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1. Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity

Author

Yaghootkar, Hanieh, Zhang, Yiying, Spracklen, Cassandra N, Karaderi, Tugce, Huang, Lam Opal, Bradfield, Jonathan, Schurmann, Claudia, Fine, Rebecca S, Preuss, Michael H, Kutalik, Zoltan, Wittemans, Laura BL, Lu, Yingchang, Metz, Sophia, Willems, Sara M, Li-Gao, Ruifang, Grarup, Niels, Wang, Shuai, Molnos, Sophie, Sandoval-Zárate, América A, Nalls, Mike A, Lange, Leslie A, Haesser, Jeffrey, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Feitosa, Mary F, Sitlani, Colleen M, Venturini, Cristina, Mahajan, Anubha, Kacprowski, Tim, Wang, Carol A, Chasman, Daniel I, Amin, Najaf, Broer, Linda, Robertson, Neil, Young, Kristin L, Allison, Matthew, Auer, Paul L, Blüher, Matthias, Borja, Judith B, Bork-Jensen, Jette, Carrasquilla, Germán D, Christofidou, Paraskevi, Demirkan, Ayse, Doege, Claudia A, Garcia, Melissa E, Graff, Mariaelisa, Guo, Kaiying, Hakonarson, Hakon, Hong, Jaeyoung, Ida Chen, Yii-Der, Jackson, Rebecca, Jakupović, Hermina, Jousilahti, Pekka, Justice, Anne E, Kähönen, Mika, Kizer, Jorge R, Kriebel, Jennifer, LeDuc, Charles A, Li, Jin, Lind, Lars, Luan, Jian'an, Mackey, David A, Mangino, Massimo, Männistö, Satu, Martin Carli, Jayne F, Medina-Gomez, Carolina, Mook-Kanamori, Dennis O, Morris, Andrew P, de Mutsert, Renée, Nauck, Matthias, Prokic, Ivana, Pennell, Craig E, Pradhan, Arund D, Psaty, Bruce M, Raitakari, Olli T, Scott, Robert A, Skaaby, Tea, Strauch, Konstantin, Taylor, Kent D, Teumer, Alexander, Uitterlinden, Andre G, Wu, Ying, Yao, Jie, Walker, Mark, North, Kari E, Kovacs, Peter, Ikram, M Arfan, van Duijn, Cornelia M, Ridker, Paul M, Lye, Stephen, Homuth, Georg, Ingelsson, Erik, Spector, Tim D, McKnight, Barbara, Province, Michael A, Lehtimäki, Terho, Adair, Linda S, Rotter, Jerome I, Reiner, Alexander P, and Wilson, James G

Subjects
Genetics, Nutrition, Prevention, Obesity, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Metabolic and endocrine, Cardiovascular, Stroke, Cancer, Adiposity, Gene Expression Regulation, Developmental, Genetic Variation, Genotype, Humans, Leptin, Models, Molecular, Protein Conformation, Racial Groups, Medical and Health Sciences, Endocrinology & Metabolism
Abstract

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

Published
2020

2. Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

Author

Pollack, Samuela, Igo, Robert P, Jensen, Richard A, Christiansen, Mark, Li, Xiaohui, Cheng, Ching-Yu, Ng, Maggie CY, Smith, Albert V, Rossin, Elizabeth J, Segrè, Ayellet V, Davoudi, Samaneh, Tan, Gavin S, Chen, Yii-Der Ida, Kuo, Jane Z, Dimitrov, Latchezar M, Stanwyck, Lynn K, Meng, Weihua, Hosseini, S Mohsen, Imamura, Minako, Nousome, Darryl, Kim, Jihye, Hai, Yang, Jia, Yucheng, Ahn, Jeeyun, Leong, Aaron, Shah, Kaanan, Park, Kyu Hyung, Guo, Xiuqing, Ipp, Eli, Taylor, Kent D, Adler, Sharon G, Sedor, John R, Freedman, Barry I, Group, DCCT EDIC Research Group Family Investigation of Nephropathy and Diabetes-Eye Research, Lee, I-Te, Sheu, Wayne H-H, Kubo, Michiaki, Takahashi, Atsushi, Hadjadj, Samy, Marre, Michel, Tregouet, David-Alexandre, Mckean-Cowdin, Roberta, Varma, Rohit, McCarthy, Mark I, Groop, Leif, Ahlqvist, Emma, Lyssenko, Valeriya, Agardh, Elisabet, Morris, Andrew, Doney, Alex SF, Colhoun, Helen M, Toppila, Iiro, Sandholm, Niina, Groop, Per-Henrik, Maeda, Shiro, Hanis, Craig L, Penman, Alan, Chen, Ching J, Hancock, Heather, Mitchell, Paul, Craig, Jamie E, Chew, Emily Y, Paterson, Andrew D, Grassi, Michael A, Palmer, Colin, Bowden, Donald W, Yaspan, Brian L, Siscovick, David, Cotch, Mary Frances, Wang, Jie Jin, Burdon, Kathryn P, Wong, Tien Y, Klein, Barbara EK, Klein, Ronald, Rotter, Jerome I, Iyengar, Sudha K, Price, Alkes, and Sobrin, Lucia

