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2. Increased hepatic PDGF-AA signaling mediates liver insulin resistance in obesity associated type 2 diabetes

Author

Abderrahmani, Amar, Yengo, Loic, Caiazzo, Robert, Canouil, Mickael, Cauchi, Stephane, Raverdy, Violeta, Plaisance, Valerie, Pawlowski, Valerie, Lobbens, Stephane, Maillet, Julie, Rolland, Laure, Boutry, Raphael, Queniat, Gurvan, Kwapich, Maxime, Tenenbaum, Mathie, Bricambert, Julien, Saussenthaler, Sophie, Anthony, Elodie, Jha, Pooja, Derop, Julien, Sand, Olivier, Rabearivelo, Iandry, Leloire, Audrey, Pigeyre, Marie, Daujat-Chavanieu, Martine, Gerbal-Chaloin, Sabine, Dayeh, Tasnim, Lassailly, Guillaume, Mathurin, Philippe, Staels, Bart, Auwerx, Johan, Schurmann, Annette, Postic, Catherine, Schafmayer, Clemens, Hampe, Jochen, Bonnefond, Amelie, Pattou, Francois, and Froguel, Philippe

Subjects
Quantitative Biology - Cell Behavior
Abstract

Type 2 diabetes (T2D) is closely linked with non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance, but the involved mechanisms are still elusive. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that both hypomethylation at a CpG site in PDGFA (encoding platelet derived growth factor alpha) and PDGFA overexpression are associated with increased T2D risk, hyperinsulinemia, increased insulin resistance and increased steatohepatitis risk. Both genetic risk score studies and human cell modeling pointed to a causative impact of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from liver. We found that PDGF-AA secretion further stimulates its own expression through protein kinase C activity and contributes to insulin resistance through decreased expression of both insulin receptor substrate 1 and of insulin receptor. Importantly, hepatocyte insulin sensitivity can be restored by PDGF-AA blocking antibodies, PDGF receptor inhibitors and by metformin opening therapeutic avenues. Conclusion: Therefore, in the liver of obese patients with T2D, the increased PDGF-AA signaling contributes to insulin resistance, opening new therapeutic avenues against T2D and NAFLD., Comment: 29 pages 7 figures 1 tables

Published
2017

4. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

Author

Schumann, Gunter, Liu, Chunyu, O'Reilly, Paul, Gao, He, Song, Parkyong, Xu, Bing, Ruggeri, Barbara, Amin, Najaf, Jia, Tianye, Preis, Sarah, Segura Lepe, Marcelo, Akira, Shizuo, Barbieri, Caterina, Baumeister, Sebastian, Cauchi, Stephane, Clarke, Toni-Kim, Enroth, Stefan, Fischer, Krista, Hällfors, Jenni, Harris, Sarah E, Hieber, Saskia, Hofer, Edith, Hottenga, Jouke-Jan, Johansson, Åsa, Joshi, Peter K, Kaartinen, Niina, Laitinen, Jaana, Lemaitre, Rozenn, Loukola, Anu, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Manichaikul, Ani, Mbarek, Hamdi, Milaneschi, Yuri, Moayyeri, Alireza, Mukamal, Kenneth, Nelson, Christopher, Nettleton, Jennifer, Partinen, Eemil, Rawal, Rajesh, Robino, Antonietta, Rose, Lynda, Sala, Cinzia, Satoh, Takashi, Schmidt, Reinhold, Schraut, Katharina, Scott, Robert, Smith, Albert Vernon, Starr, John M, Teumer, Alexander, Trompet, Stella, Uitterlinden, André G, Venturini, Cristina, Vergnaud, Anne-Claire, Verweij, Niek, Vitart, Veronique, Vuckovic, Dragana, Wedenoja, Juho, Yengo, Loic, Yu, Bing, Zhang, Weihua, Zhao, Jing Hua, Boomsma, Dorret I, Chambers, John, Chasman, Daniel I, Daniela, Toniolo, de Geus, Eco, Deary, Ian, Eriksson, Johan G, Esko, Tõnu, Eulenburg, Volker, Franco, Oscar H, Froguel, Philippe, Gieger, Christian, Grabe, Hans J, Gudnason, Vilmundur, Gyllensten, Ulf, Harris, Tamara B, Hartikainen, Anna-Liisa, Heath, Andrew C, Hocking, Lynne, Hofman, Albert, Huth, Cornelia, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Kaprio, Jaakko, Kooner, Jaspal S, Kutalik, Zoltan, Lahti, Jari, Langenberg, Claudia, Lehtimäki, Terho, Liu, Yongmei, Madden, Pamela AF, Martin, Nicholas, Morrison, Alanna, Penninx, Brenda, Pirastu, Nicola, Psaty, Bruce, and Raitakari, Olli

