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1. Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications

Author: Suzuki, Ken, Hatzikotoulas, Konstantinos, Southam, Lorraine, Taylor, Henry J., Yin, Xianyong, Lorenz, Kim M., Mandla, Ravi, Huerta-Chagoya, Alicia, Rayner, Nigel W., Bocher, Ozvan, Ana Luiza de, S. V. Arruda, Sonehara, Kyuto, Namba, Shinichi, Lee, Simon S. K., Preuss, Michael H., Petty, Lauren E., Schroeder, Philip, Vanderwerff, Brett, Kals, Mart, Bragg, Fiona, Lin, Kuang, Guo, Xiuqing, Zhang, Weihua, Yao, Jie, Kim, Young Jin, Graff, Mariaelisa, Takeuchi, Fumihiko, Nano, Jana, Lamri, Amel, Nakatochi, Masahiro, Moon, Sanghoon, Scott, Robert A., Cook, James P., Lee, Jung-Jin, Pan, Ian, Taliun, Daniel, Parra, Esteban J., Chai, Jin-Fang, Bielak, Lawrence F., Tabara, Yasuharu, Hai, Yang, Thorleifsson, Gudmar, Grarup, Niels, Sofer, Tamar, Wuttke, Matthias, Sarnowski, Chloé, Gieger, Christian, Nousome, Darryl, Trompet, Stella, Kwak, Soo-Heon, Long, Jirong, Sun, Meng, Tong, Lin, Chen, Wei-Min, Nongmaithem, Suraj S., Noordam, Raymond, Lim, Victor J. Y., Tam, Claudia H. T., Joo, Yoonjung Yoonie, Chen, Chien-Hsiun, Raffield, Laura M., Prins, Bram Peter, Nicolas, Aude, Yanek, Lisa R., Chen, Guanjie, Brody, Jennifer A., Kabagambe, Edmond, An, Ping, Xiang, Anny H., Choi, Hyeok Sun, Cade, Brian E., Tan, Jingyi, Alaine Broadaway, K., Williamson, Alice, Kamali, Zoha, Cui, Jinrui, Adair, Linda S., Adeyemo, Adebowale, Aguilar-Salinas, Carlos A., Ahluwalia, Tarunveer S., Anand, Sonia S., Bertoni, Alain, Bork-Jensen, Jette, Brandslund, Ivan, Buchanan, Thomas A., Burant, Charles F., Butterworth, Adam S., Canouil, Mickaël, Chan, Juliana C. N., Chang, Li-Ching, Chee, Miao-Li, Chen, Ji, Chen, Shyh-Huei, Chen, Yuan-Tsong, Chen, Zhengming, Chuang, Lee-Ming, Cushman, Mary, Danesh, John, Das, Swapan K., Janaka de Silva, H., Dedoussis, George, Dimitrov, Latchezar, Doumatey, Ayo P., Du, Shufa, Duan, Qing, Eckardt, Kai-Uwe, Emery, Leslie S., Evans, Daniel S., Evans, Michele K., Fischer, Krista, Floyd, James S., Ford, Ian, Franco, Oscar H., Frayling, Timothy M., Freedman, Barry I., Genter, Pauline, Gerstein, Hertzel C., Giedraitis, Vilmantas, González-Villalpando, Clicerio, González-Villalpando, Maria Elena, Gordon-Larsen, Penny, Gross, Myron, Guare, Lindsay A., Hackinger, Sophie, Han, Sohee, Hattersley, Andrew T., Herder, Christian, Horikoshi, Momoko, Howard, Annie-Green, Hsueh, Willa, Huang, Mengna, Huang, Wei, Hung, Yi-Jen, Hwang, Mi Yeong, Hwu, Chii-Min, Ichihara, Sahoko, Ikram, Mohammad Arfan, Ingelsson, Martin, Islam, Md. Tariqul, Isono, Masato, Jang, Hye-Mi, Jasmine, Farzana, Jiang, Guozhi, Jonas, Jost B., Jørgensen, Torben, Kandeel, Fouad R., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kaur, Varinderpal, Kawaguchi, Takahisa, Keaton, Jacob M., Kho, Abel N., Khor, Chiea-Chuen, Kibriya, Muhammad G., Kim, Duk-Hwan, Kronenberg, Florian, Kuusisto, Johanna, Läll, Kristi, Lange, Leslie A., Lee, Kyung Min, Lee, Myung-Shik, Lee, Nanette R., Leong, Aaron, Li, Liming, Li, Yun, Li-Gao, Ruifang, Lithgart, Symen, Lindgren, Cecilia M., Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Locke, Adam E., Louie, Tin, Luan, Jian’an, Luk, Andrea O., Luo, Xi, Lv, Jun, Lynch, Julie A., Lyssenko, Valeriya, Maeda, Shiro, Mamakou, Vasiliki, Mansuri, Sohail Rafik, Matsuda, Koichi, Meitinger, Thomas, Metspalu, Andres, Mo, Huan, Morris, Andrew D., Nadler, Jerry L., Nalls, Michael A., Nayak, Uma, Ntalla, Ioanna, Okada, Yukinori, Orozco, Lorena, Patel, Sanjay R., Patil, Snehal, Pei, Pei, Pereira, Mark A, Peters, Annette, Pirie, Fraser J., Polikowsky, Hannah G., Porneala, Bianca, Prasad, Gauri, Rasmussen-Torvik, Laura J., Reiner, Alexander P., Roden, Michael, Rohde, Rebecca, Roll, Katheryn, Sabanayagam, Charumathi, Sandow, Kevin, Sankareswaran, Alagu, Sattar, Naveed, Schönherr, Sebastian, Shahriar, Mohammad, Shen, Botong, Shi, Jinxiu, Shin, Dong Mun, Shojima, Nobuhiro, Smith, Jennifer A., So, Wing Yee, Stančáková, Alena, Steinthorsdottir, Valgerdur, Stilp, Adrienne M., Strauch, Konstantin, Taylor, Kent D., Thorand, Barbara, Thorsteinsdottir, Unnur, Tomlinson, Brian, Tran, Tam C., Tsai, Fuu-Jen, Tuomilehto, Jaakko, Tusie-Luna, Teresa, Udler, Miriam S., Valladares-Salgado, Adan, van Dam, Rob M., van Klinken, Jan B., Varma, Rohit, Wacher-Rodarte, Niels, Wheeler, Eleanor, Wickremasinghe, Ananda R., van Dijk, Ko Willems, Witte, Daniel R., Yajnik, Chittaranjan S., Yamamoto, Ken, Yamamoto, Kenichi, Yoon, Kyungheon, Yu, Canqing, Yuan, Jian-Min, Yusuf, Salim, Zawistowski, Matthew, Zhang, Liang, Zheng, Wei, Project, Biobank Japan, BioBank, Penn Medicine, Center, Regeneron Genetics, Consortium, eMERGE, Raffel, Leslie J, Igase, Michiya, Ipp, Eli, Redline, Susan, Cho, Yoon Shin, Lind, Lars, Province, Michael A., Fornage, Myriam, Hanis, Craig L., Ingelsson, Erik, Zonderman, Alan B., Psaty, Bruce M., Wang, Ya-Xing, Rotimi, Charles N., Becker, Diane M., Matsuda, Fumihiko, Liu, Yongmei, Yokota, Mitsuhiro, Kardia, Sharon L. R., Peyser, Patricia A., Pankow, James S., Engert, James C., Bonnefond, Amélie, Froguel, Philippe, Wilson, James G., Sheu, Wayne H. H., Wu, Jer-Yuarn, Geoffrey Hayes, M., Ma, Ronald C. W., Wong, Tien-Yin, Mook-Kanamori, Dennis O., Tuomi, Tiinamaija, Chandak, Giriraj R., Collins, Francis S., Bharadwaj, Dwaipayan, Paré, Guillaume, Sale, Michèle M., Ahsan, Habibul, Motala, Ayesha A., Shu, Xiao-Ou, Park, Kyong-Soo, Jukema, J Wouter, Cruz, Miguel, Chen, Yii-Der Ida, Rich, Stephen S., McKean-Cowdin, Roberta, Grallert, Harald, Cheng, Ching-Yu, Ghanbari, Mohsen, Tai, E-Shyong, Dupuis, Josee, Kato, Norihiro, Laakso, Markku, Köttgen, Anna, Koh, Woon-Puay, Bowden, Donald W., Palmer, Colin N. A., Kooner, Jaspal S., Kooperberg, Charles, Liu, Simin, North, Kari E., Saleheen, Danish, Hansen, Torben, Pedersen, Oluf, Wareham, Nicholas J., Lee, Juyoung, Kim, Bong-Jo, Millwood, Iona Y., Walters, Robin G., Stefansson, Kari, Goodarzi, Mark O., Mohlke, Karen L., Langenberg, Claudia, Haiman, Christopher A., Loos, Ruth J. F., Florez, Jose C., Rader, Daniel J., Ritchie, Marylyn D., Zöllner, Sebastian, Mägi, Reedik, Denny, Joshua C., Yamauchi, Toshimasa, Kadowaki, Takashi, Chambers, John C., Ng, Maggie C. Y., Sim, Xueling, Below, Jennifer E., Tsao, Philip S., Chang, Kyong-Mi, McCarthy, Mark I., Meigs, James B., Mahajan, Anubha, Spracklen, Cassandra N., Mercader, Josep M., Boehnke, Michael, Rotter, Jerome I., Vujkovic, Marijana, Voight, Benjamin F., Morris, Andrew P., and Zeggini, Eleftheria
Subjects: Article
Abstract: Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P
Published: 2023

2. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author: Mahajan, Anubha, Spracklen, Cassandra N., Zhang, Weihua, Ng, Maggie C. Y., Petty, Lauren E., Kitajima, Hidetoshi, Yu, Grace Z., Rüeger, Sina, Speidel, Leo, Kim, Young Jin, Horikoshi, Momoko, Mercader, Josep M., Taliun, Daniel, Moon, Sanghoon, Kwak, Soo-heon, Robertson, Neil R., Rayner, Nigel W., Loh, Marie, Kim, Bong-jo, Chiou, Joshua, Miguel-escalada, Irene, Della Briotta Parolo, Pietro, Lin, Kuang, Bragg, Fiona, Preuss, Michael H., Takeuchi, Fumihiko, Nano, Jana, Guo, Xiuqing, Lamri, Amel, Nakatochi, Masahiro, Scott, Robert A., Lee, Jung-jin, Huerta-chagoya, Alicia, Graff, Mariaelisa, Chai, Jin-fang, Parra, Esteban J., Yao, Jie, Bielak, Lawrence F., Tabara, Yasuharu, Hai, Yang, Steinthorsdottir, Valgerdur, Cook, James P., Kals, Mart, Grarup, Niels, Schmidt, Ellen M., Pan, Ian, Sofer, Tamar, Wuttke, Matthias, Sarnowski, Chloe, Gieger, Christian, Nousome, Darryl, Trompet, Stella, Long, Jirong, Sun, Meng, Tong, Lin, Chen, Wei-min, Ahmad, Meraj, Noordam, Raymond, Lim, Victor J. Y., Tam, Claudia H. T., Joo, Yoonjung Yoonie, Chen, Chien-hsiun, Raffield, Laura M., Lecoeur, Cécile, Prins, Bram Peter, Nicolas, Aude, Yanek, Lisa R., Chen, Guanjie, Jensen, Richard A., Tajuddin, Salman, Kabagambe, Edmond K., An, Ping, Xiang, Anny H., Choi, Hyeok Sun, Cade, Brian E., Tan, Jingyi, Flanagan, Jack, Abaitua, Fernando, Adair, Linda S., Adeyemo, Adebowale, Aguilar-salinas, Carlos A., Akiyama, Masato, Anand, Sonia S., Bertoni, Alain, Bian, Zheng, Bork-jensen, Jette, Brandslund, Ivan, Brody, Jennifer A., Brummett, Chad M., Buchanan, Thomas A., Canouil, Mickaël, Chan, Juliana C. N., Chang, Li-ching, Chee, Miao-li, Chen, Ji, Chen, Shyh-huei, Chen, Yuan-tsong, Chen, Zhengming, Chuang, Lee-ming, Cushman, Mary, Das, Swapan K., De Silva, H. Janaka, Dedoussis, George, Dimitrov, Latchezar, Doumatey, Ayo P., Du, Shufa, Duan, Qing, Eckardt, Kai-uwe, Emery, Leslie S., Evans, Daniel S., Evans, Michele K., Fischer, Krista, Floyd, James S., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Frayling, Timothy M., Freedman, Barry I., Fuchsberger, Christian, Genter, Pauline, Gerstein, Hertzel C., Giedraitis, Vilmantas, González-villalpando, Clicerio, González-villalpando, Maria Elena, Goodarzi, Mark O., Gordon-larsen, Penny, Gorkin, David, Gross, Myron, Guo, Yu, Hackinger, Sophie, Han, Sohee, Hattersley, Andrew T., Herder, Christian, Howard, Annie-green, Hsueh, Willa, Huang, Mengna, Huang, Wei, Hung, Yi-jen, Hwang, Mi Yeong, Hwu, Chii-min, Ichihara, Sahoko, Ikram, Mohammad Arfan, Ingelsson, Martin, Islam, Md Tariqul, Isono, Masato, Jang, Hye-mi, Jasmine, Farzana, Jiang, Guozhi, Jonas, Jost B., Jørgensen, Marit E., Jørgensen, Torben, Kamatani, Yoichiro, Kandeel, Fouad R., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kaur, Varinderpal, Kawaguchi, Takahisa, Keaton, Jacob M., Kho, Abel N., Khor, Chiea-chuen, Kibriya, Muhammad G., Kim, Duk-hwan, Kohara, Katsuhiko, Kriebel, Jennifer, Kronenberg, Florian, Kuusisto, Johanna, Läll, Kristi, Lange, Leslie A., Lee, Myung-shik, Lee, Nanette R., Leong, Aaron, Li, Liming, Li, Yun, Li-gao, Ruifang, Ligthart, Symen, Lindgren, Cecilia M., Linneberg, Allan, Liu, Ching-ti, Liu, Jianjun, Locke, Adam E., Louie, Tin, Luan, Jian’an, Luk, Andrea O., Luo, Xi, Lv, Jun, Lyssenko, Valeriya, Mamakou, Vasiliki, Mani, K. Radha, Meitinger, Thomas, Metspalu, Andres, Morris, Andrew D., Nadkarni, Girish N., Nadler, Jerry L., Nalls, Michael A., Nayak, Uma, Nongmaithem, Suraj S., Ntalla, Ioanna, Okada, Yukinori, Orozco, Lorena, Patel, Sanjay R., Pereira, Mark A., Peters, Annette, Pirie, Fraser J., Porneala, Bianca, Prasad, Gauri, Preissl, Sebastian, Rasmussen-torvik, Laura J., Reiner, Alexander P., Roden, Michael, Rohde, Rebecca, Roll, Kathryn, Sabanayagam, Charumathi, Sander, Maike, Sandow, Kevin, Sattar, Naveed, Schönherr, Sebastian, Schurmann, Claudia, Shahriar, Mohammad, Shi, Jinxiu, Shin, Dong Mun, Shriner, Daniel, Smith, Jennifer A., So, Wing Yee, Stančáková, Alena, Stilp, Adrienne M., Strauch, Konstantin, Suzuki, Ken, Takahashi, Atsushi, Taylor, Kent D., Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tomlinson, Brian, Torres, Jason M., Tsai, Fuu-jen, Tuomilehto, Jaakko, Tusie-luna, Teresa, Udler, Miriam S., Valladares-salgado, Adan, Van Dam, Rob M., Van Klinken, Jan B., Varma, Rohit, Vujkovic, Marijana, Wacher-rodarte, Niels, Wheeler, Eleanor, Whitsel, Eric A., Wickremasinghe, Ananda R., Van Dijk, Ko Willems, Witte, Daniel R., Yajnik, Chittaranjan S., Yamamoto, Ken, Yamauchi, Toshimasa, Yengo, Loïc, Yoon, Kyungheon, Yu, Canqing, Yuan, Jian-min, Yusuf, Salim, Zhang, Liang, Zheng, Wei, Hayes, M. Geoffrey, Raffel, Leslie J., Igase, Michiya, Ipp, Eli, Redline, Susan, Cho, Yoon Shin, Lind, Lars, Province, Michael A., Hanis, Craig L., Peyser, Patricia A., Ingelsson, Erik, Zonderman, Alan B., Psaty, Bruce M., Wang, Ya-xing, Rotimi, Charles N., Becker, Diane M., Matsuda, Fumihiko, Liu, Yongmei, Zeggini, Eleftheria, Yokota, Mitsuhiro, Rich, Stephen S., Kooperberg, Charles, Pankow, James S., Engert, James C., Chen, Yii-der Ida, Froguel, Philippe, Wilson, James G., Sheu, Wayne H. H., Kardia, Sharon L. R., Wu, Jer-yuarn, Ma, Ronald C. W., Wong, Tien-yin, Groop, Leif, Mook-kanamori, Dennis O., Chandak, Giriraj R., Collins, Francis S., Bharadwaj, Dwaipayan, Paré, Guillaume, Sale, Michèle M., Ahsan, Habibul, Motala, Ayesha A., Shu, Xiao-ou, Park, Kyong-soo, Jukema, J. Wouter, Cruz, Miguel, Mckean-cowdin, Roberta, Grallert, Harald, Cheng, Ching-yu, Bottinger, Erwin P., Dehghan, Abbas, Tai, E-shyong, Dupuis, Josée, Kato, Norihiro, Laakso, Markku, Köttgen, Anna, Koh, Woon-puay, Palmer, Colin N. A., Liu, Simin, Abecasis, Goncalo, Kooner, Jaspal S., Loos, Ruth J. F., North, Kari E., Haiman, Christopher A., Florez, Jose C., Saleheen, Danish, Hansen, Torben, Pedersen, Oluf, Mägi, Reedik, Langenberg, Claudia, Wareham, Nicholas J., Maeda, Shiro, Kadowaki, Takashi, Lee, Juyoung, Millwood, Iona Y., Walters, Robin G., Stefansson, Kari, Myers, Simon R., Ferrer, Jorge, Gaulton, Kyle J., Meigs, James B., Mohlke, Karen L., Gloyn, Anna L., Bowden, Donald W., Below, Jennifer E., Chambers, John C., Sim, Xueling, Boehnke, Michael, Rotter, Jerome I., Mccarthy, Mark I., Morris, Andrew P., Epidemiology, Laboratory Genetic Metabolic Diseases, Laboratory for General Clinical Chemistry, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: endocrine system diseases, nutritional and metabolic diseases, Polymorphism, Single Nucleotide/genetics, Polymorphism, Single Nucleotide, R1, Diabetes Mellitus, Type 2/epidemiology, Diabetes Mellitus, Type 2, SDG 3 - Good Health and Well-being, Risk Factors, Ethnicity, Genetics, Humans, Genetic Predisposition to Disease, human activities, Genome-Wide Association Study
Abstract: We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
Published: 2022