Subjects
Biomedical and Clinical Sciences, Genetics, Eye Disease and Disorders of Vision, Diabetes, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Good Health and Well Being, Blood Glucose, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycated Hemoglobin, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Protein Binding, Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value

Published
2019

3. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author

Walford, Geoffrey A, Gustafsson, Stefan, Rybin, Denis, Stančáková, Alena, Chen, Han, Liu, Ching-Ti, Hong, Jaeyoung, Jensen, Richard A, Rice, Ken, Morris, Andrew P, Mägi, Reedik, Tönjes, Anke, Prokopenko, Inga, Kleber, Marcus E, Delgado, Graciela, Silbernagel, Günther, Jackson, Anne U, Appel, Emil V, Grarup, Niels, Lewis, Joshua P, Montasser, May E, Landenvall, Claes, Staiger, Harald, Luan, Jian’an, Frayling, Timothy M, Weedon, Michael N, Xie, Weijia, Morcillo, Sonsoles, Martínez-Larrad, María Teresa, Biggs, Mary L, Chen, Yii-Der Ida, Corbaton-Anchuelo, Arturo, Færch, Kristine, Gómez-Zumaquero, Juan Miguel, Goodarzi, Mark O, Kizer, Jorge R, Koistinen, Heikki A, Leong, Aaron, Lind, Lars, Lindgren, Cecilia, Machicao, Fausto, Manning, Alisa K, Martín-Núñez, Gracia María, Rojo-Martínez, Gemma, Rotter, Jerome I, Siscovick, David S, Zmuda, Joseph M, Zhang, Zhongyang, Serrano-Rios, Manuel, Smith, Ulf, Soriguer, Federico, Hansen, Torben, Jørgensen, Torben J, Linnenberg, Allan, Pedersen, Oluf, Walker, Mark, Langenberg, Claudia, Scott, Robert A, Wareham, Nicholas J, Fritsche, Andreas, Häring, Hans-Ulrich, Stefan, Norbert, Groop, Leif, O’Connell, Jeff R, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, März, Winfried, Kovacs, Peter, Stumvoll, Michael, Psaty, Bruce M, Kuusisto, Johanna, Laakso, Markku, Meigs, James B, Dupuis, Josée, Ingelsson, Erik, and Florez, Jose C

Subjects
Biomedical and Clinical Sciences, Genetics, Prevention, Human Genome, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Chemokines, CC, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Male, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-bcl-2, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Published
2016

4. Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India

Author

Saxena, Richa, Saleheen, Danish, Been, Latonya F., Garavito, Martha L., Braun, Timothy, Bjonnes, Andrew, Young, Robin, Ho, Weang Kee, Rasheed, Asif, Frossard, Philippe, Sim, Xueling, Hassanali, Neelam, Radha, Venkatesan, Chidambaram, Manickam, Liju, Samuel, Rees, Simon D., Ng, Daniel Peng-Keat, Wong, Tien-Yin, Yamauchi, Toshimasa, Hara, Kazuo, Tanaka, Yasushi, Hirose, Hiroshi, McCarthy, Mark I., Morris, Andrew P., Basit, Abdul, Barnett, Anthony H., Katulanda, Prasad, Matthews, David, Mohan, Viswanathan, Wander, Gurpreet S., Singh, Jai Rup, Mehra, Narinder K., Ralhan, Sarju, Kamboh, M. Ilyas, Mulvihill, John J., Maegawa, Hiroshi, Tobe, Kazuyuki, Maeda, Shiro, Cho, Yoon S., Tai, E. Shyong, Kelly, M. Ann, Chambers, John C., Kooner, Jaspal S., Kadowaki, Takashi, Deloukas, Panos, Rader, Daniel J., Danesh, John, and Sanghera, Dharambir K.

