, Scott T, Antó, Josep Maria, Bousquet, Jean, Kumar, Ashish, Söderhäll, Cilla, Almqvist, Catarina, Cardenas, Andres, Gruzieva, Olena, Xu, Cheng-Jian, Reese, Sarah E, Kere, Juha, Brodin, Petter, Solomon, Olivia, Wielscher, Matthias, Holland, Nina, Ghantous, Akram, Hivert, Marie-France, Felix, Janine F, Koppelman, Gerard H, London, Stephanie J, Melén, Erik, Merid, Simon Kebede, Novoloaca, Alexei, Sharp, Gemma C, Küpers, Leanne K, Kho, Alvin T, Roy, Ritu, Gao, Lu, Annesi-Maesano, Isabella, Jain, Pooja, Plusquin, Michelle, Kogevinas, Manolis, Allard, Catherine, Vehmeijer, Florianne O, Kazmi, Nabila, Salas, Lucas A, Rezwan, Faisal I, Zhang, Hongmei, Sebert, Sylvain, Czamara, Darina, Rifas-Shiman, Sheryl L, Melton, Phillip E, Lawlor, Debbie A, Pershagen, Göran, Breton, Carrie V, Huen, Karen, Baiz, Nour, Gagliardi, Luigi, Nawrot, Tim S, Corpeleijn, Eva, Perron, Patrice, Duijts, Liesbeth, Nohr, Ellen Aagaard, Bustamante, Mariona, Ewart, Susan L, Karmaus, Wilfried, Zhao, Shanshan, Page, Christian M, Herceg, Zdenko, Jarvelin, Marjo-Riitta, Lahti, Jari, Baccarelli, Andrea A, Anderson, Denise, Kachroo, Priyadarshini, Relton, Caroline L, Bergström, Anna, Eskenazi, Brenda, Soomro, Munawar Hussain, Vineis, Paolo, Snieder, Harold, Bouchard, Luigi, Jaddoe, Vincent W, Sørensen, Thorkild I A, Vrijheid, Martine, Arshad, S Hasan, Holloway, John W, Håberg, Siri E, Magnus, Per, Dwyer, Terence, Binder, Elisabeth B, DeMeo, Dawn L, Vonk, Judith M, Newnham, John, Tantisira, Kelan G, Kull, Inger, Wiemels, Joseph L, Heude, Barbara, Sunyer, Jordi, Nystad, Wenche, Munthe-Kaas, Monica C, Räikkönen, Katri, Oken, Emily, Huang, Rae-Chi, Weiss, Scott T, Antó, Josep Maria, Bousquet, Jean, Kumar, Ashish, Söderhäll, Cilla, Almqvist, Catarina, Cardenas, Andres, Gruzieva, Olena, Xu, Cheng-Jian, Reese, Sarah E, Kere, Juha, Brodin, Petter, Solomon, Olivia, Wielscher, Matthias, Holland, Nina, Ghantous, Akram, Hivert, Marie-France, Felix, Janine F, Koppelman, Gerard H, London, Stephanie J, and Melén, Erik

Abstract

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Published
2021

132. Body mass index and height in young adult men in relation to subsequent risk of mood disorder

Author

Okholm, Gunhild Tidemann, Jorgensen, Terese Sara Hoj, Rozing, Maarten Pieter, Wium-Andersen, Marie Kim, Wium-Andersen, Ida Kim, Jorgensen, Martin Balslev, Sørensen, Thorkild I. A., Osler, Merete, Okholm, Gunhild Tidemann, Jorgensen, Terese Sara Hoj, Rozing, Maarten Pieter, Wium-Andersen, Marie Kim, Wium-Andersen, Ida Kim, Jorgensen, Martin Balslev, Sørensen, Thorkild I. A., and Osler, Merete

Abstract

Adolescence represents an important period in brain and mental development, which raises the question of whether measures of body size at entry into adult life influence the risk of developing mood disorders. We examined the association of BMI and height in a cohort of young men with risk of mood disorders throughout life. The study included 630,807 Danish men born 1939-1959 and 1983-1997 with measures of height and weight at conscription board examinations. Psychiatrist's diagnosis of mood disorders was obtained from national patient registries from 1969 to 2016. The associations of BMI and height with mood disorders were estimated by Cox proportional hazard regression analyses adjusting for education, cognitive ability, migration status drug and alcohol misuse. During a mean follow-up of 26.3 years, 2,608 (0.6%) and 19,690 (3.1%) men were diagnosed with bipolar disorder and depression, respectively. We found an inverse linear association of BMI with risk of bipolar disorder, whereas the association of BMI with depression was curve-linear with a decline in risk until BMI around 25 kg/m(2), and an almost constant risk across the BMI range above 25 kg/m(2). Height was not associated with bipolar disorder or depression. Comparison of brothers, assumed to share family factors of possible influence on the risk of mood disorders, showed similar results although with wider confidence intervals. BMI in the lower range at men's entry into adulthood is inversely associated with risk of bipolar disorder and depression throughout adult life, whereas height is not related.