3. Health-related quality of life for normal glycaemia, prediabetes and type 2 diabetes mellitus: Cross-sectional analysis of the ADDITION-PRO study

Author: Leal, Jose, Becker, Frauke, Feenstra, Talitha, Pagano, Eva, Jensen, Troels Mygind, Vistisen, Dorte, Witte, Daniel R, and Jorgensen, Marit Eika
Subjects: EQ-5D utility, health-related quality of life, prediabetes
Published: 2022

4. Additional file 1 of Long-term effects of intensive multifactorial treatment on aortic stiffness and central hemodynamics after 13 years with screen-detected type 2 diabetes: the ADDITION-Denmark trial

Author: Bjerg, Lasse, Laugesen, Esben, Andersen, Signe Toft, Rosborg, Jonas Frey, Charles, Morten, Vistisen, Dorte, and Witte, Daniel R.
Abstract: Additional file 1: Table S1. Characteristics of the study sample at the end of the trial (by 5 years follow-up). Table S2. Baseline and at follow-up characteristics of persons with and without hemodymanic assessment at 13 years follow-up
Published: 2022
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5. Erratum:Role of fasting duration and weekday in incretin and glucose regulation

Author: Clemmensen, Kim K.B., Quist, Jonas S., Vistisen, Dorte, Witte, Daniel R., Jonsson, Anna, Pedersen, Oluf, Hansen, Torben, Holst, Jens J., Lauritzen, Torsten, Jørgensen, Marit E., Torekov, Signe, and Færch, Kristine
Abstract: The authors and journal apologise for errors in the above paper, which appeared in volume 9 part 4, pages 279-288. The errors relate to three values given in Table 2 on page 283. The value for Unadjusted upper 95% CI of 120 min plasma glucose should be 3.0, not 3.9, the value for Adjusted Estimate of Fasting plasma glucagon should be 0.0 not 0.3, and the value for Unadjusted Estimate of 30 min plasma GLP-1 should be -0.5 not -1.5. These errors do not affect the results or conclusions. The correct Table 2 is given in full below
Published: 2021

6. Additional file 2 of Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test

Author: Jonsson, Anna, Stinson, Sara E., Torekov, Signe S., Clausen, Tine D., Færch, Kristine, Kelstrup, Louise, Grarup, Niels, Mathiesen, Elisabeth R., Damm, Peter, Witte, Daniel R., Jørgensen, Marit E., Pedersen, Oluf, Holst, Jens Juul, and Hansen, Torben
Abstract: Additional file 2: Figure S1. Title of data: QQ-plot of selected variants previously reported to associate with increased risk of type 2 diabetes. Description of data: The figure shows the observed vs. the expected P-values of the selected variants for fasting glucagon (A), 30 min glucagon (B), 120 min glucagon (C), decremental area under the curve (dAUC) 0-30 minutes of glucagon (D) and dAUC 0-120 minutes of glucagon (E) during the OGTT. There was no obvious excess of genetic variants, previously associated with type 2 diabetes, associating with circulating glucagon during OGTT.
Published: 2021
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7. Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes

Author: Miguel-Escalada, Irene, Bonàs-Guarch, Silvia, Cebola, Inês, Ponsa-Cobas, Joan, Mendieta-Esteban, Julen, Atla, Goutham, Javierre, Biola M., Rolando, Delphine M.Y., Farabella, Irene, Morgan, Claire C., García-Hurtado, Javier, Beucher, Anthony, Morán, Ignasi, Pasquali, Lorenzo, Ramos-Rodríguez, Mireia, Appel, Emil V.R., Linneberg, Allan, Gjesing, Anette P., Witte, Daniel R., Pedersen, Oluf, Grarup, Niels, Ravassard, Philippe, Torrents, David, Mercader, Josep M., Piemonti, Lorenzo, Berney, Thierry, de Koning, Eelco J.P., Kerr-Conte, Julie, Pattou, François, Fedko, Iryna O., Groop, Leif, Prokopenko, Inga, Hansen, Torben, Marti-Renom, Marc A., Fraser, Peter, and Ferrer, Jorge
Subjects: endocrine system, endocrine system diseases, Molecular Conformation, Article, Chromatin, Cohort Studies, Islets of Langerhans, Enhancer Elements, Genetic, Diabetes Mellitus, Type 2, Gene Expression Regulation, Insulin Secretion, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Promoter Regions, Genetic, Genome-Wide Association Study
Abstract: Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.
Published: 2019

8. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls

Author: Flannick, Jason, Mercader, Josep M, Fuchsberger, Christian, Udler, Miriam S, Mahajan, Anubha, Wessel, Jennifer, Teslovich, Tanya M, Caulkins, Lizz, Koesterer, Ryan, Barajas-Olmos, Francisco, Blackwell, Thomas W, Boerwinkle, Eric, Brody, Jennifer A, Centeno-Cruz, Federico, Chen, Ling, Chen, Siying, Contreras-Cubas, Cecilia, Córdova, Emilio, Correa, Adolfo, Cortes, Maria, DeFronzo, Ralph A, Dolan, Lawrence, Drews, Kimberly L, Elliott, Amanda, Floyd, James S, Gabriel, Stacey, Garay-Sevilla, Maria Eugenia, García-Ortiz, Humberto, Gross, Myron, Han, Sohee, Heard-Costa, Nancy L, Jackson, Anne U, Jørgensen, Marit E, Kang, Hyun Min, Kelsey, Megan, Kim, Bong-Jo, Koistinen, Heikki A, Kuusisto, Johanna, Leader, Joseph B, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Lyssenko, Valeriya, Manning, Alisa K, Marcketta, Anthony, Malacara-Hernandez, Juan Manuel, Martínez-Hernández, Angélica, Matsuo, Karen, Mayer-Davis, Elizabeth, Mendoza-Caamal, Elvia, Mohlke, Karen L, Morrison, Alanna C, Ndungu, Anne, Ng, Maggie CY, O'Dushlaine, Colm, Payne, Anthony J, Pihoker, Catherine, Broad Genomics Platform, Post, Wendy S, Preuss, Michael, Psaty, Bruce M, Vasan, Ramachandran S, Rayner, N William, Reiner, Alexander P, Revilla-Monsalve, Cristina, Robertson, Neil R, Santoro, Nicola, Schurmann, Claudia, So, Wing Yee, Soberón, Xavier, Stringham, Heather M, Strom, Tim M, Tam, Claudia HT, Thameem, Farook, Tomlinson, Brian, Torres, Jason M, Tracy, Russell P, van Dam, Rob M, Vujkovic, Marijana, Wang, Shuai, Welch, Ryan P, Witte, Daniel R, Wong, Tien-Yin, Atzmon, Gil, Barzilai, Nir, Blangero, John, Bonnycastle, Lori L, Bowden, Donald W, Chambers, John C, Chan, Edmund, Cheng, Ching-Yu, Cho, Yoon Shin, Collins, Francis S, de Vries, Paul S, Duggirala, Ravindranath, Glaser, Benjamin, Gonzalez, Clicerio, Gonzalez, Ma Elena, Groop, Leif, and Kooner, Jaspal Singh
Subjects: Male, General Science & Technology, Knockout, LuCamp, Whole Exome Sequencing, Decision Support Techniques, Mice, T2D-GENES, Gene Frequency, Exome Sequencing, Diabetes Mellitus, Genetics, Animals, Humans, 2.1 Biological and endogenous factors, AMP-T2D-GENES, Exome, Aetiology, ESP, Metabolic and endocrine, Broad Genomics Platform, Prevention, Diabetes, Human Genome, ProDiGY, Case-Control Studies, DiscovEHR Collaboration, SIGMA-T2D, Female, CHARGE, Type 2, GoT2D, Genome-Wide Association Study, Biotechnology
Abstract: Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791individuals with type 2 diabetes (T2D) and 24,440non-diabetic control participants from 5ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4genes at exome-wide significance, including a series of more than 30SLC30A8 alleles that conveys protection against T2D, and in 12gene sets, including those corresponding to T2D drug targets (P=6.1×10-3) and candidate genes from knockout mice (P=5.2×10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
Published: 2019

9. Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Author: Kraja, Aldi T, Liu, Chunyu, Fetterman, Jessica L, Graff, Mariaelisa, Have, Christian Theil, Gu, Charles, Yanek, Lisa R, Feitosa, Mary F, Arking, Dan E, Chasman, Daniel I, Young, Kristin, Ligthart, Symen, Hill, W David, Weiss, Stefan, Luan, Jian'an, Giulianini, Franco, Li-Gao, Ruifang, Hartwig, Fernando P, Lin, Shiow J, Wang, Lihua, Richardson, Tom G, Yao, Jie, Fernandez, Eliana P, Ghanbari, Mohsen, Wojczynski, Mary K, Lee, Wen-Jane, Argos, Maria, Armasu, Sebastian M, Barve, Ruteja A, Ryan, Kathleen A, An, Ping, Baranski, Thomas J, Bielinski, Suzette J, Bowden, Donald W, Broeckel, Ulrich, Christensen, Kaare, Chu, Audrey Y, Corley, Janie, Cox, Simon R, Uitterlinden, Andre G, Rivadeneira, Fernando, Cropp, Cheryl D, Daw, E Warwick, Van Heemst, Diana, De Las Fuentes, Lisa, Gao, He, Tzoulaki, Ioanna, Ahluwalia, Tarunveer S, De Mutsert, Renée, Emery, Leslie S, Erzurumluoglu, A Mesut, Perry, James A, Fu, Mao, Forouhi, Nita G, Gu, Zhenglong, Hai, Yang, Harris, Sarah E, Hemani, Gibran, Hunt, Steven C, Irvin, Marguerite R, Jonsson, Anna E, Justice, Anne E, Kerrison, Nicola D, Larson, Nicholas B, Lin, Keng-Hung, Love-Gregory, Latisha D, Mathias, Rasika A, Lee, Joseph H, Nauck, Matthias, Noordam, Raymond, Ong, Ken K, Pankow, James, Patki, Amit, Pattie, Alison, Petersmann, Astrid, Qi, Qibin, Ribel-Madsen, Rasmus, Rohde, Rebecca, Sandow, Kevin, Schnurr, Theresia M, Sofer, Tamar, Starr, John M, Taylor, Adele M, Teumer, Alexander, Timpson, Nicholas J, De Haan, Hugoline G, Wang, Yujie, Weeke, Peter E, Williams, Christine, Wu, Hongsheng, Yang, Wei, Zeng, Donglin, Witte, Daniel R, Weir, Bruce S, Wareham, Nicholas J, Vestergaard, Henrik, Turner, Stephen T, Torp-Pedersen, Christian, Stergiakouli, Evie, Sheu, Wayne Huey-Herng, Rosendaal, Frits R, Ikram, M Arfan, Franco, Oscar H, Ridker, Paul M, Perls, Thomas T, Pedersen, Oluf, Nohr, Ellen A, Newman, Anne B, Linneberg, Allan, Langenberg, Claudia, Kilpeläinen, Tuomas O, Kardia, Sharon LR, Jørgensen, Marit E, Jørgensen, Torben, Sørensen, Thorkild IA, Homuth, Georg, Hansen, Torben, Goodarzi, Mark O, Deary, Ian J, Christensen, Cramer, Chen, Yii-Der Ida, Chakravarti, Aravinda, Brandslund, Ivan, Bonnelykke, Klaus, Taylor, Kent D, Wilson, James G, Rodriguez, Santiago, Davies, Gail, Horta, Bernardo L, Thyagarajan, Bharat, Rao, DC, Grarup, Niels, Davila-Roman, Victor G, Hudson, Gavin, Guo, Xiuqing, Arnett, Donna K, Hayward, Caroline, Vaidya, Dhananjay, Mook-Kanamori, Dennis O, Tiwari, Hemant K, Levy, Daniel, Loos, Ruth JF, Dehghan, Abbas, Elliott, Paul, Malik, Afshan N, Scott, Robert A, Becker, Diane M, De Andrade, Mariza, Province, Michael A, Meigs, James B, Rotter, Jerome I, North, Kari E, Epidemiology, Internal Medicine, Gastroenterology & Hepatology, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Luan, Jian'an [0000-0003-3137-6337], Erzurumluoglu, Mesut [0000-0003-1322-8138], Forouhi, Nita [0000-0002-5041-248X], Ong, Kenneth [0000-0003-4689-7530], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: insulin, HbA1c, MT-nDNA candidate genes, SUSCEPTIBILITY LOCI, Quantitative Trait Loci, 610 Medicine & health, ATHEROSCLEROSIS RISK, waist-to-hip ratio, PERIPHERAL-BLOOD, DNA, Mitochondrial, Article, HOMA-IR, Body Mass Index, Cohort Studies, BMI, 360 Social problems & social services, Adipocytes, Diabetes Mellitus, GLYCEMIC TRAITS, Humans, INDIVIDUALS REVEAL, GENOME-WIDE ASSOCIATION, glucose, Glycated Hemoglobin, Genetics & Heredity, Science & Technology, Waist-Hip Ratio, mtDNA, Genetic Variation, COMMON VARIANTS, HOMA-B, 11 Medical And Health Sciences, DNA COPY NUMBER, 06 Biological Sciences, BODY-MASS INDEX, mitochondria, Genes, Mitochondrial, Metabolism, ADIPOSE-TISSUE, Cardiovascular Diseases, Life Sciences & Biomedicine
Abstract: Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
Published: 2019