Published
2013
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6. Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes m imploring stares in human islets

Author

Travers, Mary E., Mackay, Deborah J.G., Nitert, Marloes Dekker, Morris, Andrew P., Lindgren, Cecilia M., Berry, Andrew, Johnson, Paul R., Hanley, Neil, Groop, Left C., McCarthy, Mark I., and Gloyn, Anna L.

Subjects
Type 2 diabetes -- Research -- Analysis -- Genetic aspects, Health
Abstract

The molecular basis of type 2 diabetes predisposition at most established susceptibility loci remains poorly understood. KCNQ1 maps within the 11p15.5 imprinted domain, a region with an established role in congenital growth phenotypes. Variants intronic to KCNQ1 influence diabetes susceptibility when maternally inherited. By use of quantitative PCR and pyrosequencing of human adult islet and fetal pancreas samples, we investigated the imprinting status of regional transcripts and aimed to determine whether type 2 diabetes risk alleles influence regional DNA methylation and gene expression. The results demonstrate that gene expression patterns differ by developmental stage. CDKNIC showed monoallelic expression in both adult and fetal tissue, whereas PHLDA2, SLC22A18, and SLC22A18AS were biallelically expressed in both tissues. Temporal changes in imprinting were observed for KCNQ1 and KCNQIOT1, with monoallelic expression in fetal tissues and biallelic expression in adult samples. Genotype at the type 2 diabetes risk variant rs2237895 influenced methylation levels of regulatory sequence in fetal pancreas but without demonstrable effects on gene expression. We demonstrate that CDKN1C, KCNQ1, andKCNQIOT1 are most likely to mediate diabetes susceptibility at the KCNQ1 locus and identify temporal differences in imprinting status and methylation effects, suggesting that diabetes risk effects may be mediated in early development., The translation of established type 2 diabetes risk variants into an improved understanding of disease pathology is challenging. Progress has been made primarily at the few loci where causal alleles [...]

Published
2013
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7. Low-Frequency Variants in HMGA1 Are Not Associated With Type 2 Diabetes Risk

Author

Marquez, Marcel, Huyvaert, Marlène, Perry, John R.B., Pearson, Richard D., Falchi, Mario, Morris, Andrew P., Vivequin, Sidonie, Lobbens, Stéphane, Yengo, Loïc, Gaget, Stefan, Pattou, Francois, Poulain-Godefroy, Odile, Charpentier, Guillaume, Carlsson, Lena M.S., Jacobson, Peter, Sjöström, Lars, Lantieri, Olivier, Heude, Barbara, Walley, Andrew, Balkau, Beverley, Marre, Michel, Froguel, Philippe, and Cauchi, Stéphane

Published
2012
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9. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author