Published
2021

133. Genetic markers of abdominal obesity and weight loss after gastric bypass surgery

Author

Aasbrenn, Martin, Svendstrup, Mathilde, Schnurr, Theresia M., Hansen, Dorte Lindqvist, Worm, Dorte, Balslev-Harder, Marie, Grarup, Niels, Burgdorf, Kristoffer Sølvsten, Vestergaard, Henrik, Pedersen, Oluf, Angquist, Lars, Fenger, Mogens, Sørensen, Thorkild I. A., Madsbad, Sten, Hansen, Torben, Aasbrenn, Martin, Svendstrup, Mathilde, Schnurr, Theresia M., Hansen, Dorte Lindqvist, Worm, Dorte, Balslev-Harder, Marie, Grarup, Niels, Burgdorf, Kristoffer Sølvsten, Vestergaard, Henrik, Pedersen, Oluf, Angquist, Lars, Fenger, Mogens, Sørensen, Thorkild I. A., Madsbad, Sten, and Hansen, Torben

Abstract

Background Weight loss after bariatric surgery varies widely between individuals, partly due to genetic differences. In addition, genetic determinants of abdominal obesity have been shown to attenuate weight loss after dietary intervention with special attention paid to the rs1358980-T risk allele in the VEGFA locus. Here we aimed to test if updated genetic risk scores (GRSs) for adiposity measures and the rs1358980-T risk allele are linked with weight loss following gastric bypass surgery.Methods Five hundred seventy six patients with morbid obesity underwent Roux-en-Y gastric bypass. A GRS for BMI and a GRS for waist-hip-ratio adjusted for BMI (proxy for abdominal obesity), respectively, were constructed. All patients were genotyped for the rs1358980-T risk allele. Associations between the genetic determinants and weight loss after bariatric surgery were evaluated.Results The GRS for BMI was not associated with weight loss (beta = -2.0 kg/100 risk alleles, 95% CI -7.5 to 3.3, p = 0.45). Even though the GRS for abdominal obesity was associated with an attenuated weight loss response adjusted for age, sex and center (beta = -14.6 kg/100 risk alleles, 95% CI -25.4 to -3.8, p = 0.008), it was not significantly associated with weight loss after adjustment for baseline BMI (beta = -7.9 kg/100 risk alleles, 95% CI -17.5 to 1.6, p = 0.11). Similarly, the rs1358980-T risk allele was not significantly associated with weight loss (beta = -0.8 kg/risk allele, 95% CI -2.2 to 0.6, p = 0.25).Discussion GRSs for adiposity derived from large meta-analyses and the rs1358980-T risk allele in the VEGFA locus did not predict weight loss after gastric bypass surgery. The association between a GRS for abdominal obesity and the response to bariatric surgery may be dependent on the association between the GRS and baseline BMI.

Published
2021

134. Fasting plasma GLP-1 associates with overweight/obesity and cardiometabolic risk factors in children and adolescents

Author

Stinson, Sara E, Jonsson, Anna E, Lund, Morten A V, Frithioff-Bøjsøe, Christine, Holm, Louise Aas, Pedersen, Oluf, Ängquist, Lars, Sørensen, Thorkild I. A., Holst, Jens J, Christiansen, Michael, Holm, Jens-Christian, Hartmann, Bolette, Hansen, Torben, Stinson, Sara E, Jonsson, Anna E, Lund, Morten A V, Frithioff-Bøjsøe, Christine, Holm, Louise Aas, Pedersen, Oluf, Ängquist, Lars, Sørensen, Thorkild I. A., Holst, Jens J, Christiansen, Michael, Holm, Jens-Christian, Hartmann, Bolette, and Hansen, Torben