Subjects
Underage Drinking, Genetics, Alcoholism, Alcohol Use and Health, Neurosciences, Substance Misuse, Pediatric, Underpinning research, 1.1 Normal biological development and functioning, Stroke, Cardiovascular, Cancer, Oral and gastrointestinal, Good Health and Well Being, Alcohol Drinking, Animals, Behavior, Animal, Brain, Emotions, Female, Fibroblast Growth Factors, Genome-Wide Association Study, Humans, Klotho Proteins, Liver, Male, Membrane Proteins, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Polymorphism, Single Nucleotide, alcohol consumption, human, beta-Klotho, FGF21, mouse model, β-Klotho
Abstract

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10-12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

Published
2016

5. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author

Mahajan, Anubha, Go, Min Jin, Zhang, Weihua, Below, Jennifer E, Gaulton, Kyle J, Ferreira, Teresa, Horikoshi, Momoko, Johnson, Andrew D, Ng, Maggie CY, Prokopenko, Inga, Saleheen, Danish, Wang, Xu, Zeggini, Eleftheria, Abecasis, Goncalo R, Adair, Linda S, Almgren, Peter, Atalay, Mustafa, Aung, Tin, Baldassarre, Damiano, Balkau, Beverley, Bao, Yuqian, Barnett, Anthony H, Barroso, Ines, Basit, Abdul, Been, Latonya F, Beilby, John, Bell, Graeme I, Benediktsson, Rafn, Bergman, Richard N, Boehm, Bernhard O, Boerwinkle, Eric, Bonnycastle, Lori L, Burtt, Noël, Cai, Qiuyin, Campbell, Harry, Carey, Jason, Cauchi, Stephane, Caulfield, Mark, Chan, Juliana CN, Chang, Li-Ching, Chang, Tien-Jyun, Chang, Yi-Cheng, Charpentier, Guillaume, Chen, Chien-Hsiun, Chen, Han, Chen, Yuan-Tsong, Chia, Kee-Seng, Chidambaram, Manickam, Chines, Peter S, Cho, Nam H, Cho, Young Min, Chuang, Lee-Ming, Collins, Francis S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Danesh, John, Das, Debashish, de Faire, Ulf, Dedoussis, George, Deloukas, Panos, Dimas, Antigone S, Dina, Christian, Doney, Alex SF, Donnelly, Peter J, Dorkhan, Mozhgan, van Duijn, Cornelia, Dupuis, Josée, Edkins, Sarah, Elliott, Paul, Emilsson, Valur, Erbel, Raimund, Eriksson, Johan G, Escobedo, Jorge, Esko, Tonu, Eury, Elodie, Florez, Jose C, Fontanillas, Pierre, Forouhi, Nita G, Forsen, Tom, Fox, Caroline, Fraser, Ross M, Frayling, Timothy M, Froguel, Philippe, Frossard, Philippe, Gao, Yutang, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Grallert, Harald, Grant, George B, Groop, Leif C, Groves, Christopher J, Grundberg, Elin, Guiducci, Candace, Hamsten, Anders, Han, Bok-Ghee, Hara, Kazuo, and Hassanali, Neelam

Subjects
Biological Sciences, Genetics, Human Genome, Diabetes, Metabolic and endocrine, Alleles, Asian People, Case-Control Studies, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic or Latino, Humans, Polymorphism, Single Nucleotide, Risk Factors, White People, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Published
2014

6. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

Author

DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Mahajan, Anubha, Go, Min Jin, Zhang, Weihua, Below, Jennifer E, Gaulton, Kyle J, Ferreira, Teresa, Horikoshi, Momoko, Johnson, Andrew D, Ng, Maggie CY, Prokopenko, Inga, Saleheen, Danish, Wang, Xu, Zeggini, Eleftheria, Abecasis, Goncalo R, Adair, Linda S, Almgren, Peter, Atalay, Mustafa, Aung, Tin, Baldassarre, Damiano, Balkau, Beverley, Bao, Yuqian, Barnett, Anthony H, Barroso, Ines, Basit, Abdul, Been, Latonya F, Beilby, John, Bell, Graeme I, Benediktsson, Rafn, Bergman, Richard N, Boehm, Bernhard O, Boerwinkle, Eric, Bonnycastle, Lori L, Burtt, Noël, Cai, Qiuyin, Campbell, Harry, Carey, Jason, Cauchi, Stephane, Caulfield, Mark, Chan, Juliana CN, Chang, Li-Ching, Chang, Tien-Jyun, Chang, Yi-Cheng, Charpentier, Guillaume, Chen, Chien-Hsiun, Chen, Han, Chen, Yuan-Tsong, Chia, Kee-Seng, Chidambaram, Manickam, Chines, Peter S, Cho, Nam H, Cho, Young Min, Chuang, Lee-Ming, Collins, Francis S, Cornelis, Marylin C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Danesh, John, Das, Debashish, de Faire, Ulf, Dedoussis, George, Deloukas, Panos, Dimas, Antigone S, Dina, Christian, Doney, Alex S, Donnelly, Peter J, Dorkhan, Mozhgan, van Duijn, Cornelia, Dupuis, Josée, Edkins, Sarah, Elliott, Paul, Emilsson, Valur, Erbel, Raimund, Eriksson, Johan G, Escobedo, Jorge, Esko, Tonu, Eury, Elodie, Florez, Jose C, Fontanillas, Pierre, Forouhi, Nita G, Forsen, Tom, Fox, Caroline, Fraser, Ross M, Frayling, Timothy M, Froguel, Philippe, Frossard, Philippe, Gao, Yutang, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Grallert, Harald, Grant, George B, Grrop, Leif C, and Groves, Chrisropher J

Subjects
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Risk Factors, Case-Control Studies, Polymorphism, Single Nucleotide, Alleles, Asian Continental Ancestry Group, European Continental Ancestry Group, Hispanic Americans, Genome-Wide Association Study, Diabetes Mellitus, Type 2, Polymorphism, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Published
2014

7. Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study

Author

Chambers, John C, Loh, Marie, Lehne, Benjamin, Drong, Alexander, Kriebel, Jennifer, Motta, Valeria, Wahl, Simone, Elliott, Hannah R, Rota, Federica, Scott, William R, Zhang, Weihua, Tan, Sian-Tsung, Campanella, Gianluca, Chadeau-Hyam, Marc, Yengo, Loic, Richmond, Rebecca C, Adamowicz-Brice, Martyna, Afzal, Uzma, Bozaoglu, Kiymet, Mok, Zuan Yu, Ng, Hong Kiat, Pattou, François, Prokisch, Holger, Rozario, Michelle Ann, Tarantini, Letizia, Abbott, James, Ala-Korpela, Mika, Albetti, Benedetta, Ammerpohl, Ole, Bertazzi, Pier Alberto, Blancher, Christine, Caiazzo, Robert, Danesh, John, Gaunt, Tom R, de Lusignan, Simon, Gieger, Christian, Illig, Thomas, Jha, Sujeet, Jones, Simon, Jowett, Jeremy, Kangas, Antti J, Kasturiratne, Anuradhani, Kato, Norihiro, Kotea, Navaratnam, Kowlessur, Sudhir, Pitkäniemi, Janne, Punjabi, Prakash, Saleheen, Danish, Schafmayer, Clemens, Soininen, Pasi, Tai, E-Shyong, Thorand, Barbara, Tuomilehto, Jaakko, Wickremasinghe, Ananda Rajitha, Kyrtopoulos, Soterios A, Aitman, Timothy J, Herder, Christian, Hampe, Jochen, Cauchi, Stéphane, Relton, Caroline L, Froguel, Philippe, Soong, Richie, Vineis, Paolo, Jarvelin, Marjo-Riitta, Scott, James, Grallert, Harald, Bollati, Valentina, Elliott, Paul, McCarthy, Mark I, and Kooner, Jaspal S

Published
2015
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9. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Author