Scott, Robert A., primary, Scott, Laura J., additional, Mägi, Reedik, additional, Marullo, Letizia, additional, Gaulton, Kyle J., additional, Kaakinen, Marika, additional, Pervjakova, Natalia, additional, Pers, Tune H., additional, Johnson, Andrew D., additional, Eicher, John D., additional, Jackson, Anne U., additional, Ferreira, Teresa, additional, Lee, Yeji, additional, Ma, Clement, additional, Steinthorsdottir, Valgerdur, additional, Thorleifsson, Gudmar, additional, Qi, Lu, additional, Van Zuydam, Natalie R., additional, Mahajan, Anubha, additional, Chen, Han, additional, Almgren, Peter, additional, Voight, Ben F., additional, Grallert, Harald, additional, Müller-Nurasyid, Martina, additional, Ried, Janina S., additional, Rayner, Nigel W., additional, Robertson, Neil, additional, Karssen, Lennart C., additional, van Leeuwen, Elisabeth M., additional, Willems, Sara M., additional, Fuchsberger, Christian, additional, Kwan, Phoenix, additional, Teslovich, Tanya M., additional, Chanda, Pritam, additional, Li, Man, additional, Lu, Yingchang, additional, Dina, Christian, additional, Thuillier, Dorothee, additional, Yengo, Loic, additional, Jiang, Longda, additional, Sparso, Thomas, additional, Kestler, Hans A., additional, Chheda, Himanshu, additional, Eisele, Lewin, additional, Gustafsson, Stefan, additional, Frånberg, Mattias, additional, Strawbridge, Rona J., additional, Benediktsson, Rafn, additional, Hreidarsson, Astradur B., additional, Kong, Augustine, additional, Sigurðsson, Gunnar, additional, Kerrison, Nicola D., additional, Luan, Jian'an, additional, Liang, Liming, additional, Meitinger, Thomas, additional, Roden, Michael, additional, Thorand, Barbara, additional, Esko, Tõnu, additional, Mihailov, Evelin, additional, Fox, Caroline, additional, Liu, Ching-Ti, additional, Rybin, Denis, additional, Isomaa, Bo, additional, Lyssenko, Valeriya, additional, Tuomi, Tiinamaija, additional, Couper, David J., additional, Pankow, James S., additional, Grarup, Niels, additional, Have, Christian T., additional, Jørgensen, Marit E., additional, Jørgensen, Torben, additional, Linneberg, Allan, additional, Cornelis, Marilyn C., additional, van Dam, Rob M., additional, Hunter, David J., additional, Kraft, Peter, additional, Sun, Qi, additional, Edkins, Sarah, additional, Owen, Katharine R., additional, Perry, John R.B., additional, Wood, Andrew R., additional, Zeggini, Eleftheria, additional, Tajes-Fernandes, Juan, additional, Abecasis, Goncalo R., additional, Bonnycastle, Lori L., additional, Chines, Peter S., additional, Stringham, Heather M., additional, Koistinen, Heikki A., additional, Kinnunen, Leena, additional, Sennblad, Bengt, additional, Mühleisen, Thomas W., additional, Nöthen, Markus M., additional, Pechlivanis, Sonali, additional, Baldassarre, Damiano, additional, Gertow, Karl, additional, Humphries, Steve E., additional, Tremoli, Elena, additional, Klopp, Norman, additional, Meyer, Julia, additional, Steinbach, Gerald, additional, Wennauer, Roman, additional, Eriksson, Johan G., additional, Mӓnnistö, Satu, additional, Peltonen, Leena, additional, Tikkanen, Emmi, additional, Charpentier, Guillaume, additional, Eury, Elodie, additional, Lobbens, Stéphane, additional, Gigante, Bruna, additional, Leander, Karin, additional, McLeod, Olga, additional, Bottinger, Erwin P., additional, Gottesman, Omri, additional, Ruderfer, Douglas, additional, Blüher, Matthias, additional, Kovacs, Peter, additional, Tonjes, Anke, additional, Maruthur, Nisa M., additional, Scapoli, Chiara, additional, Erbel, Raimund, additional, Jöckel, Karl-Heinz, additional, Moebus, Susanne, additional, de Faire, Ulf, additional, Hamsten, Anders, additional, Stumvoll, Michael, additional, Deloukas, Panagiotis, additional, Donnelly, Peter J., additional, Frayling, Timothy M., additional, Hattersley, Andrew T., additional, Ripatti, Samuli, additional, Salomaa, Veikko, additional, Pedersen, Nancy L., additional, Boehm, Bernhard O., additional, Bergman, Richard N., additional, Collins, Francis S., additional, Mohlke, Karen L., additional, Tuomilehto, Jaakko, additional, Hansen, Torben, additional, Pedersen, Oluf, additional, Barroso, Inês, additional, Lannfelt, Lars, additional, Ingelsson, Erik, additional, Lind, Lars, additional, Lindgren, Cecilia M., additional, Cauchi, Stephane, additional, Froguel, Philippe, additional, Loos, Ruth J.F., additional, Balkau, Beverley, additional, Boeing, Heiner, additional, Franks, Paul W., additional, Barricarte Gurrea, Aurelio, additional, Palli, Domenico, additional, van der Schouw, Yvonne T., additional, Altshuler, David, additional, Groop, Leif C., additional, Langenberg, Claudia, additional, Wareham, Nicholas J., additional, Sijbrands, Eric, additional, van Duijn, Cornelia M., additional, Florez, Jose C., additional, Meigs, James B., additional, Boerwinkle, Eric, additional, Gieger, Christian, additional, Strauch, Konstantin, additional, Metspalu, Andres, additional, Morris, Andrew D., additional, Palmer, Colin N.A., additional, Hu, Frank B., additional, Thorsteinsdottir, Unnur, additional, Stefansson, Kari, additional, Dupuis, Josée, additional, Morris, Andrew P., additional, Boehnke, Michael, additional, McCarthy, Mark I., additional, and Prokopenko, Inga, additional