Abstract

CONTEXT: The importance of fasting GLP-1 in altered metabolic outcomes has been questioned.OBJECTIVE: To assess if fasting GLP-1 differs in children and adolescents with overweight/obesity compared to a population-based reference, and whether concentrations predict cardiometabolic risk (CMR) factors.METHODS: Analyses were based on The Danish Childhood Obesity Data- and Biobank, a cross-sectional study including children and adolescents, 6-19 years old, from an obesity clinic group (n = 1978) and from a population-based group (n = 2334). Fasting concentrations of plasma total GLP-1 and quantitative CMR factors were assessed. The effects of GLP-1 as a predictor of CMR risk outcomes were examined by multiple linear and logistic regression modelling.RESULTS: The obesity clinic group had higher fasting GLP-1 concentrations (median 3.3 pmol/L; interquartile range 2.3-4.3) than the population-based group (2.8 pmol/L; 2.1-3.8; P < 2.2E-16). BMI SDS, waist circumference and total body fat percentage were significant predictors of fasting GLP-1 concentrations in boys and girls. Fasting GLP-1 concentrations positively associated with HOMA-IR, fasting values of insulin, hs-CRP, C-peptide, triglycerides, ALT, HbA1c and SDS of diastolic and systolic blood pressure. A 1-SD increase in fasting GLP-1 associated with an increased risk of insulin resistance (Odds ratio [OR] 1.59), dyslipidemia (OR 1.16), increased ALT (OR 1.14), hyperglycemia (OR 1.12) and hypertension (OR 1.12).CONCLUSIONS: Overweight/obesity in children and adolescents is associated with increased fasting plasma total GLP-1 concentrations, which was predictive of higher cardiometabolic risk factors.

Published
2021

135. Evidence for shared genetics between physical activity, sedentary behaviour and adiposity-related traits

Author

Schnurr, Theresia M., Stallknecht, Bente M., Sørensen, Thorkild I. A., Kilpelainen, Tuomas O., Hansen, Torben, Schnurr, Theresia M., Stallknecht, Bente M., Sørensen, Thorkild I. A., Kilpelainen, Tuomas O., and Hansen, Torben

Abstract

Observational, cross-sectional and longitudinal studies showed that physical activity and sedentary behaviour are associated with adiposity-related traits, apparently in a bidirectional manner. Physical activity is also suggested to suppress the genetic risk of adiposity. Since phenotypic associations with genetic variants are not subject to reverse causation or confounding, they may be used as tools to shed light on cause and effect in this complex interdependency. We review the evidence for shared genetics of physical activity and adiposity-related traits and for gene-by-physical activity interactions on adiposity-related traits in human studies. We outline limitations, challenges and opportunities in studying and understanding of these relationships. In summary, physical activity and sedentary behaviour are genetically correlated with body mass index and fat percentage but may not be correlated with lean body mass. Mendelian randomisation analyses show that physical activity and sedentary behaviour have bidirectional relationships with adiposity. Several studies suggest that physical activity suppresses genetic risk of adiposity. No studies have yet tested whether adiposity enhances genetic predisposition to sedentariness. The complexity of the comprehensive causal model makes the assessment of the single or combined components challenging. Substantial progress in this field may need long-term intervention studies.

Published
2021

136. Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity

Author

Deshmukh, Harshal A, Madsen, Anne Lundager, Viñuela, Ana, Have, Christian Theil, Grarup, Niels, Tura, Andrea, Mahajan, Anubha, Heggie, Alison J, Koivula, Robert W, De Masi, Federico, Tsirigos, Konstantinos K, Linneberg, Allan, Drivsholm, Thomas, Pedersen, Oluf, Sørensen, Thorkild I A, Astrup, Arne, Gjesing, Anette A P, Pavo, Imre, Wood, Andrew R, Ruetten, Hartmut, Jones, Angus G, Koopman, Anitra D M, Cederberg, Henna, Rutters, Femke, Ridderstrale, Martin, Laakso, Markku, McCarthy, Mark I, Frayling, Tim M, Ferrannini, Ele, Franks, Paul W, Pearson, Ewan R, Mari, Andrea, Hansen, Torban, Walker, Mark, Deshmukh, Harshal A, Madsen, Anne Lundager, Viñuela, Ana, Have, Christian Theil, Grarup, Niels, Tura, Andrea, Mahajan, Anubha, Heggie, Alison J, Koivula, Robert W, De Masi, Federico, Tsirigos, Konstantinos K, Linneberg, Allan, Drivsholm, Thomas, Pedersen, Oluf, Sørensen, Thorkild I A, Astrup, Arne, Gjesing, Anette A P, Pavo, Imre, Wood, Andrew R, Ruetten, Hartmut, Jones, Angus G, Koopman, Anitra D M, Cederberg, Henna, Rutters, Femke, Ridderstrale, Martin, Laakso, Markku, McCarthy, Mark I, Frayling, Tim M, Ferrannini, Ele, Franks, Paul W, Pearson, Ewan R, Mari, Andrea, Hansen, Torban, and Walker, Mark