10. A data-driven approach at characterizing heterogeneity in neuropathy assessments

Author: Johnston, Luke, Andersen, Signe Toft, Charles, Morten, Jørgensen, Marit E., Jensen, Troels S., Bjerg, Lasse, and Witte, Daniel R.
Abstract: Poster presentation to the European Diabetes Epidemiology Group in Mondorf-Les-Bains, Luxembourg from May 11-14, 2019.
Published: 2019
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11. Habitual activity associates with lower fasting and greater glucose-induced GLP-1 response in men

Author: Janus, Charlotte, Vistisen, Dorte, Amadid, Hanan, Witte, Daniel R, Lauritzen, Torsten, Brage, Søren, Bjerregaard, Anne-Louise, Hansen, Torben, Holst, Jens Juul, Jørgensen, Marit Eika, Pedersen, Oluf, Færch, Kristine, and Torekov, Signe
Abstract: RATIONALE: The hormone glucagon-like peptide-1 (GLP-1) decreases blood glucose and appetite. Greater physical activity (PA) is associated with lower incidence of type 2 diabetes. While acute exercise may increase glucose-induced response of GLP-1, it is unknown how habitual PA affects GLP-1 secretion. We hypothesised that habitual PA associates with greater glucose-induced GLP-1 responses in overweight individuals.METHODS: Cross-sectional analysis of habitual PA levels and GLP-1 concentrations in 1326 individuals (mean (SD) age 66 (7) years, BMI 27.1 (4.5) kg/m2) from the ADDITION-PRO cohort. Fasting and oral glucose-stimulated GLP-1 responseswere measured using validated radioimmunoassay. PA was measured using 7-days combined accelerometry and heart rate monitoring. From this, energy expenditure (PAEE;kJ/kg/day) and fractions of time spent in activity intensities (hours/day) were calculated. Cardiorespiratory fitness (CRF;ml O2/kg/min) was calculated using step tests. Age-, BMI- and insulin sensitivity-adjusted associations between PA and GLP-1, stratified by sex, were evaluated by linear regression analysis.RESULTS: In 703 men, fasting GLP-1 concentrations were 20% lower (95%CI: -33;-3%, P=0.02) for every hour of moderate-intensity PA performed. Higher CRF and PAEE were associated with 1-2% lower fasting GLP-1 (P=0.01). For every hour moderate-intensity PA, the glucose-stimulated GLP-1 response was 16% greater at peak 30 min (1;33%, PrAUC0-30=0.04) and 20% greater at full response (3;40%, PrAUC0-120=0.02). No associations were found in women who performed PA 22 min/day versus 32 min/day for men.CONCLUSION: Moderate-intensity PA is associated with lower fasting and greater glucose-induced GLP-1 responses in overweight men, possibly contributing to improved glucose and appetite regulation with increased habitual PA.
Published: 2019

12. Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Author: Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R, Torres, Jason M, Rayner, N William, Payne, Anthony J, Steinthorsdottir, Valgerdur, Scott, Robert A, Grarup, Niels, Cook, James P, Schmidt, Ellen M, Wuttke, Matthias, Sarnowski, Chloé, Mägi, Reedik, Nano, Jana, Gieger, Christian, Trompet, Stella, Lecoeur, Cécile, Preuss, Michael H, Prins, Bram Peter, Guo, Xiuqing, Bielak, Lawrence F, Below, Jennifer E, Bowden, Donald W, Chambers, John Campbell, Kim, Young Jin, Ng, Maggie C Y, Petty, Lauren E, Sim, Xueling, Zhang, Weihua, Bennett, Amanda J, Bork-Jensen, Jette, Brummett, Chad M, Canouil, Mickaël, Ec Kardt, Kai-Uwe, Fischer, Krista, Kardia, Sharon L R, Kronenberg, Florian, Läll, Kristi, Liu, Ching-Ti, Locke, Adam E, Luan, Jian'an, Ntalla, Ioanna, Nylander, Vibe, Schönherr, Sebastian, Schurmann, Claudia, Yengo, Loïc, Bottinger, Erwin P, Brandslund, Ivan, Christensen, Cramer, Dedoussis, George, Florez, Jose C, Ford, Ian, Franco, Oscar H, Frayling, Timothy M, Giedraitis, Vilmantas, Hackinger, Sophie, Hattersley, Andrew T, Herder, Christian, Ikram, M Arfan, Ingelsson, Martin, Jørgensen, Marit E, Jørgensen, Torben, Kriebel, Jennifer, Kuusisto, Johanna, Ligthart, Symen, Lindgren, Cecilia M, Linneberg, Allan, Lyssenko, Valeriya, Mamakou, Vasiliki, Meitinger, Thomas, Mohlke, Karen L, Morris, Andrew D, Nadkarni, Girish, Pankow, James S, Peters, Annette, Sattar, Naveed, Stančáková, Alena, Strauch, Konstantin, Taylor, Kent D, Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Witte, Daniel R, Dupuis, Josée, Peyser, Patricia A, Zeggini, Eleftheria, Loos, Ruth J F, Froguel, Philippe, Ingelsson, Erik, Lind, Lars, Groop, Leif, Laakso, Markku, Collins, Francis S, Jukema, J Wouter, Palmer, Colin N A, Grallert, Harald, Metspalu, Andres, Dehghan, Abbas, Köttgen, Anna, Abecasis, Goncalo R, Meigs, James B, Rotter, Jerome I, Marchini, Jonathan, Pedersen, Oluf, Hansen, Torben, Langenberg, Claudia, Wareham, Nicholas J, Stefansson, Kari, Gloyn, Anna L, Morris, Andrew P, Boehnke, Michael, and McCarthy, Mark I
Subjects: endocrine system diseases
Abstract: We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
Published: 2018

13. Rare and low-frequency coding variants alter human adult height

Author: Marouli, Eirini, Graff, Mariaelisa, Medina-Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R, Kjaer, Troels R, Fine, Rebecca S, Lu, Yingchang, Schurmann, Claudia, Highland, Heather M, Rueger, Sina, Thorleifsson, Gudmar, Justice, Anne E, Lamparter, David, Stirrups, Kathleen E, Turcot, Valerie, Young, Kristin L, Winkler, Thomas W, Esko, Tonu, Karaderi, Tugce, Locke, Adam E, Masca, Nicholas GD, Ng, Maggie CY, Mudgal, Poorva, Rivas, Manuel A, Vedantam, Sailaja, Mahajan, Anubha, Guo, Xiuqing, Abecasis, Goncalo, Aben, Katja K, Adair, Linda S, Alam, Dewan S, Albrecht, Eva, Allin, Kristine H, Allison, Matthew, Amouyel, Philippe, Appel, Emil V, Arveiler, Dominique, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Banas, Bernhard, Bang, Lia E, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blueher, Matthias, Boeing, Heiner, Boerwinkle, Eric, Boeger, Carsten A, Bonnycastle, Lori L, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Carey, David J, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Galbany, Jordi Corominas, Cox, Amanda J, Cuellar-Partida, Gabriel, Danesh, John, Davies, Gail, de Bakker, Paul IW, de Borst, Gert J, de Denus, Simon, de Groot, Mark CH, de Mutsert, Renee, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, den Hollander, Anneke I, Dennis, Joe G, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dunning, Alison M, Easton, Douglas F, Ebeling, Tapani, Edwards, Todd L, Ellinor, Patrick T, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Faul, Jessica D, Feitosa, Mary F, Feng, Shuang, Ferrannini, Ele, Ferrario, Marco M, Ferrieres, Jean, Florez, Jose C, Ford, Ian, Fornage, Myriam, Franks, Paul W, Frikke-Schmidt, Ruth, Galesloot, Tessel E, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Giri, Ayush, Girotto, Giorgia, Gordon, Scott D, Gordon-Larsen, Penny, Gorski, Mathias, Grarup, Niels, Grove, Megan L, Gudnason, Vilmundur, Gustafsson, Stefan, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B, Hattersley, Andrew T, Hayward, Caroline, He, Liang, Heid, Iris M, Heikkila, Kauko, Helgeland, Oyvind, Hernesniemi, Jussi, Hewitt, Alex W, Hocking, Lynne J, Hollensted, Mette, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hoyng, Carel B, Huang, Paul L, Hveem, Kristian, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jansson, Jan-Hakan, Jarvik, Gail P, Jensen, Gorm B, Jhun, Min A, Jia, Yucheng, Jiang, Xuejuan, Johansson, Stefan, Jorgensen, Marit E, Jorgensen, Torben, Jousilahti, Pekka, Jukema, J Wouter, Kahali, Bratati, Kahn, Rene S, Kahonen, Mika, Kamstrup, Pia R, Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kee, Frank, Keeman, Renske, Kiemeney, Lambertus A, Kitajima, Hidetoshi, Kluivers, Kirsten B, Kocher, Thomas, Komulainen, Pirjo, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kovacs, Peter, Kriebel, Jennifer, Kuivaniemi, Helena, Kury, Sebastien, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lakka, Timo A, Lange, Ethan M, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Larson, Eric B, Lee, I-Te, Lehtimaki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindstrom, Jaana, Linneberg, Allan, Liu, Yeheng, Liu, Yongmei, Lophatananon, Artitaya, Luan, Jian'an, Lubitz, Steven A, Lyytikainen, Leo-Pekka, Mackey, David A, Madden, Pamela AF, Manning, Alisa K, Mannisto, Satu, Marenne, Gaelle, Marten, Jonathan, Martin, Nicholas G, Mazul, Angela L, Meidtner, Karina, Metspalu, Andres, Mitchell, Paul, Mohlke, Karen L, Mook-Kanamori, Dennis O, Morgan, Anna, Morris, Andrew D, Morris, Andrew P, Mueller-Nurasyid, Martina, Munroe, Patricia B, Nalls, Mike A, Nauck, Matthias, Nelson, Christopher P, Neville, Matt, Nielsen, Sune F, Nikus, Kjell, Njolstad, Pal R, Nordestgaard, Borge G, Ntalla, Ioanna, O'Connel, Jeffrey R, Oksa, Heikki, Loohuis, Loes M Olde, Ophoff, Roel A, Owen, Katharine R, Packard, Chris J, Padmanabhan, Sandosh, Palmer, Colin NA, Pasterkamp, Gerard, Patel, Aniruddh P, Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Person, Thomas N, Pirie, Ailith, Polasek, Ozren, Posthuma, Danielle, Raitakari, Olli T, Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F, Reiner, Alex P, Renstrom, Frida, Ridker, Paul M, Rioux, John D, Robertson, Neil, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Sandow, Kevin, Sapkota, Yadav, Sattar, Naveed, Schmidt, Marjanka K, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo P, Shah, Svati, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S, Smith, Albert Vernon, Smith, Jennifer A, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Starr, John M, Steinthorsdottir, Valgerdur, Stringham, Heather M, Stumvoll, Michael, Surendran, Praveen, 't Hart, Leen M, Tansey, Katherine E, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorsteinsdottir, Unnur, Thuesen, Betina H, Toenjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P, Uher, Rudolf, Uitterlinden, Andre G, Ulivi, Sheila, van der Laan, Sander W, Van Der Leij, Andries R, van Duijn, Cornelia M, van Schoor, Natasja M, van Setten, Jessica, Varbo, Anette, Varga, Tibor V, Varma, Rohit, Edwards, Digna R Velez, Vermeulen, Sita H, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Vozzi, Diego, Walker, Mark, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wang, Yiqin, Wareham, Nicholas J, Warren, Helen R, Wessel, Jennifer, Willems, Sara M, Wilson, James G, Witte, Daniel R, Woods, Michael O, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Rotter, Jerome I, Boehnke, Michael, Kathiresan, Sekar, McCarthy, Mark I, Willer, Cristen J, Stefansson, Kari, Borecki, Ingrid B, Liu, Dajiang J, North, Kari E, Heard-Costa, Nancy L, Pers, Tune H, Lindgren, Cecilia M, Oxvig, Claus, Kutalik, Zoltan, Rivadeneira, Fernando, Loos, Ruth JF, Frayling, Timothy M, Hirschhorn, Joel N, Deloukas, Panos, Lettre, Guillaume, Consortium, EPIC-InterAct, Consortium, EPIC-CVD, Consortium, CHD Exome, Consortium, ExomeBP, Consortium, T2D-Genes, Consortium, GoT2D Genes, Consortium, Global Lipids Genetics, Consortium, ReproGen, Investigators, MAGIC, Marouli, Eirini, Graff, Mariaelisa, Medina Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R., Kjaer, Troels R., Fine, Rebecca S., Lu, Yingchang, Schurmann, Claudia, Highland, Heather M., Rüeger, Sina, Thorleifsson, Gudmar, Justice, Anne E., Lamparter, David, Stirrups, Kathleen E., Turcot, Valérie, Young, Kristin L., Winkler, Thomas W., Esko, Tõnu, Karaderi, Tugce, Locke, Adam E., Masca, Nicholas G. D., Ng, Maggie C. Y., Mudgal, Poorva, Rivas, Manuel A., Vedantam, Sailaja, Mahajan, Anubha, Guo, Xiuqing, Abecasis, Goncalo, Aben, Katja K., Adair, Linda S., Alam, Dewan S., Albrecht, Eva, Allin, Kristine H., Allison, Matthew, Amouyel, Philippe, Appel, Emil V., Arveiler, Dominique, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Banas, Bernhard, Bang, Lia E., Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bonnycastle, Lori L., Bork Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Burt, Amber A., Butterworth, Adam S., Carey, David J., Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Galbany, Jordi Coromina, Cox, Amanda J., Cuellar Partida, Gabriel, Danesh, John, Davies, Gail, De Bakker, Paul I. W., De Borst, Gert J., De Denus, Simon, De Groot, Mark C. H., De Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Den Hollander, Anneke I., Dennis, Joe G., Di Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dunning, Alison M., Easton, Douglas F., Ebeling, Tapani, Edwards, Todd L., Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki Eleni, Faul, Jessica D., Feitosa, Mary F., Feng, Shuang, Ferrannini, Ele, Ferrario, Marco M., Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franks, Paul W., Frikke Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Giri, Ayush, Girotto, Giorgia, Gordon, Scott D., Gordon Larsen, Penny, Gorski, Mathia, Grarup, Niel, Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Hayward, Caroline, He, Liang, Heid, Iris M., Heikkilä, Kauko, Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Hocking, Lynne J., Hollensted, Mette, Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hoyng, Carel B., Huang, Paul L., Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan Håkan, Jarvik, Gail P., Jensen, Gorm B., Jhun, Min A., Jia, Yucheng, Jiang, Xuejuan, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jousilahti, Pekka, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Keeman, Renske, Kiemeney, Lambertus A., Kitajima, Hidetoshi, Kluivers, Kirsten B., Kocher, Thoma, Komulainen, Pirjo, Kontto, Jukka, Kooner, Jaspal S., Kooperberg, Charle, Kovacs, Peter, Kriebel, Jennifer, Kuivaniemi, Helena, Küry, Sébastien, Kuusisto, Johanna, LA BIANCA, Martina, Laakso, Markku, Lakka, Timo A., Lange, Ethan M., Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Larson, Eric B., Lee, I. Te, Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li Gao, Ruifang, Lin, Honghuang, Lin, Li An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Yeheng, Liu, Yongmei, Lophatananon, Artitaya, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo Pekka, Mackey, David A., Madden, Pamela A. F., Manning, Alisa K., Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Martin, Nicholas G., Mazul, Angela L., Meidtner, Karina, Metspalu, Andre, Mitchell, Paul, Mohlke, Karen L., Mook Kanamori, Dennis O., Morgan, Anna, Morris, Andrew D., Morris, Andrew P., Müller Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Nauck, Matthia, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Ntalla, Ioanna, O'Connel, Jeffrey R., Oksa, Heikki, Loohuis, Loes M. Olde, Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Person, Thomas N., Pirie, Ailith, Polasek, Ozren, Posthuma, Danielle, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Renström, Frida, Ridker, Paul M., Rioux, John D., Robertson, Neil, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sandow, Kevin, Sapkota, Yadav, Sattar, Naveed, Schmidt, Marjanka K., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura Lepe, Marcelo P., Shah, Svati, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S., Smith, Albert Vernon, Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Steinthorsdottir, Valgerdur, Stringham, Heather M., Stumvoll, Michael, Surendran, Praveen, Hart'T, Leen M., Tansey, Katherine E., Tardif, Jean Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Ulivi, Sheila, Van Der Laan, Sander W., Van Der Leij, Andries R., Van Duijn, Cornelia M., Van Schoor, Natasja M., Van Setten, Jessica, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vozzi, Diego, Walker, Mark, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Wareham, Nicholas J., Warren, Helen R., Wessel, Jennifer, Willems, Sara M., Wilson, James G., Witte, Daniel R., Woods, Michael O., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Rotter, Jerome I., Boehnke, Michael, Kathiresan, Sekar, Mccarthy, Mark I., Willer, Cristen J., Stefansson, Kari, Borecki, Ingrid B., Liu, Dajiang J., North, Kari E., Heard Costa, Nancy L., Pers, Tune H., Lindgren, Cecilia M., Oxvig, Clau, Kutalik, Zoltán, Rivadeneira, Fernando, Loos, Ruth J. F., Frayling, Timothy M., Hirschhorn, Joel N., Deloukas, Pano, Lettre, Guillaume, Pharmacoepidemiology and Clinical Pharmacology, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Neurology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, Action on Hearing Loss, Home Office, National Institutes of Health, Public Health England, EPIC-InterAct Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium, MAGIC Investigators, Physiology, Human genetics, APH - Personalized Medicine, APH - Aging & Later Life, Epidemiology and Data Science, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Male, ReproGen Consortium, Multifactorial Inheritance, Genome-wide association study, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Androgen, ADAMTS Proteins, Gene Frequency, Missing heritability problem, MISSING HERITABILITY, Receptors, 2.1 Biological and endogenous factors, Pregnancy-Associated Plasma Protein-A, Aetiology, Non-U.S. Gov't, Glycosaminoglycans, Genetics, Multidisciplinary, Genome, CHD Exome+ Consortium, Medicine (all), Research Support, Non-U.S. Gov't, T2D-Genes Consortium, Global Lipids Genetics Consortium, Multidisciplinary Sciences, Phenotype, NADPH Oxidase 4, Receptors, Androgen, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Interferon Regulatory Factors, Science & Technology - Other Topics, Intercellular Signaling Peptides and Proteins, Female, Proteoglycans, EPIC-InterAct Consortium, ExomeBP Consortium, Common disease-common variant, Human, Adult, General Science & Technology, Biology, Development, Research Support, Article, GENETIC ARCHITECTURE, N.I.H, 03 medical and health sciences, MAGIC Investigators, Research Support, N.I.H., Extramural, Somatomedins, Genetic variation, MD Multidisciplinary, Journal Article, gene, height, rare, Humans, Hedgehog Proteins, Interleukin-11 Receptor alpha Subunit, Allele, GENOME-WIDE ASSOCIATION, Gene, Allele frequency, Alleles, Genetic association, Genetic association study, Glycoproteins, Science & Technology, MUTATIONS, Genome, Human, ta1184, Human Genome, Extramural, Genetic Variation, NADPH Oxidases, ta3121, Body Height, INTERLEUKIN-11, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], MICE, 030104 developmental biology, GoT2D Genes Consortium, Proteolysis, Procollagen N-Endopeptidase, Cell Adhesion Molecules
Abstract: Contains fulltext : 169801.pdf (Publisher’s version ) (Closed access) Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
Published: 2017