Schumann, Gunter, Coin, Lachlan J., Lourdusamy, Anbarasu, Charoen, Pimphen, Berger, Karen H., Stacey, David, Desrivières, Sylvane, Aliev, Fazil A., Khan, Anokhi A., Amin, Najaf, Aulchenko, Yurii S., Bakalkin, Georgy, Bakker, Stephan J., Balkau, Beverley, Beulens, Joline W., Bilbao, Ainhoa, de Boer, Rudolf A., Beury, Delphine, Bots, Michiel L., Breetvelt, Elemi J., Cauchi, Stéphane, Cavalcanti-Proença, Christine, Chambers, John C., Clarke, Toni-Kim, Dahmen, Norbert, de Geus, Eco J., Dick, Danielle, Ducci, Francesca, Easton, Alanna, Edenberg, Howard J., Esk, Tõnu, Fernández-Medarde, Alberto, Foroud, Tatiana, Freimer, Nelson B., Girault, Jean-Antoine, Grobbee, Diederick E., Guarrera, Simonetta, Gudbjartsson, Daniel F., Hartikainen, Anna-Liisa, Heath, Andrew C., Hesselbrock, Victor, Hofman, Albert, Hottenga, Jouke-Jan, Isohanni, Matti K., Kaprio, Jaakko, Khaw, Kay-Tee, Kuehnel, Brigitte, Laitinen, Jaana, Lobbens, Stéphane, Luan, Jian'an, Mangino, Massimo, Maroteaux, Matthieu, Matullo, Giuseppe, McCarthy, Mark I., Mueller, Christian, Navis, Gerjan, Numans, Mattijs E., Núñez, Alejandro, Nyholt, Dale R., Onland-Moret, Charlotte N., Oostra, Ben A., O'Reilly, Paul F., Palkovits, Miklos, Penninx, Brenda W., Polidoro, Silvia, Pouta, Anneli, Prokopenko, Inga, Ricceri, Fulvio, Santos, Eugenio, Smit, Johannes H., Soranzo, Nicole, Song, Kijoung, Sovio, Ulla, Stumvoll, Michael, Surakk, Ida, Thorgeirsson, Thorgeir E., Thorsteinsdottir, Unnur, Troakes, Claire, Tyrfingsson, Thorarinn, Tönjes, Anke, Uiterwaal, Cuno S., Uitterlinden, Andre G., van der Harst, Pim, van der Schouw, Yvonne T., Staehlin, Oliver, Vogelzangs, Nicole, Vollenweider, Peter, Waeber, Gerard, Wareham, Nicholas J., Waterworth, Dawn M., Whitfield, John B., Wichmann, Erich H., Willemsen, Gonneke, Witteman, Jacqueline C., Yuan, Xin, Zhai, Guangju, Zhao, Jing H., Zhang, Weihua, Martin, Nicholas G., Metspalu, Andres, Doering, Angela, Scott, James, Spector, Tim D., Loos, Ruth J., Boomsma, Dorret I., Mooser, Vincent, Peltonen, Leena, Stefansson, Kari, van Duijn, Cornelia M., Vineis, Paolo, Sommer, Wolfgang H., Kooner, Jaspal S., Spanagel, Rainer, Heberlein, Ulrike A., Jarvelin, Marjo-Riitta, Elliott, Paul, and Singer, Burton H.

Published
2011

21. Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk

Author

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

Subjects
Type 2 diabetes -- Research -- Risk factors -- Genetic aspects, Health
Abstract

It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14_136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14_136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease. Diabetes 61:524-530, 2012, Insulin resistance and pancreatic β-cell dysfunction are the two physiologic hallmarks of type 2 diabetes, and the expectation was that the majority of susceptibility loci identified in genome-wide association studies [...]

Published
2012
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22. Effects of genetic susceptibility for type 2 diabetes on the evolution of glucose homeostasis traits before and after diabetes diagnosis: data from the D.E.S.I.R. study

Author

Gautier, Alain, Roussel, Ronan, Lange, Celine, Piguel, Xavier, Cauchi, Stephane, Vol, Sylviane, Froguel, Philippe, Balkau, Beverley, and Bonnet, Fabrice

Subjects
Genetic susceptibility -- Research, Glucose metabolism -- Physiological aspects -- Genetic aspects -- Research, Type 2 diabetes -- Genetic aspects -- Diagnosis -- Risk factors -- Research, Health
Abstract