Abstract

Context: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta cell glucose sensitivity.Objective: To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies.Design: We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and non-diabetic subjects from 6 independent cohorts (n=5,706). Beta-cell glucose sensitivity was calculated from mixed-meal and oral glucose tolerance tests, and its associations between known glycaemia related SNPS and GWAS SNPs were estimated using linear regression models.Results: Beta-cell glucose sensitivity was moderately heritable (h2 ranged between 34 to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P-value=2.64x10-9) and rs9368219 in the CDKAL1 (P-value=3.15x10-9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity.Conclusion: We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta cell glucose sensitivity.

Published
2021

137. Overweight in childhood of exclusively breastfed infants with a high weight at 5 months

Author

Morgen, Camilla Schmidt, Larsson, Melanie Wange, Ängquist, Lars, Sørensen, Thorkild I A, Michaelsen, Kim F., Morgen, Camilla Schmidt, Larsson, Melanie Wange, Ängquist, Lars, Sørensen, Thorkild I A, and Michaelsen, Kim F.

Abstract

High infant weight increases the risk of childhood overweight, while breastfeeding may reduce the risk. However, some infants have a very high weight gain even though they are exclusively breastfed. We examined the risk of a high body mass index (BMI) and overweight in childhood for infants ≥2.5 SD above the median weight-for-age (WAZ) at age 5 months according to duration of exclusive breastfeeding (≤2, >2 to <4 or ≥4 months). The study is based on 13,401 7-year-old and 9,819 11-year-old children enrolled into the Danish National Birth Cohort (born 1997-2003). Linear and logistic regression analyses were used to examine the associations while adjusting for presumed confounders including birth weight. The results showed that infants ≥2.5 SD at 5 months, breastfed exclusively ≤2, >2 to <4 or ≥4 months had adjusted odds ratios (ORs) for overweight at age 7 at 3.67 (95% confidence interval [CI] [2.10, 6.43]), 3.42 (95% CI [2.32, 5.04]) and 3.19 (95% CI [1.90, 5.36]) respectively, when compared with infants <2.5 SD WAZ exclusively breastfed ≥4 months. The corresponding results for BMI z-scores were 0.82 (95% CI [0.60, 1.04]), 0.63 (95% CI [0.48, 0.78]) and 0.57 (95% CI [0.38, 0.77]). For the ≥2.5 SD infants, the differences in risk of overweight and BMI according to duration of exclusive breastfeeding were neither significantly different among the 7-year nor among the 11-year-old children. A high infant weight increases the odds of overweight and is associated with a higher BMI in childhood. Whereas the odds and BMI z-scores tended to be lower for those exclusively breastfed longer, the differences were not statistically significant.