14. A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Author: Van Zuydam, Natalie R, Ahlqvist, Emma, Sandholm, Niina, Deshmukh, Harshal, Rayner, N William, Abdalla, Moustafa, Ladenvall, Claes, Ziemek, Daniel, Fauman, Eric, Robertson, Neil R, McKeigue, Paul M, Valo, Erkka, Forsblom, Carol, Harjutsalo, Valma, Finnish Diabetic Nephropathy Study (FinnDiane), Perna, Annalisa, Rurali, Erica, Marcovecchio, M Loredana, Igo, Robert P, Salem, Rany M, Perico, Norberto, Lajer, Maria, Käräjämäki, Annemari, Imamura, Minako, Kubo, Michiaki, Takahashi, Atsushi, Sim, Xueling, Liu, Jianjun, Van Dam, Rob M, Jiang, Guozhi, Tam, Claudia HT, Luk, Andrea OY, Lee, Heung Man, Lim, Cadmon KP, Szeto, Cheuk Chun, So, Wing Yee, Chan, Juliana CN, Group, Hong Kong Diabetes Registry Theme-Based Research Scheme Project, Ang, Su Fen, Dorajoo, Rajkumar, Wang, Ling, Clara, Tan Si Hua, McKnight, Amy-Jayne, Duffy, Seamus, Warren 3 And Genetics Of Kidneys In Diabetes (GoKinD) Study Group, Pezzolesi, Marcus G, GENIE (GEnetics Of Nephropathy An International Effort) Consortium, Marre, Michel, Gyorgy, Beata, Hadjadj, Samy, Hiraki, Linda T, Diabetes Control And Complications Trial (DCCT)/Epidemiology Of Diabetes Interventions And Complications (EDIC) Research Group, Ahluwalia, Tarunveer S, Almgren, Peter, Schulz, Christina-Alexandra, Orho-Melander, Marju, Linneberg, Allan, Christensen, Cramer, Witte, Daniel R, Grarup, Niels, Brandslund, Ivan, Melander, Olle, Paterson, Andrew D, Tregouet, David, Maxwell, Alexander P, Lim, Su Chi, Ma, Ronald CW, Tai, E Shyong, Maeda, Shiro, Lyssenko, Valeriya, Tuomi, Tiinamaija, Krolewski, Andrzej S, Rich, Stephen S, Hirschhorn, Joel N, Florez, Jose C, Dunger, David, Pedersen, Oluf, Hansen, Torben, Rossing, Peter, Remuzzi, Giuseppe, SUrrogate Markers For Micro- And Macrovascular Hard Endpoints For Innovative Diabetes Tools (SUMMIT) Consortium, Brosnan, Mary Julia, Palmer, Colin NA, Groop, Per-Henrik, Colhoun, Helen M, Groop, Leif C, McCarthy, Mark I, van Zuydam, Natalie R [0000-0002-9809-1398], Sandholm, Niina [0000-0003-4322-6942], Dunger, David [0000-0002-2566-9304], Groop, Per-Henrik [0000-0003-4055-6954], Colhoun, Helen M [0000-0002-8345-3288], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, endocrine system diseases, Polymorphism, Single Nucleotide, SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium, Medical and Health Sciences, Kidney Failure, Endocrinology & Metabolism, Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group, Diabetes Mellitus, 80 and over, Genetics, Humans, 2.1 Biological and endogenous factors, Diabetic Nephropathies, Genetic Predisposition to Disease, Renal Insufficiency, Renal Insufficiency, Chronic, Chronic, Polymorphism, Aetiology, Metabolic and endocrine, Aged, Aged, 80 and over, Finnish Diabetic Nephropathy Study, Diabetes, Human Genome, nutritional and metabolic diseases, Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group, Single Nucleotide, Middle Aged, Good Health and Well Being, Diabetes Mellitus, Type 2, Hong Kong Diabetes Registry Theme-based Research Scheme Project Group, Case-Control Studies, GENIE (GEnetics of Nephropathy an International Effort) Consortium, Kidney Failure, Chronic, Female, Type 2, Genome-Wide Association Study
Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
Published: 2018

15. Correction to:Soluble CD163, adiponectin, C-reactive protein and progression of dysglycaemia in individuals at high risk of type 2 diabetes mellitus: the ADDITION-PRO cohort (Diabetologia, 10.1007/s00125-016-4075-4)

Author: Deichgræber, Pia, Witte, Daniel R., Møller, Holger J., Skriver, Mette V., Richelsen, Bjørn, Jørgensen, Marit E., Johansen, Nanna B., and Sandbæk, Annelli
Abstract: The authors have discovered a coding error in the statistical analysis syntax file used for the mixed-effect model analyses in this paper. The error has led to differences (first decimal) in the estimates for the main results. Although the conclusions stand unaltered the actual change over time for many parameters is smaller than previously reported and the direction of change reversed for fasting insulin, HOMA-IR and HOMA-β.
Published: 2018

16. New blood pressure–associated loci identified in meta-analyses of 475 000 individuals

Author: Kraja, Aldi T., Cook, James P., Warren, Helen R., Surendran, Praveen, Liu, Chunyu, Evangelou, Evangelos, Manning, Alisa K., Grarup, Niels, Drenos, Fotios, Sim, Xueling, Smith, Albert Vernon, Amin, Najaf, Blakemore, Alexandra I.F., Bork-Jensen, Jette, Brandslund, Ivan, Farmaki, Aliki-Eleni, Fava, Cristiano, Ferreira, Teresa, Herzig, Karl-Heinz, Giri, Ayush, Giulianini, Franco, Grove, Megan L., Guo, Xiuqing, Harris, Sarah E., Have, Christian T., Havulinna, Aki S., Zhang, He, Jørgensen, Marit E., Käräjämäki, AnneMari, Kooperberg, Charles, Linneberg, Allan, Little, Louis, Liu, Yongmei, Bonnycastle, Lori L., Lu, Yingchang, Mägi, Reedik, Mahajan, Anubha, Malerba, Giovanni, Marioni, Riccardo E., Mei, Hao, Menni, Cristina, Morrison, Alanna C., Padmanabhan, Sandosh, Palmas, Walter, Poveda, Alaitz, Rauramaa, Rainer, Rayner, Nigel William, Riaz, Muhammad, Rice, Ken, Richard, Melissa A., Smith, Jennifer A., Southam, Lorraine, Stančáková, Alena, Stirrups, Kathleen E., Tragante, Vinicius, Tuomi, Tiinamaija, Tzoulaki, Ioanna, Varga, Tibor V., Weiss, Stefan, Yiorkas, Andrianos M., Young, Robin, Zhang, Weihua, Barnes, Michael R., Cabrera, Claudia P., Gao, He, Boehnke, Michael, Boerwinkle, Eric, Chambers, John C., Connell, John M., Christensen, Cramer K., de Boer, Rudolf A., Deary, Ian J., Dedoussis, George, Deloukas, Panos, Dominiczak, Anna F., Dörr, Marcus, Joehanes, Roby, Edwards, Todd L., Esko, Tõnu, Fornage, Myriam, Franceschini, Nora, Franks, Paul W., Gambaro, Giovanni, Groop, Leif, Hallmans, Göran, Hansen, Torben, Hayward, Caroline, Heikki, Oksa, Ingelsson, Erik, Tuomilehto, Jaakko, Jarvelin, Marjo-Riitta, Kardia, Sharon L.R., Karpe, Fredrik, Kooner, Jaspal S., Lakka, Timo A., Langenberg, Claudia, Lind, Lars, Loos, Ruth J.F., Laakso, Markku, McCarthy, Mark I., Melander, Olle, Mohlke, Karen L., Morris, Andrew P., Palmer, Colin N.A., Pedersen, Oluf, Polasek, Ozren, Poulter, Neil R., Province, Michael A., Psaty, Bruce M., Ridker, Paul M., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Sever, Peter J., Skaaby, Tea, Stafford, Jeanette M., Starr, John M., van der Harst, Pim, van der Meer, Peter, van Duijn, Cornelia M., Vergnaud, Anne-Claire, Gudnason, Vilmundur, Wareham, Nicholas J., Wilson, James G., Willer, Cristen J., Witte, Daniel R., Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S., Danesh, John, Asselbergs, Folkert W., Wain, Louise V., Ehret, Georg B., Chasman, Daniel I., Caulfield, Mark J., Elliott, Paul, Lindgren, Cecilia M., Levy, Daniel, Newton-Cheh, Christopher, Munroe, Patricia B., and Howson, Joanna M.M.
Abstract: Background—Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.\ud \ud Methods and Results—Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P
Published: 2017

17. Effect of secular trends on age-related trajectories of cardiovascular risk factors: the Whitehall II longitudinal study 1985–2009