Published
2017
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10. A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

Author

Manning, Alisa, primary, Highland, Heather M., additional, Gasser, Jessica, additional, Sim, Xueling, additional, Tukiainen, Taru, additional, Fontanillas, Pierre, additional, Grarup, Niels, additional, Rivas, Manuel A., additional, Mahajan, Anubha, additional, Locke, Adam E., additional, Cingolani, Pablo, additional, Pers, Tune H., additional, Viñuela, Ana, additional, Brown, Andrew A., additional, Wu, Ying, additional, Flannick, Jason, additional, Fuchsberger, Christian, additional, Gamazon, Eric R., additional, Gaulton, Kyle J., additional, Im, Hae Kyung, additional, Teslovich, Tanya M., additional, Blackwell, Thomas W., additional, Bork-Jensen, Jette, additional, Burtt, Noël P., additional, Chen, Yuhui, additional, Green, Todd, additional, Hartl, Christopher, additional, Kang, Hyun Min, additional, Kumar, Ashish, additional, Ladenvall, Claes, additional, Ma, Clement, additional, Moutsianas, Loukas, additional, Pearson, Richard D., additional, Perry, John R.B., additional, Rayner, N. William, additional, Robertson, Neil R., additional, Scott, Laura J., additional, van de Bunt, Martijn, additional, Eriksson, Johan G., additional, Jula, Antti, additional, Koskinen, Seppo, additional, Lehtimäki, Terho, additional, Palotie, Aarno, additional, Raitakari, Olli T., additional, Jacobs, Suzanne B.R., additional, Wessel, Jennifer, additional, Chu, Audrey Y., additional, Scott, Robert A., additional, Goodarzi, Mark O., additional, Blancher, Christine, additional, Buck, Gemma, additional, Buck, David, additional, Chines, Peter S., additional, Gabriel, Stacey, additional, Gjesing, Anette P., additional, Groves, Christopher J., additional, Hollensted, Mette, additional, Huyghe, Jeroen R., additional, Jackson, Anne U., additional, Jun, Goo, additional, Justesen, Johanne Marie, additional, Mangino, Massimo, additional, Murphy, Jacquelyn, additional, Neville, Matt, additional, Onofrio, Robert, additional, Small, Kerrin S., additional, Stringham, Heather M., additional, Trakalo, Joseph, additional, Banks, Eric, additional, Carey, Jason, additional, Carneiro, Mauricio O., additional, DePristo, Mark, additional, Farjoun, Yossi, additional, Fennell, Timothy, additional, Goldstein, Jacqueline I., additional, Grant, George, additional, Hrabé de Angelis, Martin, additional, Maguire, Jared, additional, Neale, Benjamin M., additional, Poplin, Ryan, additional, Purcell, Shaun, additional, Schwarzmayr, Thomas, additional, Shakir, Khalid, additional, Smith, Joshua D., additional, Strom, Tim M., additional, Wieland, Thomas, additional, Lindstrom, Jaana, additional, Brandslund, Ivan, additional, Christensen, Cramer, additional, Surdulescu, Gabriela L., additional, Lakka, Timo A., additional, Doney, Alex S.F., additional, Nilsson, Peter, additional, Wareham, Nicholas J., additional, Langenberg, Claudia, additional, Varga, Tibor V., additional, Franks, Paul W., additional, Rolandsson, Olov, additional, Rosengren, Anders H., additional, Farook, Vidya S., additional, Thameem, Farook, additional, Puppala, Sobha, additional, Kumar, Satish, additional, Lehman, Donna M., additional, Jenkinson, Christopher P., additional, Curran, Joanne E., additional, Hale, Daniel Esten, additional, Fowler, Sharon P., additional, Arya, Rector, additional, DeFronzo, Ralph A., additional, Abboud, Hanna E., additional, Syvänen, Ann-Christine, additional, Hicks, Pamela J., additional, Palmer, Nicholette D., additional, Ng, Maggie C.Y., additional, Bowden, Donald W., additional, Freedman, Barry I., additional, Esko, Tõnu, additional, Mägi, Reedik, additional, Milani, Lili, additional, Mihailov, Evelin, additional, Metspalu, Andres, additional, Narisu, Narisu, additional, Kinnunen, Leena, additional, Bonnycastle, Lori L., additional, Swift, Amy, additional, Pasko, Dorota, additional, Wood, Andrew