Published
2021

143. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Author

Perry, John R. B., Day, Felix, Elks, Cathy E., Sulem, Patrick, Thompson, Deborah J., Ferreira, Teresa, He, Chunyan, Chasman, Daniel I., Esko, Tõnu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q., Corre, Tanguy, Cousminer, Diana L., Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D., Kjellqvist, Sanela, Lunetta, Kathryn L., McMahon, George, Nolte, Ilja M., Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Tšernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K., Amin, Najaf, Bierut, Laura J., Byrne, Enda M., Hottenga, Jouke-Jan, Koller, Daniel L., Mangino, Massimo, Pers, Tune H., Yerges-Armstrong, Laura M., Zhao, Jing Hua, Andrulis, Irene L., Anton-Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E., Chang-Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix-Trench, Georgia, Collée, Margriet J., Couch, Fergus J., Couper, David, Coviello, Andrea D., Cox, Angela, Czene, Kamila, D’adamo, Adamo Pio, Smith, George Davey, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K., Dunning, Alison M., Eiriksdottir, Gudny, Eriksson, Johan G., Fasching, Peter A., Ferrucci, Luigi, Flesch-Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E., García-Closas, Montserrat, Geller, Frank, de Geus, Eco E. J., Giles, Graham G., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Guénel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A., Heath, Andrew C., Hofman, Albert, Hooning, Maartje J., Hopper, John L., Hu, Frank B., Hunter, David J., Karasik, David, Kiel, Douglas P., Knight, Julia A., Kosma, Veli-Matti, Kutalik, Zoltan, Lai, Sandra, Lambrechts, Diether, Lindblom, Annika, Mägi, Reedik, Magnusson, Patrik K., Mannermaa, Arto, Martin, Nicholas G., Masson, Gisli, McArdle, Patrick F., McArdle, Wendy L., Melbye, Mads, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L., Nevanlinna, Heli, Neven, Patrick, Nohr, Ellen A., Oldehinkel, Albertine J., Oostra, Ben A., Palotie, Aarno, Peacock, Munro, Pedersen, Nancy L., Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P., Postma, Dirkje S., Pouta, Anneli, Pylkäs, Katri, Radice, Paolo, Ring, Susan, Rivadeneira, Fernando, Robino, Antonietta, Rose, Lynda M., Rudolph, Anja, Salomaa, Veikko, Sanna, Serena, Schlessinger, David, Schmidt, Marjanka K., Southey, Mellissa C., Sovio, Ulla, Stampfer, Meir J., Stöckl, Doris, Storniolo, Anna M., Timpson, Nicholas J., Tyrer, Jonathan, Visser, Jenny A., Vollenweider, Peter, Völzke, Henry, Waeber, Gerard, Waldenberger, Melanie, Wallaschofski, Henri, Wang, Qin, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Wright, Margaret J., Boomsma, Dorret I., Econs, Michael J., Khaw, Kay-Tee, Loos, Ruth J. F., McCarthy, Mark I., Montgomery, Grant W., Rice, John P., Streeten, Elizabeth A., Thorsteinsdottir, Unnur, van Duijn, Cornelia M., Alizadeh, Behrooz Z., Bergmann, Sven, Boerwinkle, Eric, Boyd, Heather A., Crisponi, Laura, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B., Ingelsson, Erik, Järvelin, Marjo-Riitta, Kraft, Peter, Lawlor, Debbie, Metspalu, Andres, Pennell, Craig E., Ridker, Paul M., Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Strachan, David P., Uitterlinden, André G., Wareham, Nicholas J., Widen, Elisabeth, Zygmunt, Marek, Murray, Anna, Easton, Douglas F., Stefansson, Kari, Murabito, Joanne M., and Ong, Ken K.

Published
2014
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145. Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios

Author

Besenbacher, Søren, Liu, Siyang, Izarzugaza, José M. G., Grove, Jakob, Belling, Kirstine, Bork-Jensen, Jette, Huang, Shujia, Als, Thomas D., Li, Shengting, Yadav, Rachita, Rubio-García, Arcadio, Lescai, Francesco, Demontis, Ditte, Rao, Junhua, Ye, Weijian, Mailund, Thomas, Friborg, Rune M., Pedersen, Christian N. S., Xu, Ruiqi, Sun, Jihua, Liu, Hao, Wang, Ou, Cheng, Xiaofang, Flores, David, Rydza, Emil, Rapacki, Kristoffer, Damm Sørensen, John, Chmura, Piotr, Westergaard, David, Dworzynski, Piotr, Sørensen, Thorkild I. A., Lund, Ole, Hansen, Torben, Xu, Xun, Li, Ning, Bolund, Lars, Pedersen, Oluf, Eiberg, Hans, Krogh, Anders, Børglum, Anders D., Brunak, Søren, Kristiansen, Karsten, Schierup, Mikkel H., Wang, Jun, Gupta, Ramneek, Villesen, Palle, and Rasmussen, Simon

Published
2015
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146. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences

Author

Karlsson Linnér, Richard, Biroli, Pietro, Kong, Edward, Meddens, S. Fleur W., Wedow, Robbee, Fontana, Mark Alan, Lebreton, Maël, Tino, Stephen P., Abdellaoui, Abdel, Hammerschlag, Anke R., Nivard, Michel G., Okbay, Aysu, Rietveld, Cornelius A., Timshel, Pascal N., Trzaskowski, Maciej, Vlaming, Ronald de, Zünd, Christian L., Bao, Yanchun, Buzdugan, Laura, Caplin, Ann H., Chen, Chia-Yen, Eibich, Peter, Fontanillas, Pierre, Gonzalez, Juan R., Joshi, Peter K., Karhunen, Ville, Kleinman, Aaron, Levin, Remy Z., Lill, Christina M., Meddens, Gerardus A., Muntané, Gerard, Sanchez-Roige, Sandra, Rooij, Frank J. van, Taskesen, Erdogan, Yang, Wu, Zhang, Futao, Agee, Michelle, Alipanahi, Babak, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Furlotte, Nicholas A., Huber, Karen E., Litterman, Nadia K., Mccreight, Jennifer C., Mcintyre, Matthew H., Mountain, Joanna L., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand, Awadalla, Philip, Battle, Alexis, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark, Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Gregory, Heijmans, Bastiaan, Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johannes, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg-Guzman, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Markus, Marigorta, Urko M., Metspalu, Andres, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthias, Penninx, Brenda, Perola, Markus, Pervjakova, Natalia, Pierce, Brandon, Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli, Ring, Susan, Ripatti, Samuli, Rotzchke, Olaf, Rüeger, Sina, Saha, Ashis, Scholz, Markus, Schramm, Katharina, Seppälä, Ilkka, Stumvoll, Michael, Sullivan, Patrick, Hoen, Peter-Bram t, Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, Dongen, Jenny van, Meurs, Joyce van, Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Beauchamp, Jonathan P., Lee, James J., Pers, Tune H., Turley, Patrick, Chen, Guo-Bo, Emilsson, Valur, Oskarsson, Sven, Pickrell, Joseph K., Thom, Kevin, Timshel, Pascal, de Vlaming, Ronald, Ahluwalia, Tarunveer S., Bacelis, Jonas, Baumbach, Clemens, Bjornsdottir, Gyda, Brandsma, Johannes H., Concas, Maria Pina, Derringer, Jaime, Galesloot, Tessel E., Girotto, Giorgia, Gupta, Richa, Hall, Leanne M., Harris, Sarah E., Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E., Kaasik, Kadri, Kalafati, Ioanna P., Karlsson, Robert, Kong, Augustine, Lahti, Jari, Lee, Sven J. van der, de Leeuw, Christiaan, Lind, Penelope A., Lindgren, Karl-Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B., Most, Peter J. van der, Oldmeadow, Christopher, Payton, Antony, Peyrot, Wouter J., Qian, Yong, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E., Shi, Jianxin, Smith, Albert V., Poot, Raymond A., Pourcain, Beate St, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z., Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E., Biino, Ginevra, Bønnelykke, Klaus, Boyle, Patricia A., Campbell, Harry, Cappuccio, Francesco P., Davies, Gail, De Neve, Jan-Emmanuel, Deloukas, Panos, Demuth, Ilja, Ding, Jun, Eisele, Lewin, Eklund, Niina, Evans, David M., Faul, Jessica D., Feitosa, Mary F., Forstner, Andreas J., Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V., Harris, Tamara B., Heath, Andrew C., Hocking, Lynne J., Holliday, Elizabeth G., Homuth, Georg, Horan, Michael A., Hottenga, Jouke-Jan, de Jager, Philip L., Jugessur, Astanand, Kaakinen, Marika A., Kanoni, Stavroula, Keltigangas-Järvinen, Liisa, Kiemeney, Lambertus A. L. M., Kolcic, Ivana, Koskinen, Seppo, Kraja, Aldi T., Kroh, Martin, Latvala, Antti, Launer, Lenore J., Lebreton, Maël P., Levinson, Douglas F., Lichtenstein, Paul, Lichtner, Peter, Liewald, David C. M., Loukola, Anu, Madden, Pamela A., Mägi, Reedik, Mäki-Opas, Tomi, Marioni, Riccardo E., Marques-Vidal, Pedro, Mcmahon, George, Meisinger, Christa, Meitinger, Thomas, Milaneschi, Yusplitri, Myhre, Ronny, Nelson, Christopher P., Nyholt, Dale R., Ollier, William E. R., Palotie, Aarno, Paternoster, Lavinia, Pedersen, Nancy L., Petrovic, Katja E., Porteous, David J., Räikkönen, Katri, Ring, Susan M., Robino, Antonietta, Rostapshova, Olga, Rudan, Igor, Rustichini, Aldo, Salomaa, Veikko, Sanders, Alan R., Sarin, Antti-Pekka, Schmidt, Helena, Scott, Rodney J., Smith, Blair H., Smith, Jennifer A., Staessen, Jan A., Steinhagen-Thiessen, Elisabeth, Strauch, Konstantin, Terracciano, Antonio, Tobin, Martin D., Ulivi, Sheila, Vaccargiu, Simona, Quaye, Lydia, Venturini, Cristina, Vinkhuyzen, Anna A. E., Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johannes, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klaus, Bertram, Lars, Bisgaard, Hans, Borecki, Ingrid B, Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., Duijn, Cornelia M. van, Eriksson, Johan G., Franke, Barbara, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans-Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, Harst, Pim