OBJECTIVE--To assess the impact of genetic susceptibility on evolution toward type 2 diabetes (T2D) by analyzing time trajectories of fasting glucose, glycated hemoglobin ([HbA.sub.1c]), insulin sensitivity (homeostasis model assessment [HOMA2%S]), and β-cell secretion (HOMA2%B) in a large nondiabetie cohort. We also examined whether baseline [HbA.sub.1c] modified the effect of genetic predisposition on the time trajectories. RESEARCH DESIGN AND METHODS--Time trajectories were drawn in 4,744 participants from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) cohort based on samples collected every 3 years over a 9-year follow-up. Trajectories were analyzed according to the TCFTL2 common variant, a family history of T2D, and a combination of at-risk alleles from nine T2D-associated genes. RESULTS--There was a marked decrease in HOMA2%B in parallel to a steep increase in [HbA.sub.1c] over the 3 years before incident diabetes, which was not influenced by genetic predisposition when considered alone. However, after the onset of T2D, the TCFTL2 at-risk variant was associated with a greater decrease in HOMA2%B. There was a joint effect of a family history of T2D with the presence of the TCF7L2 risk allele with a greater rise in [HbA.sub.1c] conferred by the coexistence of a family history and the T risk allele. An [HbA.sub.1c] ≥ 5.7% at baseline was associated with a greater increase in both glyeemia and [HbA.sub.1c] levels in the presence of a combination of diabetes at-risk alleles. CONCLUSIONS--After incident T2D, TCFTL2 at-risk variants were associated with a faster decrease in β-cell function compared with those with the CC genotype. There was a joint effect of family history of T2D and TCFTL2 risk variant on the rise in glycemia and the decrease in insulin secretion at the end of follow-up, suggesting the joint influence of the combination of diabetes genetic predisposition with familial factors on the evolution of glycemia over time. Diabetes 60:2654-2663, 2011, Impaired fasting glucose and type 2 diabetes (T2D) arise from a failure of the β-cell to adequately compensate for insulin resistance (1-6). Previous evidence suggests that the combination of moderately [...]

Published
2011
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23. Parental origin of sequence variants associated with complex diseases

Author

Kong, Augustine, Steinthorsdottir, Valgerdur, Masson, Gisli, Thorleifsson, Gudmar, Sulem, Patrick, Besenbacher, Soren, Jonasdottir, Aslaug, Sigurdsson, Asgeir, Th. Kristinsson, Kari, Jonasdottir, Adalbjorg, Frigge, Michael L., Gylfason, Arnaldur, Olason, Pall I., Gudjonsson, Sigurjon A., Sverrisson, Sverrir, Stacey, Simon N., Sigurgeirsson, Bardur, Benediktsdottir, Kristrun R., Sigurdsson, Helgi, Jonsson, Thorvaldur, Benediktsson, Rafn, Olafsson, Jon H., Th. Johannsson, Oskar, Hreidarsson, Astradur B., Sigurdsson, Gunnar, Voight, Benjamin F., Scott, Laura J., Dina, Christian, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S., Welch, Ryan P., McCulloch, Laura J., Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J., Raychaudhuri, Soumya, Purcell, Shaun, McCarroll, Steve A., Langenberg, Claudia, Hoffmann, Oliver M., Dupuis, Josée, Qi, Lu, Segrè, Ayellet V., van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Bennett, Amanda J., Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L., Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P., Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn, Couper, David J., Crawford, Gabe, Doney, Alex S. F., Elliott, Katherine S., Elliott, Amanda L., Erdos, Michael R., Fox, Caroline S., Franklin, Christopher S., Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J., Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U., Johnson, Paul R. V., Jørgensen, Torben, Kao, Wen H. L., Klopp, Norman, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Alouisius, Lindgren, Cecilia M., Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R., Payne, Felicity, Perry, John R. B., Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, William Rayner, N., Robertson, Neil R., Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J., Saxena, Richa, Shields, Beverley M., Shrader, Peter, Smith, Nicholas, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M., Sun, Qi, Swift, Amy J., Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, van Dam, Rob, van Herpt, Thijs, Walters, Bragi G., Weedon, Michael N., Witteman, Jacqueline, Bergman, Richard N., Cauchi, Stephane, Collins, Francis S., Gloyn, Anna L., Gyllensten, Ulf, Hansen, Torben, Hide, Winston A., Hitman, Graham A., Hofman, Albert, Hunter, David, Hveem, Kristian, Laakso, Markku, Mohlke, Karen L., Morris, Andrew D., Palmer, Colin N. A., Pramstaller, Peter P., Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D., Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J., Watanabe, Richard M., Abecasis, Goncalo R., Barroso, Inês, Boehm, Bernhard O., Campbell, Harry, Daly, Mark J., Florez, Jose C., Frayling, Timothy M., Groop, Leif, Hattersley, Andrew T., Hu, Frank B., Meigs, James B., Morris, Andrew P., Pankow, James S., Pedersen, Oluf, Sladek, Rob, Thorsteinsdottir, Unnur, Wichmann, H.-Erich, Wilson, James F., Illig, Thomas, Froguel, Philippe, van Duijn, Cornelia M., Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I., Ferguson-Smith, Anne C., and Gudbjartsson, Daniel F.