R., additional, Fadista, João, additional, Pollin, Toni I., additional, Barzilai, Nir, additional, Atzmon, Gil, additional, Glaser, Benjamin, additional, Thorand, Barbara, additional, Strauch, Konstantin, additional, Peters, Annette, additional, Roden, Michael, additional, Müller-Nurasyid, Martina, additional, Liang, Liming, additional, Kriebel, Jennifer, additional, Illig, Thomas, additional, Grallert, Harald, additional, Gieger, Christian, additional, Meisinger, Christa, additional, Lannfelt, Lars, additional, Musani, Solomon K., additional, Griswold, Michael, additional, Taylor, Herman A., additional, Wilson, Gregory, additional, Correa, Adolfo, additional, Oksa, Heikki, additional, Scott, William R., additional, Afzal, Uzma, additional, Tan, Sian-Tsung, additional, Loh, Marie, additional, Chambers, John C., additional, Sehmi, Jobanpreet, additional, Kooner, Jaspal Singh, additional, Lehne, Benjamin, additional, Cho, Yoon Shin, additional, Lee, Jong-Young, additional, Han, Bok-Ghee, additional, Käräjämäki, Annemari, additional, Qi, Qibin, additional, Qi, Lu, additional, Huang, Jinyan, additional, Hu, Frank B., additional, Melander, Olle, additional, Orho-Melander, Marju, additional, Below, Jennifer E., additional, Aguilar, David, additional, Wong, Tien Yin, additional, Liu, Jianjun, additional, Khor, Chiea-Chuen, additional, Chia, Kee Seng, additional, Lim, Wei Yen, additional, Cheng, Ching-Yu, additional, Chan, Edmund, additional, Tai, E Shyong, additional, Aung, Tin, additional, Linneberg, Allan, additional, Isomaa, Bo, additional, Meitinger, Thomas, additional, Tuomi, Tiinamaija, additional, Hakaste, Liisa, additional, Kravic, Jasmina, additional, Jørgensen, Marit E., additional, Lauritzen, Torsten, additional, Deloukas, Panos, additional, Stirrups, Kathleen E., additional, Owen, Katharine R., additional, Farmer, Andrew J., additional, Frayling, Timothy M., additional, O'Rahilly, Stephen P., additional, Walker, Mark, additional, Levy, Jonathan C., additional, Hodgkiss, Dylan, additional, Hattersley, Andrew T., additional, Kuulasmaa, Teemu, additional, Stančáková, Alena, additional, Barroso, Inês, additional, Bharadwaj, Dwaipayan, additional, Chan, Juliana, additional, Chandak, Giriraj R., additional, Daly, Mark J., additional, Donnelly, Peter J., additional, Ebrahim, Shah B., additional, Elliott, Paul, additional, Fingerlin, Tasha, additional, Froguel, Philippe, additional, Hu, Cheng, additional, Jia, Weiping, additional, Ma, Ronald C.W., additional, McVean, Gilean, additional, Park, Taesung, additional, Prabhakaran, Dorairaj, additional, Sandhu, Manjinder, additional, Scott, James, additional, Sladek, Rob, additional, Tandon, Nikhil, additional, Teo, Yik Ying, additional, Zeggini, Eleftheria, additional, Watanabe, Richard M., additional, Koistinen, Heikki A., additional, Kesaniemi, Y. Antero, additional, Uusitupa, Matti, additional, Spector, Timothy D., additional, Salomaa, Veikko, additional, Rauramaa, Rainer, additional, Palmer, Colin N.A., additional, Prokopenko, Inga, additional, Morris, Andrew D., additional, Bergman, Richard N., additional, Collins, Francis S., additional, Lind, Lars, additional, Ingelsson, Erik, additional, Tuomilehto, Jaakko, additional, Karpe, Fredrik, additional, Groop, Leif, additional, Jørgensen, Torben, additional, Hansen, Torben, additional, Pedersen, Oluf, additional, Kuusisto, Johanna, additional, Abecasis, Gonçalo, additional, Bell, Graeme I., additional, Blangero, John, additional, Cox, Nancy J., additional, Duggirala, Ravindranath, additional, Seielstad, Mark, additional, Wilson, James G., additional, Dupuis, Josee, additional, Ripatti, Samuli, additional, Hanis, Craig L., additional, Florez, Jose C., additional, Mohlke, Karen L., additional, Meigs, James B., additional, Laakso, Markku, additional, Morris, Andrew P., additional, Boehnke, Michael, additional, Altshuler, David, additional, McCarthy, Mark I., additional, Gloyn, Anna L., additional, and Lindgren, Cecilia M., additional