van der, Hayward, Caroline, Hinds, David A., Hoffmann, Wolfgang, Hyppönen, Elina, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Pendleton, Neil, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Smith, George Davey, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Johannesson, Magnus, Koellinger, Philipp D., Cesarini, David, Benjamin, Daniel J., Auton, Adam, Boardman, Jason D., Clark, David W., Conlin, Andrew, Dolan, Conor C., Fischbacher, Urs, Harris, Kathleen Mullan, Hasler, Gregor, Ikram, Mohammad A., Jain, Sonia, Kessler, Ronald C., Kooyman, Maarten, Mackillop, James, Männikkö, Minna, Morcillo-Suarez, Carlos, Mcqueen, Matthew B., Schmidt, Klaus M., Smart, Melissa C., Sutter, Matthias, White, Jon, Wit, Harriet de, Fehr, Ernst, Kumari, Meena, Laibson, David, Navarro, Arcadi, Palmer, Abraham A., Schunk, Daniel, Stein, Murray B., Svento, Rauli, Timmers, Paul R. H. 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Roy, Timpson Nicholas J., Tiemeier Henning, Uitterlinden Andre G., Vitart Veronique, Vollenweider Peter, Weir David R., Wilson James F., Wright Alan F., Conley Dalton C., Krueger Robert F., Smith George Davey, Laibson David I., Medland Sarah E., Johannesson Magnu, Koellinger Philipp D., Cesarini David, Benjamin Daniel J., Auton Adam, Boardman Jason D., Clark David W., Conlin Andrew, Dolan Conor C., Fischbacher Ur, Groenen Patrick J. F., Harris Kathleen Mullan, Hasler Gregor, Hofman Albert, Ikram Mohammad A., Jain Sonia, Karlsson Robert, Kessler Ronald C., Kooyman Maarten, MacKillop Jame, Mannikko Minna, Morcillo-Suarez Carlo, McQueen Matthew B., Schmidt Klaus M., Smart Melissa C., Sutter Matthia, White Jon, de Wit Harriet, Fehr Ernst, Kumari Meena, Laibson David, Meyer Michelle N., Navarro Arcadi, Palmer Abraham A., Schunk Daniel, Stein Murray B., Svento Rauli, Timmers Paul R. H. J., Ursano Robert J., Wagner Gert G., Beauchamp Jonathan P., Karlsson Linnér, Richard, Biroli, Pietro, Kong, Edward, Meddens, S. Fleur W., Wedow, Robbee, Fontana, Mark Alan, Lebreton, Maël, Tino, Stephen P., Abdellaoui, Abdel, Hammerschlag, Anke R., Nivard, Michel G., Okbay, Aysu, Rietveld, Cornelius A., Timshel, Pascal N., Trzaskowski, Maciej, Vlaming, Ronald de, Zünd, Christian L., Bao, Yanchun, Buzdugan, Laura, Caplin, Ann H., Chen, Chia-Yen, Eibich, Peter, Fontanillas, Pierre, Gonzalez, Juan R., Joshi, Peter K., Karhunen, Ville, Kleinman, Aaron, Levin, Remy Z., Lill, Christina M., Meddens, Gerardus A., Muntané, Gerard, Sanchez-Roige, Sandra, Rooij, Frank J. van, Taskesen, Erdogan, Wu, Yang, Zhang, Futao, Agee, Michelle, Alipanahi, Babak, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Furlotte, Nicholas A., Huber, Karen E., Litterman, Nadia K., Mccreight, Jennifer C., Mcintyre, Matthew H., Mountain, Joanna L., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. 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E., Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johanne, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klau, Bertram, Lar, Bisgaard, Han, Borecki, Ingrid B, Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., Duijn, Cornelia M. van, Eriksson, Johan G., Franke, Barbara, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans-Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, Harst, Pim van der, Hayward, Caroline, Hinds, David A., Hoffmann, Wolfgang, Hyppönen, Elina, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Pendleton, Neil, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Smith, George Davey, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Johannesson, Magnu, Koellinger, Philipp D., Cesarini, David, Benjamin, Daniel J., Auton, Adam, Boardman, Jason D., Clark, David W., Conlin, Andrew, Dolan, Conor C., Fischbacher, Ur, Harris, Kathleen Mullan, Hasler, Gregor, Ikram, Mohammad A., Jain, Sonia, Kessler, Ronald C., Kooyman, Maarten, Mackillop, Jame, Männikkö, Minna, Morcillo-Suarez, Carlo, Mcqueen, Matthew B., Schmidt, Klaus M., Smart, Melissa C., Sutter, Matthia, White, Jon, Wit, Harriet de, Fehr, Ernst, Kumari, Meena, Laibson, David, Navarro, Arcadi, Palmer, Abraham A., Schunk, Daniel, Stein, Murray B., Svento, Rauli, Timmers, Paul R. H. J., Ursano, Robert J., Wagner, Gert G., Applied Economics, Hematology, Epidemiology, Urology, Department of Marketing Management, Internal Medicine, Medical Informatics, Cell biology, Erasmus MC other, Molecular Genetics, Econometrics, Child and Adolescent Psychiatry / Psychology, Radiology & Nuclear Medicine, Epidemiologie, RS: CARIM - R3.02 - Hypertension and target organ damage, RS: Carim - V02 Hypertension and target organ damage, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Public Health Research (PHR), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Linnér, Richard Karlsson, Biroli , Pietro, Meddens, S Fleur W, and Beauchamp, Jonathan P