Published
2009
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24. TCF7L2 rs7903146--macronutrient interaction in obese individuals' responses to a 10-wk randomized hypoenergetic diet

Author

Grau, Katrine, Cauchi, Stephane, Holst, Claus, Astrup, Arne, Martinez, J. Alfredo, Saris, Wim H.M., Blaak, Ellen E., Oppert, Jean-Michel, Arner, Peter, Rossner, Stephan, Macdonald, Ian A., Klimcakova, Eva, Langin, Dominique, Pedersen, Oluf, Froguel, Philippe, and Sorensen, Thorkild I.A.

Subjects
Overweight persons -- Food and nutrition, Overweight persons -- Health aspects, Transcription factors -- Physiological aspects, Transcription factors -- Research, Type 2 diabetes -- Risk factors, Type 2 diabetes -- Genetic aspects, Type 2 diabetes -- Research, Food/cooking/nutrition, Health
Abstract

Background: Transcription factor 7-like 2 (TCF7L2) rs7903146 associates with type 2 diabetes and may operate via impaired glucagon-like peptide 1 secretion, which is stimulated more by fat than by carbohydrate ingestion. Objective: The objective was to examine the interaction between TCF7L2 rs7903146 and dietary fat and carbohydrate [high-fat, low-carbohydrate: 40-45% of energy as fat (HF); compared with low-fat, high-carbohydrate: 20-25% of energy as fat (LF)] in obese individuals' responses to a 10-wk hypoenergetic diet (-600 kcal/d). Design: European, obese participants (n = 771) were randomly assigned to receive an HF or an LF diet. Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REEL fasting fat oxidation in percentage of REE (FatOx), homeostasis model assessed insulin release (HOMA-[beta]), and HOMA--insulin resistance (HOMA-IR) were determined at baseline and after the intervention; 739 individuals were genotyped for rs7903146. Results: Average weight loss was 6.9 kg with the LF and 6.6 kg with the HF (difference between diets, NS) diet. Among individuals who were homozygous for the T-risk allele, those in the HF diet group experienced smaller weight losses (Aweight) (2.6 kg; P = 0.009; n = 622), smaller AFFM (1.6 kg; P = 0.027; n = 609), smaller [DELTA]WC (3.3 cm; P = 0.010; n = 608), and a smaller AHOMA-IR (1.3 units; P = 0.004; n = 615) than did the LF diet group. For C allele carriers, there were no differences between the HF and LF diet groups. For the HF diet group, each additional T allele was associated with a reduced loss of FM (0.67 kg; P = 0.019; n = 609). TCFTL2 rs7903146 was not associated with [DELTA]AREE, [DELTA]FatOx, [DELTA]HOMA-[beta], or dropout. Conclusion: Our results suggest that obese individuals who are homozygous for the TCF7L2 rs7903146 T-risk allele are more sensitive to LF than to HF weight-loss diets. Am J Clin Nutr 2010;91:472-9. doi: 10.3945/ajcn.2009.27947.

Published
2010

25. Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits

Author

Bonnefond, Amelie, Vaxillaire, Martine, Labrune, Yann, Lecoeur, Cecile, Chevre, Jean-Claude, Bouatia-Naji, Nabila, Cauchi, Stephane, Balkau, Beverley, Marre, Michel, Tichet, Jean, Riveline, Jean-Pierre, Hadjadj, Samy, Gallois, Yves, Czernichow, Sebastien, Hercberg, Serge, Kaakinen, Marika, Wiesner, Susanne, Charpentier, Guillaume, Levy-Marchal, Claire, Elliott, Paul, Jarvelin, Marjo-Riitta, Horber, Fritz, Dina, Christian, Pedersen, Oluf, Sladek, Robert, Meyre, David, and Froguel, Philippe