Published
2017
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11. Detailed Investigation of the Role of Common and Low-Frequency WFS1 Variants in Type 2 Diabetes Risk

Author

Fawcett, Katherine A., primary, Wheeler, Eleanor, additional, Morris, Andrew P., additional, Ricketts, Sally L., additional, Hallmans, Göran, additional, Rolandsson, Olov, additional, Daly, Allan, additional, Wasson, Jon, additional, Permutt, Alan, additional, Hattersley, Andrew T., additional, Glaser, Benjamin, additional, Franks, Paul W., additional, McCarthy, Mark I., additional, Wareham, Nicholas J., additional, Sandhu, Manjinder S., additional, and Barroso, Inês, additional

Published
2009
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12. Genome-Wide Association Analysis in UK Subjects Provides Evidence for a Novel Type 2 Diabetes Susceptibility Gene in the CDKAL1 Region of Chromosome 6.

Author

Zeggini, Eleftheria, Weedon, Michael N., Lindgren, Cecilia M., Lango, Hana, Timpson, Nicholas J., Rayner, Nigel W., Elliott, Kate, Groves, Christopher J., Perry, John, Hitman, Graham A., Walker, Mark, Barrett, Jeffrey C., Donnelly, Peter, Clayton, David G., Morris, Andrew P., Cardon, Lon R., Palmer, Colin N., Morris, Andrew, Frayling, Timothy M., and Hattersley, Andrew T.

Subjects
TYPE 2 diabetes, CHROMOSOMES, GENOMES, PROTEINS
Abstract

The capacity to undertake systematic surveys of common variation through genome-wide association analysis has the potential to deliver substantial insights into type 2 diabetes (T2D) pathogenesis. We recently completed genotyping of 1954 T2D cases (enriched for positive family history/early onset) and 2922 population-based controls (all UK origin) on the Affymetrix 500k chip as part of the Wellcome Trust Case-Control Consortium. The preliminary analyses reported here are based on ∼309,000 SNPs with exemplary quality control and minor allele frequency (MAF)>5% [estimated to provide ∼60% coverage of CEU HapMap (MAF>5%, pairwise, r²>0.8)]. Variants within TCF7L2 emerge as the strongest cluster of susceptibility variants (12 SNPs, best = rs7901695, p=9.9x 10[sup -13]), but we find an additional 5 signals achieving nominal genome-wide significance with additive model p<6x10[sup -6] (controlling the false discovery rate at 0.05). These signals (located on chromosomes 1, 2, 6, 12 and 16) include a cluster of 5 SNPs with p< 10[sup -4] at ∼20.8Mbp on chr6, in a region including the CDK5 regulatory subunit associated protein 1-like 1 gene (CDKAL1) [for example, rs9465871, OR(95%CIs) for allele T (MAF∼80%) dominance: 0.51(0.37-0.70), exact p=1x10[sup -5]]. Extensive replication studies in 3073 T2D cases and 3879 controls (0.70(0.53-0.92), exact p=0.005) and meta-analysis across all ∼11800 subjects (0.61 (0.49-0.75), exact p=5.7x 10[sup -7]) provide supporting evidence for this finding. Haplotype-based analyses across a 2Mb region surrounding rs9465871 show no additional signal. Based on HapMap CEU data, rs9465871 is in perfect LD with several other intronic variants within CDKAL1; we have thus far covered ∼60% of common variation in the region (r²>0.8). Whilst further replication studies and fine-mapping will be required to refine the allelic architecture of this locus, these findings provide strong preliminary evidence that the CDKAL1 region harbours a novel locus affecting T2D risk. [ABSTRACT FROM AUTHOR]

Published
2007

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