Author: Hulmán, Adam, Tabák, Adam G, Nyári, Tibor A, Vistisen, Dorte, Kivimäki, Mika, Brunner, Eric J, and Witte, Daniel R
Subjects: Adult, Aged, 80 and over, Male, Aging, quantile regression, Smoking, blood pressure, cholesterol, Middle Aged, Lipids, Anthropometric Measures as Markers and Risk Factors, Body Mass Index, secular trend, Sex Factors, Socioeconomic Factors, ageing, Cardiovascular Diseases, Risk Factors, Body Composition, Humans, Female, Obesity, Longitudinal Studies, Aged
Abstract: Background: Secular trends in cardiovascular risk factors have been described, but few studies have examined simultaneously the effects of both ageing and secular trends within the same cohort. Methods: Development of cardiovascular risk factors over the past three decades was analysed using serial measurements from 10 308 participants aged from 35 to 80 years over 25 years of follow-up from five clinical examination phases of the Whitehall II study. Changes of body mass index, waist circumference, blood pressure and total and high-density lipoprotein cholesterol distribution characteristics were analysed with quantile regression models in the 57–61 age group. Age-related trajectories of risk factors were assessed by fitting mixed-effects models with adjustment for year of birth to reveal secular trends. Results: Average body mass index and waist circumference increased faster with age in women than in men, but the unfavourable secular trend was more marked in men. Distributions showed a fattening of the right tail in each consecutive phase, meaning a stronger increase in higher percentiles. Despite the higher obesity levels in younger birth cohorts, total cholesterol decreased markedly in the 57–61 age group along the entire distribution rather than in higher extremes only. Conclusion: The past three decades brought strong and heterogeneous changes in cardiovascular risk factor distributions. Secular trends appear to modify age-related trajectories of cardiovascular risk factors, which may be a source of bias in longitudinal analyses.
Published: 2014

18. is involved in the development of nonalcoholic fatty liver disease

Author: Vazquez-Chantada, Mercedes, Gonzalez-Lahera, Aintzane, Martinez-Arranz, Ibon, Garcia-Monzon, Carmelo, Regueiro, Manuela M., Garcia-Rodriguez, Juan L., Schlangen, Karin A., Mendibil, Iñaki, Rodriguez-Ezpeleta, Naiara, Lozano, Juan J., Banasik, Karina, Justesen, Johanne M., Joergensen, Torben, Witte, Daniel R., Lauritzen, Torsten, Hansen, Torben, Pedersen, Oluf, Veyrie, Nicolas, Clement, Karine, Tordjman, Joan, Tran, Albert, Le Marchand-Brustel, Yannik, Buque, Xabier, Aspichueta, Patricia, Echevarria-Uraga, Jose J., Martin-Duce, Antonio, Caballeria, Joan, Gual, Philippe, Castro, Azucena, Mato, Jose M., Martinez-Chantar, Maria L., and Aransay, Ana M.
Published: 2013
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19. Motivational counseling to reduce sitting time: A community-based randomized controlled trial in adults

Author: Aadahl, Mette, Linneberg, Allan, Møller, Trine C., Rosenørn, Solveig, Dunstan, David W., Witte, Daniel R., and Jørgensen, Torben
Abstract: Background Sedentary behavior is regarded as a distinct risk factor for cardiometabolic morbidity and mortality, but knowledge of the efficacy of interventions targeting reductions in sedentary behavior is limited. Purpose To investigate the effect of an individualized face-to-face motivational counseling intervention aimed at reducing sitting time. Design A randomized, controlled, observer-blinded, community-based trial with two parallel groups using open-end randomization with 1:1 allocation. Setting/participants A total of 166 sedentary adults were consecutively recruited from the population-based Health2010 Study. Intervention Participants were randomized to a control (usual lifestyle) or intervention group with four individual theory-based counseling sessions. Main outcome measures Objectively measured overall sitting time (ActivPAL 3TM, 7 days); secondary measures were breaks in sitting time, anthropometricmeasures, and cardiometabolic biomarkers, assessed at baseline and after 6 months. Data were collected in 2010–2012 and analyzed in 2013–2014 using repeated measures multiple regression analyses. Results Ninety-three participants were randomized to the intervention group and 73 to the control group, and 149 completed the study. The intervention group had a mean sitting time decrease of –0.27 hours/day, corresponding to 2.9% of baseline sitting time (hours/day); the control group increased mean sitting time by 0.06 hours/day. The between-group difference in change, –0.32 hours/day (95% CI=–0.87, 0.24, p=0.26), was not statistically significant. Significant differences in change in fasting serum insulin of –5.9 pmol/L (95% CI=–11.4, –0.5, p=0.03); homeostasis model assessment–estimated insulin resistance of –0.28 (95% CI=–0.53, –0.03, p=0.03); and waist circumference of –1.42 cm (95% CI=–2.54, –0.29, p=0.01) were observed in favor of the intervention group. Conclusions Although the observed decrease in sitting time was not significant, a community-based, individually tailored, theory-based intervention program aimed at reducing sitting time may be effective for increasing standing and improving cardiometabolic health in sedentary adults. Trial registration This study is registered at Clinicaltrials.gov (NCT00289237).
Published: 2014

20. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

Author: Horikoshi, Momoko Yaghootkar, Hanieh Mook-Kanamori, Dennis O. and Sovio, Ulla Taal, H. Rob Hennig, Branwen J. Bradfield, Jonathan P. St Pourcain, Beate Evans, David M. Charoen, Pimphen Kaakinen, Marika Cousminer, Diana L. Lehtimaki, Terho Kreiner-Moller, Eskil Warrington, Nicole M. and Bustamante, Mariona Feenstra, Bjarke Berry, Diane J. and Thiering, Elisabeth Pfab, Thiemo Barton, Sheila J. Shields, Beverley M. Kerkhof, Marjan van Leeuwen, Elisabeth M. and Fulford, Anthony J. Kutalik, Zoltan Zhao, Jing Hua den Hoed, Marcel Mahajan, Anubha Lindi, Virpi Goh, Liang-Kee and Hottenga, Jouke-Jan Wu, Ying Raitakari, Olli T. Harder, Marie N. Meirhaeghe, Aline Ntalla, Ioanna Salem, Rany M. and Jameson, Karen A. Zhou, Kaixin Monies, Dorota M. Lagou, Vasiliki Kirin, Mirna Heikkinen, Jani Adair, Linda S. and Alkuraya, Fowzan S. Al-Odaib, Ali Amouyel, Philippe and Andersson, Ehm Astrid Bennett, Amanda J. Blakemore, Alexandra I. F. Buxton, Jessica L. Dallongeville, Jean Das, Shikta de Geus, Eco J. C. Estivill, Xavier Flexeder, Claudia Froguel, Philippe Geller, Frank Godfrey, Keith M. Gottrand, Frederic and Groves, Christopher J. Hansen, Torben Hirschhorn, Joel N. and Hofman, Albert Hollegaard, Mads V. Hougaard, David M. and Hyppoenen, Elina Inskip, Hazel M. Isaacs, Aaron Jorgensen, Torben Kanaka-Gantenbein, Christina Kemp, John P. Kiess, Wieland Kilpelainen, Tuomas O. Klopp, Norman Knight, Bridget A. Kuzawa, Christopher W. McMahon, George Newnham, John P. and Niinikoski, Harri Oostra, Ben A. Pedersen, Louise and Postma, Dirkje S. Ring, Susan M. Rivadeneira, Fernando and Robertson, Neil R. Sebert, Sylvain Simell, Olli Slowinski, Torsten Tiesler, Carla M. T. Toenjes, Anke Vaag, Allan and Viikari, Jorma S. Vink, Jacqueline M. Vissing, Nadja Hawwa and Wareham, Nicholas J. Willemsen, Gonneke Witte, Daniel R. and Zhang, Haitao Zhao, Jianhua Wilson, James F. Stumvoll, Michael Prentice, Andrew M. Meyer, Brian F. Pearson, Ewan R. and Boreham, Colin A. G. Cooper, Cyrus Gillman, Matthew W. and Dedoussis, George V. Moreno, Luis A. Pedersen, Oluf and Saarinen, Maiju Mohlke, Karen L. Boomsma, Dorret I. Saw, Seang-Mei Lakka, Timo A. Koerner, Antje Loos, Ruth J. F. and Ong, Ken K. Vollenweider, Peter van Duijn, Cornelia M. and Koppelman, Gerard H. Hattersley, Andrew T. Holloway, John W. and Hocher, Berthold Heinrich, Joachim Power, Chris Melbye, Mads and Guxens, Monica Pennell, Craig E. Bonnelykke, Klaus and Bisgaard, Hans Eriksson, Johan G. Widen, Elisabeth and Hakonarson, Hakon Uitterlinden, Andre G. Pouta, Anneli and Lawlor, Debbie A. Smith, George Davey Frayling, Timothy M. and McCarthy, Mark I. Grant, Struan F. A. Jaddoe, Vincent W. V. and Jarvelin, Marjo-Riitta Timpson, Nicholas J. Prokopenko, Inga and Freathy, Rachel M. MAGIC Early Growth Genetics EGG
Abstract: Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
Published: 2013

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

Author: Scott, Robert A, Chu, Audrey Y, Grarup, Niels, Manning, Alisa K, Hivert, Marie-France, Shungin, Dmitry, Tönjes, Anke, Yesupriya, Ajay, Barnes, Daniel, Bouatia-Naji, Nabila, Glazer, Nicole L, Jackson, Anne U, Kutalik, Zoltán, Lagou, Vasiliki, Marek, Diana, Rasmussen-Torvik, Laura J, Stringham, Heather M, Tanaka, Toshiko, Aadahl, Mette, Arking, Dan E, Bergmann, Sven, Boerwinkle, Eric, Bonnycastle, Lori L, Bornstein, Stefan R, Brunner, Eric, Bumpstead, Suzannah J, Brage, Soren, Carlson, Olga D, Chen, Han, Chen, Yii-Der Ida, Chines, Peter S, Collins, Francis S, Couper, David J, Dennison, Elaine M, Dowling, Nicole F, Egan, Josephine S, Ekelund, Ulf, Erdos, Michael R, Forouhi, Nita G, Fox, Caroline S, Goodarzi, Mark O, Grässler, Jürgen, Gustafsson, Stefan, Hallmans, Göran, Hansen, Torben, Hingorani, Aroon, Holloway, John W, Hu, Frank B, Isomaa, Bo, Jameson, Karen A, Johansson, Ingegerd, Jonsson, Anna, Jørgensen, Torben, Kivimaki, Mika, Kovacs, Peter, Kumari, Meena, Kuusisto, Johanna, Laakso, Markku, Lecoeur, Cécile, Lévy-Marchal, Claire, Li, Guo, Loos, Ruth JF, Lyssenko, Valeri, Marmot, Michael, Marques-Vidal, Pedro, Morken, Mario A, Müller, Gabriele, North, Kari E, Pankow, James S, Payne, Felicity, Prokopenko, Inga, Psaty, Bruce M, Renström, Frida, Rice, Ken, Rotter, Jerome I, Rybin, Denis, Sandholt, Camilla H, Sayer, Avan A, Shrader, Peter, Schwarz, Peter EH, Siscovick, David S, Stancáková, Alena, Stumvoll, Michael, Teslovich, Tanya M, Waeber, Gérard, Williams, Gordon H, Witte, Daniel R, Wood, Andrew R, Xie, Weijia, Boehnke, Michael, Cooper, Cyrus, Ferrucci, Luigi, Froguel, Philippe, Groop, Leif, Kao, WH Linda, Vollenweider, Peter, Walker, Mark, Watanabe, Richard M, Pedersen, Oluf, and Meigs, James B
Subjects: Blood Glucose, Genotype, Prevention, Diabetes, Single Nucleotide, Motor Activity, Medical and Health Sciences, Body Mass Index, Endocrinology & Metabolism, Gene Expression Regulation, Genetic, Clinical Research, 2.3 Psychological, Genetics, 2.1 Biological and endogenous factors, Humans, Obesity, Aetiology, social and economic factors, Polymorphism, Life Style, Metabolic and endocrine, Nutrition, Epigenesis
Abstract: Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.
Published: 2012

22. PREVALENCE OF CARDIAL AUTONOMIC NEUROPATHY IN A POPULATION WITH SCREEN DETECTED DIABETES – ADDITION DENMARK

Author: Charles, Morten, Ejskjær, Niels, Lauritzen, Torsten, Witte, Daniel R, Borch-Johnsen, Knut, and Sandbæk, Annelli
Published: 2011

23. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm

Author: Gretarsdottir, Solveig, Baas, Annette F., Thorleifsson, Gudmar, Holm, Hilma, den Heijer, Martin, de Vries, Jean-Paul P. M., Kranendonk, Steef E., Zeebregts, Clark J. A. M., van Sterkenburg, Steven M., Geelkerken, Robert H., van Rij, Andre M., Williams, Michael J. A., Boll, Albert P. M., Kostic, Jelena P., Jonasdottir, Adalbjorg, Jonasdottir, Aslaug, Walters, G. Bragi, Masson, Gisli, Sulem, Patrick, Saemundsdottir, Jona, Mouy, Magali, Magnusson, Kristinn P., Tromp, Gerard, Elmore, James R., Sakalihasan, Natzi, Limet, Raymond, Defraigne, Jean-Olivier, Ferrell, Robert E., Ronkainen, Antti, Ruigrok, Ynte M., Wijmenga, Cisca, Grobbee, Diederick E., Shah, Svati H., Granger, Christopher B., Quyyumi, Arshed A., Vaccarino, Viola, Patel, Riyaz S., Zafari, A. Maziar, Levey, Allan I., Austin, Harland, Girelli, Domenico, Pignatti, Pier Franco, Olivieri, Oliviero, Martinelli, Nicola, Malerba, Giovanni, Trabetti, Elisabetta, Becker, Lewis C., Becker, Diane M., Reilly, Muredach P., Rader, Daniel J., Mueller, Thomas, Dieplinger, Benjamin, Haltmayer, Meinhard, Urbonavicius, Sigitas, Lindblad, Bengt, Gottsater, Anders, Gaetani, Eleonora, Pola, Roberto, Wells, Philip, Rodger, Marc, Forgie, Melissa, Langlois, Nicole, Corral, Javier, Vicente, Vicente, Fontcuberta, Jordi, Espana, Francisco, Grarup, Niels, Jorgensen, Torben, Witte, Daniel R., Hansen, Torben, Pedersen, Oluf, Aben, Katja K., de Graaf, Jacqueline, Holewijn, Suzanne, Folkersen, Lasse, Franco-Cereceda, Anders, Eriksson, Per, Collier, David A., Stefansson, Hreinn, Steinthorsdottir, Valgerdur, Rafnar, Thorunn, Valdimarsson, Einar M., Magnadottir, Hulda B., Sveinbjornsdottir, Sigurlaug, Olafsson, Isleifur, Magnusson, Magnus Karl, Palmason, Robert, Haraldsdottir, Vilhelmina, Andersen, Karl, Onundarson, Pall T., Thorgeirsson, Gudmundur, Kiemeney, Lambertus A., Powell, Janet T., Carey, David J., Kuivaniemi, Helena, Lindholt, Jes S., Jones, Gregory T., Kong, Augustine, Blankensteijn, Jan D., Matthiasson, Stefan E., Thorsteinsdottir, Unnur, and Stefansson, Kari
Published: 2010

24. The role of physical activity in the development of first cardiovascular disease event: a tree-structured survival analysis of the Danish ADDITION-PRO cohort

Author: Amadid, Hanan, Johansen, Nanna B, Bjerregaard, Anne-Louise, Brage, Søren, Færch, Kristine, Lauritzen, Torsten, Witte, Daniel R, Sandbæk, Annelli, Jørgensen, Marit E, and Vistisen, Dorte
Subjects: 3. Good health
Abstract: Background Ambiguity exists in relation to the role of physical activity (PA) for cardiovascular disease (CVD) risk reduction. We examined the interplay between PA dimensions and more conventional CVD risk factors to assess which PA dimensions were associated with the first CVD event and whether subgroup differences exist. Methods A total of 1449 individuals [median age 65.8 (IQR: 61.2, 70.7) years] with low to high risk of type 2 diabetes and free from CVD from the Danish ADDITION-PRO study were included for survival analysis. PA was measured by individually calibrated heart rate and movement sensing for 7 consecutive days. The associations of different PA dimensions (PA energy expenditure, time spent in light-, moderate- and vigorous intensity PA), sedentary time and other conventional CVD risk factors with the first CVD event were examined by tree-structured survival analysis. Baseline information was linked to data on the first CVD event (ischemic heart disease, ischemic stroke, heart failure, atrial flutter/fibrillation and atherosclerotic disease) and mortality obtained from Danish registers. Results During a median follow-up time of 5.5 (IQR: 5.1–6.1) years, a total of 201 individuals (13.9%) developed CVD. Overall CVD incidence rate was 2.6/100 person-years. PA energy expenditure above 43 kJ/kg/day was associated with lower rates of CVD events among participants ≤ 70 years and with HbA1c ≤ 5.7% (39 mmol/mol), systolic blood pressure ≤ 156 mmHg and albumin creatinine ratio ≤ 70 (incidence rates 0.0–0.8/100 person-years). Conclusions Any type of PA resulting in increased PA energy expenditure may over time be the best prevention strategy to uphold reduced risk of CVD.