Subjects
Netherlands Twin Register (NTR), Male, LD, Medizin, Poison control, Genome-wide association study, DETERMINANTS, Cathie Marsh Institute, PREFERENCES, Q1, Genome-wide association studies, HV, 0302 clinical medicine, Genetics, Behavioral/methods, GWAS, Genetics & Heredity, Genetics, 0303 health sciences, PERSONALITY, Genetic Predisposition to Disease/genetics, Behavior/physiology, Polymorphism, Single Nucleotide/genetics, 3. Good health, Manchester Institute for Collaborative Research on Ageing, Meta-analysis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Genetic Loci/genetics, Behavioural genetics, Genome-Wide Association Study/methods, Medical genetics, Female, Life Sciences & Biomedicine, Single Nucleotide/genetics, medicine.medical_specialty, ResearchInstitutes_Networks_Beacons/MICRA, Genotype, Single-nucleotide polymorphism, Genetics, Behavioral, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, ddc:330, medicine, GENDER-DIFFERENCES, SNP, Humans, Genetic Predisposition to Disease, Polymorphism, behavioural genetics, Behavioral/methods, 030304 developmental biology, Genetic association, Behavior, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Data Science, Case-control study, risk tolerance, GWAS, genetic architechture, Genetic Loci, Case-Control Studies, genome-wide association studies, ResearchInstitutes_Networks_Beacons/cathie_marsh_institute, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance. This research was carried out under the auspices of the Social Science Genetic Association Consortium. The research was also conducted using the UK Biobank Resource under application number 11425. The study was supported by funding from the Ragnar Söderberg Foundation (E9/11 and E42/15); the Swedish Research Council (421-2013-1061); the Jan Wallander and Tom Hedelius Foundation; an ERC Consolidator Grant to Philipp Koellinger (647648 EdGe); the Pershing Square Fund of the Foundations of Human Behavior; the Open Philanthropy Project; the National Institute on Aging, National Institutes of Health through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to the National Bureau of Economic Research and R01-AG042568-02 to the University of Southern California; the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-152); and the Social Sciences and Humanities Research Council of Canada. We thank the International Cannabis Consortium, the eQTLgen Consortium, and the Psychiatric Genomics Consortium for sharing summary statistics from the GWAS of lifetime cannabis use, eQTL summary statistics, and summary statistics from the GWAS of ADHD, respectively. A full list of acknowledgments is provided in the Supplementary Note.

Published
2019

148. Genetic markers of abdominal obesity and weight loss after gastric bypass surgery

Author

Aasbrenn, Martin, primary, Svendstrup, Mathilde, additional, Schnurr, Theresia M., additional, Lindqvist Hansen, Dorte, additional, Worm, Dorte, additional, Balslev-Harder, Marie, additional, Grarup, Niels, additional, Burgdorf, Kristoffer Sølvsten, additional, Vestergaard, Henrik, additional, Pedersen, Oluf, additional, Ängquist, Lars, additional, Fenger, Mogens, additional, Sørensen, Thorkild I. A., additional, Madsbad, Sten, additional, and Hansen, Torben, additional

Published
2021
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