25. A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes

Author: van Zuydam, Natalie R, Ahlqvist, Emma, Sandholm, Niina, Deshmukh, Harshal, Rayner, N William, Abdalla, Moustafa, Ladenvall, Claes, Ziemek, Daniel, Fauman, Eric, Robertson, Neil R, Mckeigue, Paul M, Valo, Erkka, Forsblom, Carol, Harjutsalo, Valma, Perna, Annalisa, Rurali, Erica, Marcovecchio, M Loredana, Igo, Robert P, Salem, Rany M, Perico, Norberto, Lajer, Maria, Käräjämäki, Annemari, Imamura, Minako, Kubo, Michiaki, Takahashi, Atsushi, Sim, Xueling, Liu, Jianjun, van Dam, Rob M, Jiang, Guozhi, Tam, Claudia H T, Luk, Andrea O Y, Lee, Heung Man, Lim, Cadmon K P, Szeto, Cheuk Chun, Wing Yee, So, Chan, Juliana C N, Ang, Su Fen, Dorajoo, Rajkumar, Wang, Ling, Clara, Tan Si Hua, Mcknight, Amy-Jayne, Duffy, Seamus, Pezzolesi, Marcus G, Marre, Michel, Gyorgy, Beata, Hadjadj, Samy, Hiraki, Koivula, S, Uggeldahl, T, Forslund, T, Halonen, A, Koistinen, A, Koskiaho, P, Laukkanen, M, Saltevo, J, Tiihonen, M, Forsen, M, Granlund, H, Jonsson, Ac, Nyroos, B, Kinnunen, P, Orvola, A, Salonen, T, Vähänen, A, Paldanius, Kr, Riihelä, M, Ryysy, L, Laukkanen, Kh, Nyländen, P, Sademies, A, Anderson, S, Asplund, B, Byskata, U, Liedes, P, Kuusela, M, Virkkala, T, Nikkola, A, Ritola, E, Niska, Tm, Saarinen, H, Oukko-Ruponen, Se, Virtanen, T, Lyytinen, Va, Kari, Ph, Simonen, T, Kaprio, Sa, Kärkkäinen, J, Rantaeskola, B, Kääriäinen, Tp, Haaga, J, Pietiläinen, Al, Klemetti, S, Nyandoto, T, Rontu, E, Satuli-Autere, S, Toivonen, Kr, Lansimaki, Hv, Ahonen, R, Ivaska-Suomela, M, Jauhiainen, A, Laine, Mm, Pellonpää, T, Puranen, R, Airas, Ma, Laakso, J, Rautavaara, K, Erola, Rm, Jatkola, E, Lönnblad, Tr, Malm, A, Mäkelä, J, Rautamo, E, Hentunen, P, Lagerstam, J, Feodoroff, M, Gordin, D, Heikkilä, O, Hietala, K, Fagerudd, J, Korolainen, M, Kyllönen, L, Kytö, J, Lindh, S, Pettersson-Fernholm, K, Rosengård-Bärlund, M, Sandelin, A, Thorn, L, Tuomikangas, J, Vesisenaho, T, Wadén, J, Sipilä, V, Kalliomäki, Ft, Koskelainen, J, Nikkanen, R, Savolainen, N, Sulonen, H, Valtonen, E, Norvio, L, Hämäläinen, A, Toivanen, E, Parta, Ja, Pirttiniemi, I, Aranko, S, Ervasti, S, Kauppinen-Mäkelin, R, Kuusisto, A, Leppälä, T, Nikkilä, K, Pekkonen, L, Jokelainen, Ks, Kananen, K, Karjalainen, M, Kemppainen, P, Mankinen, Am, Reponen, A, Sankari, M, Suominen, P, Lappalainen, A, Liimatainen, M, Santaholma, J, Aimolahti, A, Huovinen, E, Ilkka, V, Lehtimäki, M, Pälikkö-Kontinen, E, Vanhanen, A, Koskinen, E, Siitonen, T, Huttunen, E, Ikäheimo, R, Karhapää, P, Kekäläinen, P, Laakso, M, Lakka, T, Lampainen, E, Moilanen, L, Tanskanen, S, Niskanen, L, Tuovinen, U, Vauhkonen, I, Voutilainen, E, Rcw, Ma, Chan, Jcn, Huang, Y, Lan, Hy, Lok, S, Tomlinson, B, Tsui, Skw, Yu, W, Yip, Kyl, Chan, Tf, Fan, X, So, Wy, Szeto, Cc, Tang, N, Luk, Ao, Tian, X, Jiang, G, Tam, Cht, Lee, Hm, Lim, Ckp, Chan, Kkh, Xie, F, Acw, Ng, Cheung, Gpy, Yeung, Mw, Mai, S, Zhang, S, Yu, P, Weng, M, Maxwell, Ap, Mcknight, Aj, Savage, Da, Walker, J, Thomas, S, Viberti, Gc, Boulton, Ajm, Marshall, S, Demaine, Ag, Millward, Ba, Bain, Sc, Sandholm, N, Forsblom, C, Harjutsalo, V, Mäkinen, Vp, Ahola, Aj, Dahlström, E, Lehto, M, Lithovius, R, Panduru, Nm, Parkkonen, M, Saraheimo, M, Söderlund, J, Soro-Paavonen, A, Syreeni, A, Thorn, Lm, Tolonen, N, Groop, Ph, Mckay, Gj, Salem, Rm, Isakova, T, Palmer, C, Guiducci, C, Taylor, A, Mirel, Db, Williams, Ww, Hirschhorn, Jn, Florez, Jc, Brennan, Ep, Sadlier, Dm, Martin, F, Godson, C, Mayer, L, Gubitosi-Klug, R, Bourne, P, Schutta, M, Lackaye, Me, Gregory, Ns, Kruger, D, Jones, Jk, Bhan, A, Golden, E, Aiello, L, Larkin, M, Nathan, D, Ziegler, G, Caulder, S, Pittman, C, Luttrell, L, Lopes-Virella, M, Johnson, M, Gunyou, K, Bergenstal, R, Vittetoe, B, Sivitz, W, Flaherty, N, Bantle, J, Hitt, S, Goldstein, D, Hainsworth, D, Cimino, L, Orchard, T, Wigley, C, Dagogo-Jack, S, Strowig, S, Raskin, P, Barnie, A, Zinman, B, Fahlstrom, R, Palmer, J, Harth, J, Driscoll, M, Mcdonald, C, Lipps Hagan, J, May, M, Levandoski, L, White, N, Gatcomb, P, Tamborlane, W, Adelman, D, Colson, S, Molitch, M, Lorenzi, G, Mudaliar, S, Johnsonbaugh, S, Miller, R, Canady, J, Schade, D, Bernal, Ml, Malone, J, Morrison, A, Martin, C, Herman, W, Pop-Busui, R, Cowie, C, Leschek, E, Cleary, P, Lachin, J, Braffett, B, Steffes, M, Arends, V, Blodi, B, Danis, R, Lawrence, D, Wabers, H, Soliman, E, Zhang, Zm, Campbell, C, Hensley, S, Keasler, L, Mark, M, Albertini, M, Boustany, C, Ehlgen, A, Gerl, M, Huber, J, Schölch, C, Zimdahl-Gelling, H, Groop, L, Agardh, E, Ahlqvist, E, Ajanki, T, Al Maghrabi, N, Almgren, P, Apelqvist, J, Bengtsson, E, Berglund, L, Björckbacka, H, Blom-Nilsson, U, Borell, M, Burström, A, Cilio, C, Cinthio, M, Dreja, K, Dunér, P, Engelbertsen, D, Fadista, J, Gomez, M, Goncalves, I, Hedblad, B, Hultgårdh, A, Johansson, Me, Kennbäck, C, Kravic, J, Ladenvall, C, Lernmark, Å, Lindholm, E, Ling, C, Luthman, H, Melander, O, Neptin, M, Nilsson, J, Nilsson, P, Nilsson, T, Nordin, G, Orho-Melander, M, Ottoson-Laakso, E, Persson, A, Persson, M, Persson, Må, Postma, J, Pranter, E, Rattik, S, Sterner, G, Tindberg, L, Wigren, M, Zetterqvist, A, Åkerlund, M, Ostling, G, Kanninen, T, Ahonen-Bishopp, A, Eliasson, A, Herrala, T, Tikka-Kleemola, P, Hamsten, A, Betsholtz, C, Björkholm, A, Foroogh, F, Genové, G, Gertow, K, Gigante, B, He, B, Leander, K, Mcleod, O, Nastase-Mannila, M, Patrakka, J, Silveira, A, Strawbridge, R, Tryggvason, K, Vikström, M, Ohrvik, J, Österholm, Am, Thorand, B, Gieger, C, Grallert, H, Ludwig, T, Nitz, B, Schneider, A, Wang-Sattler, R, Zierer, A, Remuzzi, G, Benigni, A, Donadelli, R, Lesti, Md, Noris, M, Perico, N, Perna, A, Piras, R, Ruggenenti, P, Rurali, E, Dunger, D, Chassin, L, Dalton, N, Deanfield, J, Horsford, J, Rice, C, Rudd, J, Walker, N, Whitehead, K, Wong, M, Colhoun, H, Adams, F, Akbar, T, Belch, J, Deshmukh, H, Dove, F, Ellingford, A, Farran, B, Ferguson, M, Henderson, G, Houston, G, Khan, F, Leese, G, Liu, Y, Livingstone, S, Looker, H, Mccann, M, Mcgurnaghan, S, Morris, A, Newton, D, Pearson, E, Reekie, G, Smith, N, Shore, A, Aizawa, K, Ball, C, Bellenger, N, Casanova, F, Frayling, T, Gates, P, Gooding, K, Hattersley, A, Ling, R, Mawson, D, Shandas, R, Strain, D, Thorn, C, Smith, U, Hammarstedt, A, Häring, H, Pedersen, O, Sesti, G, Fagerholm, E, Toppila, I, Valo, E, Salomaa, V, Havulinna, A, Kristiansson, K, Okamo, P, Peltola, T, Perola, M, Pietilä, A, Ripatti, S, Taimi, M, Ylä-Herttuala, S, Babu, M, Dijkstra, M, Gurzeler, E, Huusko, J, Kholová, I, Merentie, M, Poikolainen, M, Mccarthy, M, Groves, C, Juliusdottir, T, Karpe, F, Lagou, V, Rayner, W, Robertson, N, van Zuydam, N, Cobelli, C, Di Camillo, B, Finotello, F, Sambo, F, Toffolo, G, Trifoglio, E, Bellazzi, R, Barbarini, N, Bucalo, M, Larizza, C, Magni, P, Malovini, A, Marini, S, Mulas, F, Quaglini, S, Sacchi, L, Vitali, F, Ferrannini, E, Boldrini, B, Kozakova, M, Mari, A, Morizzo, C, Mota, L, Natali, A, Palombo, C, Venturi, E, Walker, M, Patrono, C, Pagliaccia, F, Rocca, B, Nuutila, P, Haukkala, J, Knuuti, J, Roivainen, A, Saraste, A, Mckeague, P, Colombo, M, Steckel-Hamann, B, Bokvist, K, Shankar, S, Thomas, M, Gan, Lm, Heinonen, S, Jönsson-Rylander, Ac, Momo, R, Schnecke, V, Unwin, R, Walentinsson, A, Whatling, C, Nogoceke, E, Pacheco, Gd, Formentini, I, Schindler, T, Tortoli, P, Bassi, L, Boni, E, Dallai, A, Guidi, F, Lenge, M, Matera, R, Ramalli, A, Ricci, S, Viti, J, Jablonka, B, Crowther, D, Gassenhuber, J, Hess, S, Hubschle, T, Juretschke, Hp, Rutten, H, Sadowski, T, Wohlfart, P, Brosnan, J, Clerin, V, Fauman, E, Hyde, C, Malarstig, A, Pullen, N, Tilley, M, Tuthill, T, Vangjeli, C, Linda T, Ziemek D., Ahluwalia, Tarunveer S, Almgren, Peter, Schulz, Christina-Alexandra, Orho-Melander, Marju, Linneberg, Allan, Christensen, Cramer, Witte, Daniel R, Grarup, Niels, Brandslund, Ivan, Melander, Olle, Paterson, Andrew D, Tregouet, David, Maxwell, Alexander P, Lim, Su Chi, Ronald C W, Ma, Tai, E Shyong, Maeda, Shiro, Lyssenko, Valeriya, Tuomi, Tiinamaija, Krolewski, Andrzej S, Rich, Stephen S, Hirschhorn, Joel N, Florez, Jose C, Dunger, David, Pedersen, Oluf, Hansen, Torben, Rossing, Peter, Remuzzi, Giuseppe, Brosnan, Mary Julia, Palmer, Colin N A, Groop, Per-Henrik, Colhoun, Helen M, Groop, Leif C, Mccarthy, Mark, I, Palombo, Carlo, Clinicum, Diabetes and Obesity Research Program, Research Programs Unit, Nefrologian yksikkö, Department of Medicine, Institute for Molecular Medicine Finland, Tiinamaija Tuomi Research Group, Endokrinologian yksikkö, Per Henrik Groop / Principal Investigator, Leif Groop Research Group, HUS Abdominal Center, HUS Internal Medicine and Rehabilitation, and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: 0301 basic medicine, Male, endocrine system diseases, Endocrinology, Diabetes and Metabolism, LOCI, Genome-wide association study, Type 2 diabetes, Bioinformatics, Kidney Failure, 0302 clinical medicine, Genome-wide analysis, 80 and over, Diabetic Nephropathies, Renal Insufficiency, Chronic, Genome-wide analysis, Type 2 Diabetes, Aged, 80 and over, RISK, INSULIN-RESISTANCE, diabetes, Diabetes, STAGE RENAL-DISEASE, Single Nucleotide, Middle Aged, Type 2 Diabetes, SUSCEPTIBILITY GENES, Adult, Aged, Case-Control Studies, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Failure, Chronic, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, OBESITY, BIOLOGICAL PATHWAYS, nephropathy, Medical genetics, Type 2, kidney, medicine.medical_specialty, Diabetic Nephropathies/epidemiology, Settore BIO/14 - FARMACOLOGIA, Renal Insufficiency, Chronic/complications, NEPHROPATHY, SNP, 030209 endocrinology & metabolism, Nephropathy, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, Journal Article, Diabetes Mellitus, Internal Medicine, medicine, Medicine [Science], Polymorphism, Diabetic Kidney Disease, METAANALYSIS, Genetic heterogeneity, business.industry, Diabetes Mellitus, Type 2/complications, association, Case-control study, nutritional and metabolic diseases, Kidney Failure, Chronic/complications, FAT DISTRIBUTION, medicine.disease, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Microalbuminuria, genetic, business
Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore)

26. Habitual physical activity is associated with lower fasting and greater glucose-induced GLP-1 response in men

Author: Janus, Charlotte, Vistisen, Dorte, Amadid, Hanan, Witte, Daniel R, Lauritzen, Torsten, Brage, Søren, Bjerregaard, Anne-Louise, Hansen, Torben, Holst, Jens J, Jørgensen, Marit E, Pedersen, Oluf, Færch, Kristine, and Torekov, Signe S
Subjects: exercise, glucagon-like peptide-1 (GLP-1), overweight, prediabetes, habitual physical activity, 3. Good health
Abstract: RATIONALE: The hormone glucagon-like peptide-1 (GLP-1) decreases blood glucose and appetite. Greater physical activity (PA) is associated with lower incidence of type 2 diabetes. While acute exercise may increase glucose-induced response of GLP-1, it is unknown how habitual PA affects GLP-1 secretion. We hypothesised that habitual PA associates with greater glucose-induced GLP-1 responses in overweight individuals. METHODS: Cross-sectional analysis of habitual PA levels and GLP-1 concentrations in 1326 individuals (mean (s.d.) age 66 (7) years, BMI 27.1 (4.5) kg/m2) from the ADDITION-PRO cohort. Fasting and oral glucose-stimulated GLP-1 responses were measured using validated radioimmunoassay. PA was measured using 7-day combined accelerometry and heart rate monitoring. From this, energy expenditure (PAEE; kJ/kg/day) and fractions of time spent in activity intensities (h/day) were calculated. Cardiorespiratory fitness (CRF; mL O2/kg/min) was calculated using step tests. Age-, BMI- and insulin sensitivity-adjusted associations between PA and GLP-1, stratified by sex, were evaluated by linear regression analysis. RESULTS: In 703 men, fasting GLP-1 concentrations were 20% lower (95% CI: -33; -3%, P = 0.02) for every hour of moderate-intensity PA performed. Higher CRF and PAEE were associated with 1-2% lower fasting GLP-1 (P = 0.01). For every hour of moderate-intensity PA, the glucose-stimulated GLP-1 response was 16% greater at peak 30 min (1; 33%, P rAUC0-30 = 0.04) and 20% greater at full response (3; 40%, P rAUC0-120 = 0.02). No associations were found in women who performed PA 22 min/day vs 32 min/day for men. CONCLUSION: Moderate-intensity PA is associated with lower fasting and greater glucose-induced GLP-1 responses in overweight men, possibly contributing to improved glucose and appetite regulation with increased habitual PA.

27. Hyperglycaemia, type 2 diabetes, and depressive symptoms

Author: Mika Kivimäki, Tabak, Adam G., David Batty, G., Archana Singh-Manoux, Markus Jokela, Akbaraly, Tasnime N., Witte, Daniel R., Brunner, Eric J., Marmot, Michael G., and Lawlor, Debbie A.

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

Author: Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R, Torres, Jason M, Rayner, N William, Payne, Anthony J, Steinthorsdottir, Valgerdur, Scott, Robert A, Grarup, Niels, Cook, James P, Schmidt, Ellen M, Wuttke, Matthias, Sarnowski, Chloé, Mägi, Reedik, Nano, Jana, Gieger, Christian, Trompet, Stella, Lecoeur, Cécile, Preuss, Michael H, Prins, Bram Peter, Guo, Xiuqing, Bielak, Lawrence F, Below, Jennifer E, Bowden, Donald W, Chambers, John Campbell, Kim, Young Jin, Ng, Maggie CY, Petty, Lauren E, Sim, Xueling, Zhang, Weihua, Bennett, Amanda J, Bork-Jensen, Jette, Brummett, Chad M, Canouil, Mickaël, Ec Kardt, Kai-Uwe, Fischer, Krista, Kardia, Sharon LR, Kronenberg, Florian, Läll, Kristi, Liu, Ching-Ti, Locke, Adam E, Luan, Jian'an, Ntalla, Ioanna, Nylander, Vibe, Schönherr, Sebastian, Schurmann, Claudia, Yengo, Loïc, Bottinger, Erwin P, Brandslund, Ivan, Christensen, Cramer, Dedoussis, George, Florez, Jose C, Ford, Ian, Franco, Oscar H, Frayling, Timothy M, Giedraitis, Vilmantas, Hackinger, Sophie, Hattersley, Andrew T, Herder, Christian, Ikram, M Arfan, Ingelsson, Martin, Jørgensen, Marit E, Jørgensen, Torben, Kriebel, Jennifer, Kuusisto, Johanna, Ligthart, Symen, Lindgren, Cecilia M, Linneberg, Allan, Lyssenko, Valeriya, Mamakou, Vasiliki, Meitinger, Thomas, Mohlke, Karen L, Morris, Andrew D, Nadkarni, Girish, Pankow, James S, Peters, Annette, Sattar, Naveed, Stančáková, Alena, Strauch, Konstantin, Taylor, Kent D, Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Witte, Daniel R, Dupuis, Josée, Peyser, Patricia A, Zeggini, Eleftheria, Loos, Ruth JF, Froguel, Philippe, Ingelsson, Erik, Lind, Lars, Groop, Leif, Laakso, Markku, Collins, Francis S, Jukema, J Wouter, Palmer, Colin NA, Grallert, Harald, Metspalu, Andres, Dehghan, Abbas, Köttgen, Anna, Abecasis, Goncalo R, Meigs, James B, Rotter, Jerome I, Marchini, Jonathan, Pedersen, Oluf, Hansen, Torben, Langenberg, Claudia, Wareham, Nicholas J, Stefansson, Kari, Gloyn, Anna L, Morris, Andrew P, Boehnke, Michael, and McCarthy, Mark I
Subjects: Male, endocrine system diseases, Genome, Human, Chromosome Mapping, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, 3. Good health, Body Mass Index, Epigenesis, Genetic, High-Throughput Screening Assays, Islets of Langerhans, Sex Factors, Diabetes Mellitus, Type 2, Gene Frequency, Meta-Analysis as Topic, Genetic Loci, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract: We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

29. The role of physical activity in the development of first cardiovascular disease event: a tree-structured survival analysis of the Danish ADDITION-PRO cohort

Author: Amadid, Hanan, Johansen, Nanna B, Bjerregaard, Anne-Louise, Brage, Søren, Færch, Kristine, Lauritzen, Torsten, Witte, Daniel R, Sandbæk, Annelli, Jørgensen, Marit E, and Vistisen, Dorte
Subjects: Male, Time Factors, Denmark, Type 2 diabetes, Middle Aged, Protective Factors, Cardiovascular disease, Prognosis, Risk Assessment, 3. Good health, Prospective cohort study, Objective physical activity, Cardiovascular Diseases, Risk Factors, Humans, Female, Healthy Lifestyle, Prospective Studies, Tree-structured survival analysis, Sedentary Behavior, Exercise, Risk Reduction Behavior, Aged
Abstract: BACKGROUND: Ambiguity exists in relation to the role of physical activity (PA) for cardiovascular disease (CVD) risk reduction. We examined the interplay between PA dimensions and more conventional CVD risk factors to assess which PA dimensions were associated with the first CVD event and whether subgroup differences exist. METHODS: A total of 1449 individuals [median age 65.8 (IQR: 61.2, 70.7) years] with low to high risk of type 2 diabetes and free from CVD from the Danish ADDITION-PRO study were included for survival analysis. PA was measured by individually calibrated heart rate and movement sensing for 7 consecutive days. The associations of different PA dimensions (PA energy expenditure, time spent in light-, moderate- and vigorous intensity PA), sedentary time and other conventional CVD risk factors with the first CVD event were examined by tree-structured survival analysis. Baseline information was linked to data on the first CVD event (ischemic heart disease, ischemic stroke, heart failure, atrial flutter/fibrillation and atherosclerotic disease) and mortality obtained from Danish registers. RESULTS: During a median follow-up time of 5.5 (IQR: 5.1-6.1) years, a total of 201 individuals (13.9%) developed CVD. Overall CVD incidence rate was 2.6/100 person-years. PA energy expenditure above 43 kJ/kg/day was associated with lower rates of CVD events among participants ≤ 70 years and with HbA1c ≤ 5.7% (39 mmol/mol), systolic blood pressure ≤ 156 mmHg and albumin creatinine ratio ≤ 70 (incidence rates 0.0-0.8/100 person-years). CONCLUSIONS: Any type of PA resulting in increased PA energy expenditure may over time be the best prevention strategy to uphold reduced risk of CVD.

30. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author: Surendran, Praveen, Feofanova, Elena V, Lahrouchi, Najim, Ntalla, Ioanna, Karthikeyan, Savita, Cook, James, Chen, Lingyan, Mifsud, Borbala, Yao, Chen, Kraja, Aldi T, Cartwright, James H, Hellwege, Jacklyn N, Giri, Ayush, Tragante, Vinicius, Thorleifsson, Gudmar, Liu, Dajiang J, Prins, Bram P, Stewart, Isobel D, Cabrera, Claudia P, Eales, James M, Akbarov, Artur, Auer, Paul L, Bielak, Lawrence F, Bis, Joshua C, Braithwaite, Vickie S, Brody, Jennifer A, Daw, E Warwick, Warren, Helen R, Drenos, Fotios, Nielsen, Sune Fallgaard, Faul, Jessica D, Fauman, Eric B, Fava, Cristiano, Ferreira, Teresa, Foley, Christopher N, Franceschini, Nora, Gao, He, Giannakopoulou, Olga, Giulianini, Franco, Gudbjartsson, Daniel F, Guo, Xiuqing, Harris, Sarah E, Havulinna, Aki S, Helgadottir, Anna, Huffman, Jennifer E, Hwang, Shih-Jen, Kanoni, Stavroula, Kontto, Jukka, Larson, Martin G, Li-Gao, Ruifang, Lindström, Jaana, Lotta, Luca A, Lu, Yingchang, Luan, Jian'an, Mahajan, Anubha, Malerba, Giovanni, Masca, Nicholas GD, Mei, Hao, Menni, Cristina, Mook-Kanamori, Dennis O, Mosen-Ansorena, David, Müller-Nurasyid, Martina, Paré, Guillaume, Paul, Dirk S, Perola, Markus, Poveda, Alaitz, Rauramaa, Rainer, Richard, Melissa, Richardson, Tom G, Sepúlveda, Nuno, Sim, Xueling, Smith, Albert V, Smith, Jennifer A, Staley, James R, Stanáková, Alena, Sulem, Patrick, Thériault, Sébastien, Thorsteinsdottir, Unnur, Trompet, Stella, Varga, Tibor V, Velez Edwards, Digna R, Veronesi, Giovanni, Weiss, Stefan, Willems, Sara M, Yao, Jie, Young, Robin, Yu, Bing, Zhang, Weihua, Zhao, Jing-Hua, Zhao, Wei, Evangelou, Evangelos, Aeschbacher, Stefanie, Asllanaj, Eralda, Blankenberg, Stefan, Bonnycastle, Lori L, Bork-Jensen, Jette, Brandslund, Ivan, Braund, Peter S, Burgess, Stephen, Cho, Kelly, Christensen, Cramer, Connell, John, Mutsert, Renée De, Dominiczak, Anna F, Dörr, Marcus, Eiriksdottir, Gudny, Farmaki, Aliki-Eleni, Gaziano, J Michael, Grarup, Niels, Grove, Megan L, Hallmans, Göran, Hansen, Torben, Have, Christian T, Heiss, Gerardo, Jørgensen, Marit E, Jousilahti, Pekka, Kajantie, Eero, Kamat, Mihir, Käräjämäki, AnneMari, Karpe, Fredrik, Koistinen, Heikki A, Kovesdy, Csaba P, Kuulasmaa, Kari, Laatikainen, Tiina, Lannfelt, Lars, Lee, I-Te, Lee, Wen-Jane, LifeLines Cohort Study, Linneberg, Allan, Martin, Lisa W, Moitry, Marie, Nadkarni, Girish, Neville, Matt J, Palmer, Colin NA, Papanicolaou, George J, Pedersen, Oluf, Peters, James, Poulter, Neil, Rasheed, Asif, Rasmussen, Katrine L, Rayner, N William, Mägi, Reedik, Renström, Frida, Rettig, Rainer, Rossouw, Jacques, Schreiner, Pamela J, Sever, Peter S, Sigurdsson, Emil L, Skaaby, Tea, Sun, Yan V, Sundstrom, Johan, Thorgeirsson, Gudmundur, Esko, Tõnu, Trabetti, Elisabetta, Tsao, Philip S, Tuomi, Tiinamaija, Turner, Stephen T, Tzoulaki, Ioanna, Vaartjes, Ilonca, Vergnaud, Anne-Claire, Willer, Cristen J, Wilson, Peter WF, Witte, Daniel R, Yonova-Doing, Ekaterina, Zhang, He, Aliya, Naheed, Almgren, Peter, Amouyel, Philippe, Asselbergs, Folkert W, Barnes, Michael R, Blakemore, Alexandra I, Boehnke, Michael, Bots, Michiel L, Bottinger, Erwin P, Buring, Julie E, Chambers, John C, Chen, Yii-Der Ida, Chowdhury, Rajiv, Conen, David, Correa, Adolfo, Davey Smith, George, Boer, Rudolf A De, Deary, Ian J, Dedoussis, George, Deloukas, Panos, Di Angelantonio, Emanuele, Elliott, Paul, EPIC-CVD, EPIC-InterAct, Felix, Stephan B, Ferrières, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W, Franks, Stephen, Frossard, Philippe, Gambaro, Giovanni, Gaunt, Tom R, Groop, Leif, Gudnason, Vilmundur, Harris, Tamara B, Hayward, Caroline, Hennig, Branwen J, Herzig, Karl-Heinz, Ingelsson, Erik, Tuomilehto, Jaakko, Järvelin, Marjo-Riitta, Jukema, J Wouter, Kardia, Sharon LR, Kee, Frank, Kooner, Jaspal S, Kooperberg, Charles, Launer, Lenore J, Lind, Lars, Loos, Ruth JF, Majumder, Abdulla Al Shafi, Laakso, Markku, McCarthy, Mark I, Melander, Olle, Mohlke, Karen L, Murray, Alison D, Nordestgaard, Børge Grønne, Orho-Melander, Marju, Packard, Chris J, Padmanabhan, Sandosh, Palmas, Walter, Polasek, Ozren, Porteous, David J, Prentice, Andrew M, Province, Michael A, Relton, Caroline L, Rice, Kenneth, Ridker, Paul M, Rolandsson, Olov, Rosendaal, Frits R, Rotter, Jerome I, Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Sattar, Naveed, Sheu, Wayne H-H, Smith, Blair H, Soranzo, Nicole, Spector, Timothy D, Starr, John M, Sebert, Sylvain, Taylor, Kent D, Lakka, Timo A, Timpson, Nicholas J, Tobin, Martin D, Understanding Society Scientific Group, Van Der Harst, Pim, Van Der Meer, Peter, Ramachandran, Vasan S, Verweij, Niek, Virtamo, Jarmo, Völker, Uwe, Weir, David R, Zeggini, Eleftheria, Charchar, Fadi J, Million Veteran Program, Wareham, Nicholas J, Langenberg, Claudia, Tomaszewski, Maciej, Butterworth, Adam S, Caulfield, Mark J, Danesh, John, Edwards, Todd L, Holm, Hilma, Hung, Adriana M, Lindgren, Cecilia M, Liu, Chunyu, Manning, Alisa K, Morris, Andrew P, Morrison, Alanna C, O'Donnell, Christopher J, Psaty, Bruce M, Saleheen, Danish, Stefansson, Kari, Boerwinkle, Eric, Chasman, Daniel I, Levy, Daniel, Newton-Cheh, Christopher, Munroe, Patricia B, and Howson, Joanna MM
Subjects: Gene Frequency, Genotype, GATA5 Transcription Factor, Hypertension, Mutation, Phospholipase C beta, Humans, Blood Pressure, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, 3. Good health, Genome-Wide Association Study
Abstract: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

31. Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

Author: Bonàs-Guarch, Sílvia, Guindo-Martínez, Marta, Miguel-Escalada, Irene, Grarup, Niels, Sebastian, David, Rodriguez-Fos, Elias, Sánchez, Friman, Planas-Fèlix, Mercè, Cortes-Sánchez, Paula, González, Santi, Timshel, Pascal, Pers, Tune H, Morgan, Claire C, Moran, Ignasi, Atla, Goutham, González, Juan R, Puiggros, Montserrat, Martí, Jonathan, Andersson, Ehm A, Díaz, Carlos, Badia, Rosa M, Udler, Miriam, Leong, Aaron, Kaur, Varindepal, Flannick, Jason, Jørgensen, Torben, Linneberg, Allan, Jørgensen, Marit E, Witte, Daniel R, Christensen, Cramer, Brandslund, Ivan, Appel, Emil V, Scott, Robert A, Luan, Jian'an, Langenberg, Claudia, Wareham, Nicholas J, Pedersen, Oluf, Zorzano, Antonio, Florez, Jose C, Hansen, Torben, Ferrer, Jorge, Mercader, Josep Maria, and Torrents, David
Subjects: Male, Chromosomes, Human, X, Genotype, Models, Genetic, Risk Factors, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Insulin Resistance, Polymorphism, Single Nucleotide, Alleles, 3. Good health, Genome-Wide Association Study
Abstract: The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.

32. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Turcot, Valérie, Lu, Yingchang, Highland, Heather M, Schurmann, Claudia, Justice, Anne E, Fine, Rebecca S, Bradfield, Jonathan P, Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E, Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E, Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L, Alfred, Tamuno, Feitosa, Mary F, Masca, Nicholas GD, Manning, Alisa K, Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie CY, Reiner, Alex P, Vedantam, Sailaja, Willems, Sara M, Winkler, Thomas W, Abecasis, Gonçalo, Aben, Katja K, Alam, Dewan S, Alharthi, Sameer E, Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Bang, Lia E, Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Brumat, Marco, Burt, Amber A, Butterworth, Adam S, Campbell, Peter T, Cappellani, Stefania, Carey, David J, Catamo, Eulalia, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der I, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J, Crosslin, David S, Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul IW, Groot, Mark CH, Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, Heijer, Martin, Hollander, Anneke I, Ruijter, Hester M, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Edwards, Todd L, Ellinghaus, David, Ellinor, Patrick T, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Farooqi, I Sadaf, Faul, Jessica D, Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Ford, Ian, Fornage, Myriam, Franco, Oscar H, Franke, Andre, Franks, Paul W, Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmantas, Gjesing, Anette P, Gordon-Larsen, Penny, Gorski, Mathias, Grabe, Hans-Jörgen, Grant, Struan FA, Grarup, Niels, Griffiths, Helen L, Grove, Megan L, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B, Hattersley, Andrew T, Have, Christian T, Hayward, Caroline, He, Liang, Heard-Costa, Nancy L, Heath, Andrew C, Heid, Iris M, Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Huang, Paul L, Huffman, Jennifer E, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jansson, Jan-Håkan, Jarvik, Gail P, Jensen, Gorm B, Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E, Jørgensen, Torben, Jukema, J Wouter, Kahali, Bratati, Kahn, René S, Kähönen, Mika, Kamstrup, Pia R, Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A, Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kooperberg, Charles, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Ethan M, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Liu, Yongmei, Lo, Ken S, Lophatananon, Artitaya, Lotery, Andrew J, Loukola, Anu, Luan, Jian'an, Lubitz, Steven A, Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L, McCarthy, Mark I, McKean-Cowdin, Roberta, Medland, Sarah E, Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L, Moilanen, Leena, Moitry, Marie, Montgomery, Grant W, Mook-Kanamori, Dennis O, Moore, Carmel, Mori, Trevor A, Morris, Andrew D, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Nalls, Mike A, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Nielsen, Sune F, Nikus, Kjell, Njølstad, Pål R, Nordestgaard, Børge G, Nyholt, Dale R, O'Connel, Jeffrey R, O'Donoghue, Michelle L, Olde Loohuis, Loes M, Ophoff, Roel A, Owen, Katharine R, Packard, Chris J, Padmanabhan, Sandosh, Palmer, Colin NA, Palmer, Nicholette D, Pasterkamp, Gerard, Patel, Aniruddh P, Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Person, Thomas N, Peters, Annette, Petersen, Eva RB, Peyser, Patricia A, Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J, Puolijoki, Hannu, Raitakari, Olli T, Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F, Renström, Frida, Rheinberger, Myriam, Ridker, Paul M, Rioux, John D, Rivas, Manuel A, Roberts, David J, Robertson, Neil R, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo P, Shah, Svati H, Sheu, Wayne H-H, Sim, Xueling, Slater, Andrew J, Small, Kerrin S, Smith, Albert V, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Starr, John M, Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E, Strauch, Konstantin, Stringham, Heather M, Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J, Tada, Hayato, Tansey, Katherine E, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P, Uher, Rudolf, Uitterlinden, André G, Uusitupa, Matti, Laan, Sander W, Duijn, Cornelia M, Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V, Varma, Rohit, Velez Edwards, Digna R, Vermeulen, Sita H, Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E, Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wang, Yiqin, Ware, Erin B, Wareham, Nicholas J, Warren, Helen R, Waterworth, Dawn M, Wessel, Jennifer, White, Harvey D, Willer, Cristen J, Wilson, James G, Witte, Daniel R, Wood, Andrew R, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Rotter, Jerome I, Pospisilik, John A, Rivadeneira, Fernando, Borecki, Ingrid B, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, North, Kari E, Lindgren, Cecilia M, Hirschhorn, Joel N, and Loos, Ruth JF
Subjects: 2. Zero hunger, Adult, Male, Genetic Variation, Proteins, Syndrome, Body Mass Index, Gene Frequency, Animals, Humans, Drosophila, Female, Obesity, Energy Intake, Energy Metabolism
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

33. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes

Author: Lorenzo Piemonti, Goutham Atla, Torben Hansen, Claire Morgan, Inês Cebola, Jorge Ferrer, Inga Prokopenko, Irene Farabella, Irene Miguel-Escalada, Marc A. Marti-Renom, Lorenzo Pasquali, Emil V. R. Appel, Niels Grarup, Javier García-Hurtado, Leif Groop, Josep M. Mercader, Eelco J.P. de Koning, Mireia Ramos-Rodríguez, Anette P. Gjesing, Delphine M.Y. Rolando, Allan Linneberg, Sílvia Bonàs-Guarch, François Pattou, Philippe Ravassard, Daniel R. Witte, Biola M. Javierre, Julie Kerr-Conte, Joan Ponsa-Cobas, David Torrents, Anthony Beucher, Peter Fraser, Thierry Berney, Iryna O. Fedko, Ole Birger Pedersen, Julen Mendieta-Esteban, Ignasi Moran, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Research Centre For Prevention and Health, Department 84/85, Copenhagen University Hospital Glostrup, Steno Diabetes Center, University of Copenhagen = Københavns Universitet (KU), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Steno Diabetes Center and Hagedorn Research Institute, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), IRCCS Ospedale San Raffaele [Milan, Italy], Centre médical universitaire de Genève (CMU), Therapie Cellulaire du Diabete, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Clinical Sciences, Diabetes and Endocrinology Unit, Lund University [Lund], Gene Regulation, Stem Cells and Cancer Program, CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain, The Babraham Institute, The Babraham Institute, Cambridge, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), Miguel-Escalada, Irene, Bonàs-Guarch, Silvia, Cebola, Inê, Ponsa-Cobas, Joan, Mendieta-Esteban, Julen, Atla, Goutham, Javierre, Biola M, Rolando, Delphine M Y, Farabella, Irene, Morgan, Claire C, García-Hurtado, Javier, Beucher, Anthony, Morán, Ignasi, Pasquali, Lorenzo, Ramos-Rodríguez, Mireia, Appel, Emil V R, Linneberg, Allan, Gjesing, Anette P, Witte, Daniel R, Pedersen, Oluf, Grarup, Niel, Ravassard, Philippe, Torrents, David, Mercader, Josep M, Piemonti, Lorenzo, Berney, Thierry, de Koning, Eelco J P, Kerr-Conte, Julie, Pattou, Françoi, Fedko, Iryna O, Groop, Leif, Prokopenko, Inga, Hansen, Torben, Marti-Renom, Marc A, Fraser, Peter, Ferrer, Jorge, and Hubrecht Institute for Developmental Biology and Stem Cell Research
Subjects: Epigenomics, endocrine system diseases, Metabolic disorders, Gene regulatory network, Molecular Conformation, Genome-wide association study, VARIANTS, Genome-wide association studies, Genome, Cohort Studies, 0302 clinical medicine, Genetics research, Insulin Secretion, Gene Regulatory Networks, TRANSCRIPTION, Promoter Regions, Genetic, 11 Medical and Health Sciences, ComputingMilieux_MISCELLANEOUS, Genetics, Genetics & Heredity, RISK, 0303 health sciences, geography.geographical_feature_category, ddc:617, CELL IDENTITY, Islet, Chromatin, READ ALIGNMENT, medicine.anatomical_structure, Enhancer Elements, Genetic, Life Sciences & Biomedicine, EXPRESSION, endocrine system, Biology, MECHANISMS, 03 medical and health sciences, Islets of Langerhans, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Enhancer, Gene, 030304 developmental biology, geography, Science & Technology, Pancreatic islets, 06 Biological Sciences, SUPER-ENHANCERS, TCF7L2, Diabetes Mellitus, Type 2, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract: Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals. This research was supported by the National Institute for Health Research Imperial Biomedical Research Centre. Work was funded by grants from the Wellcome Trust (nos. WT101033 to J.F. and WT205915 to I.P.), Horizon 2020 (Research and Innovation Programme nos. 667191, to J.F., 633595, to I.P., and 676556, to M.A.M.-R.; Marie Sklodowska-Curie 658145, to I.M.-E., and 43062 ZENCODE, to G.A.), European Research Council (nos. 789055, to J.F., and 609989, to M.A.M.-R.). Marató TV3 (no. 201611, to J.F. and M.A.M.-R.), Ministerio de Ciencia Innovación y Universidades (nos. BFU2014-54284-R, RTI2018-095666, to J.F., BFU2017-85926-P, to M.A.M.-R., IJCI-2015-23352, to I.F.), AGAUR (to M.A.M.-R.). UK Medical Research Council (no. MR/L007150/1, to P.F., MR/L02036X/1 to J.F.), World Cancer Research Fund (WCRF UK, to I.P.) and World Cancer Research Fund International (no. 2017/1641 to I.P.), Biobanking and Biomolecular Resources Research Infrastructure (nos. BBMRI-NL, NWO 184.021.007, to I.O.F.). Work in IDIBAPS, CRG and CNAG was supported by the CERCA Programme, Generalitat de Catalunya and Centros de Excelencia Severo Ochoa (no. SEV-2012-0208). Human islets were provided through the European islet distribution program for basic research supported by JDRF (no. 3-RSC-2016-160-I-X). We thank N. Ruiz-Gomez for technical assistance; R. L. Fernandes, T. Thorne (University of Reading) and A. Perdones-Montero (Imperial College London) for helpful discussions regarding Machine Learning approaches; B. Lenhard and M. Merkenschlager (London Institute of Medical Sciences, Imperial College London), F. Müller (University of Birmingham) and J. L. Gómez-Skarmeta (Centro Andaluz de Biología del Desarrollo) for critical comments on the draft; the CRG Genomics Unit; and the Imperial College High Performance Computing Service.
Published: 2019

34. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center
Subjects: 0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Published: 2018

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34 results on '"Witte, Daniel R."'

1. Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications

2. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

3. Health-related quality of life for normal glycaemia, prediabetes and type 2 diabetes mellitus: Cross-sectional analysis of the ADDITION-PRO study

4. Additional file 1 of Long-term effects of intensive multifactorial treatment on aortic stiffness and central hemodynamics after 13 years with screen-detected type 2 diabetes: the ADDITION-Denmark trial

5. Erratum:Role of fasting duration and weekday in incretin and glucose regulation

6. Additional file 2 of Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test

7. Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes

8. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls

9. Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

10. A data-driven approach at characterizing heterogeneity in neuropathy assessments

11. Habitual activity associates with lower fasting and greater glucose-induced GLP-1 response in men

12. Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

13. Rare and low-frequency coding variants alter human adult height

14. A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

15. Correction to:Soluble CD163, adiponectin, C-reactive protein and progression of dysglycaemia in individuals at high risk of type 2 diabetes mellitus: the ADDITION-PRO cohort (Diabetologia, 10.1007/s00125-016-4075-4)

16. New blood pressure–associated loci identified in meta-analyses of 475 000 individuals

17. Effect of secular trends on age-related trajectories of cardiovascular risk factors: the Whitehall II longitudinal study 1985–2009

18. is involved in the development of nonalcoholic fatty liver disease

19. Motivational counseling to reduce sitting time: A community-based randomized controlled trial in adults

20. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

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

22. PREVALENCE OF CARDIAL AUTONOMIC NEUROPATHY IN A POPULATION WITH SCREEN DETECTED DIABETES – ADDITION DENMARK

23. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm

24. The role of physical activity in the development of first cardiovascular disease event: a tree-structured survival analysis of the Danish ADDITION-PRO cohort

25. A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes

26. Habitual physical activity is associated with lower fasting and greater glucose-induced GLP-1 response in men

27. Hyperglycaemia, type 2 diabetes, and depressive symptoms

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

29. The role of physical activity in the development of first cardiovascular disease event: a tree-structured survival analysis of the Danish ADDITION-PRO cohort

30. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

31. Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

32. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

33. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes

34. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

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34 results on '"Witte, Daniel R."'

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