Subjects
Biological assay -- Usage -- Genetic aspects -- Physiological aspects -- Research -- Health aspects, Single nucleotide polymorphisms -- Research -- Usage -- Physiological aspects -- Genetic aspects -- Health aspects, Hexokinases -- Physiological aspects -- Genetic aspects -- Research -- Usage -- Health aspects, Diabetics -- Health aspects -- Genetic aspects -- Research -- Usage -- Physiological aspects, Health
Abstract

OBJECTIVE--A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice. RESEARCH DESIGN AND METHODS--The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control-related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients. RESULTS--Our study confirms a strong association between the rs7072268-T allele and increased A1C (β = 0.029%; P = 2.22 x [10.sup.-7]). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT-related parameters, n = 18,694). In contrast, rs7072268-T allele decreases hemoglobin levels (n = 13,416; β = -0.054 g/dl; P = 3.74 x [10.sup.-6]) and hematocrit (n = 11,492; β = -0.13%; P = 2.26 x [10.sup.-4]), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018). CONCLUSIONS--HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state., Type 2 diabetes is a major source of early excess morbidity and mortality, which result from lack of adequate blood glucose control in most diabetic patients (1). In the absence [...]

Published
2009
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27. Impact of common type 2 diabetes risk polymorphisms in the DESIR prospective study

Author

Vaxillaire, Martine, Veslot, Jacques, Dina, Christian, Proenca, Christine, Cauchi, Stephane, Charpentier, Guillaume, Tichet, Jean, Fumeron, Frederic, Marre, Michel, Meyre, David, Balkau, Beverley, and Froguel, Philippe

Subjects
Genetic polymorphisms -- Analysis -- Physiological aspects -- Genetic aspects, Type 2 diabetes -- Genetic aspects -- Risk factors, Health, Analysis, Physiological aspects, Genetic aspects, Risk factors
Abstract

OBJECTIVE--The emerging picture of type 2 diabetes genetics involves differently assembled gene variants, each modestly increasing risk with environmental exposure. However, the relevance of these genes for disease prediction has [...]

Published
2008

28. TCF7L2 variation predicts hyperglycemia incidence in a French general population: the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study

Author

Cauchi, Stephane, Meyre, David, Choquet, Helene, Dina, Christian, Born, Catherine, Marre, Michel, Balkau, Beverley, and Froguel, Philippe

Subjects
Diabetes -- Genetic aspects -- Risk factors, French -- Health aspects -- Genetic aspects, Hyperglycemia -- Risk factors -- Genetic aspects, Health, Genetic aspects, Risk factors, Health aspects
Abstract

Recently, case-control studies demonstrated that a TCF7L2 (transcription factor 7-like 2 gene) noncoding variant (rs7903146 T at-risk allele) was strongly associated with an increased risk of type 2 diabetes. However, [...]

Published
2006

29. Transcription factor TCF7L2 genetic study in the French population: expression in human β-cells and adipose tissue and strong association with type 2 diabetes

Author

Cauchi, Stephane, Meyre, David, Dina, Christian, Choquet, Helene, Samson, Chantal, Gallina, Sophie, Balkau, Beverly, Charpentier, Guillaume, Pattou, Francois, Staels, Bart, Fruhbeck, Gema, and Froguel, Philippe

Subjects
Genetic variation -- Research -- Genetic aspects, Genetic susceptibility -- Research -- Genetic aspects, Type 2 diabetes -- Genetic aspects -- Risk factors -- Research, Health, Research, Genetic aspects, Risk factors
Abstract

Recently, the transcription factor 7-like 2 (TCF7L2) gene has been associated with type 2 diabetes in subjects of European origin in the DeCode study. We genotyped the two most associated variants (rs7903146 and rs12255372) in 2,367 French type 2 diabetic subjects and in 2,499 control subjects. Both the T-allele of rs7903146 and the T-allele of rs12255372 significantly increase type 2 diabetes risk with an allelic odds ratio (OR) of 1.69 (95% CI 1.55-1.83) (P = 6.0 x [10.sup.-35]) and 1.60 (1.47-1.74) (P = 7.6 x [10.sup.-28]), respectively. In nonobese type 2 diabetic subjects (BMI, To date, positional cloning for type 2 diabetes genes has not been very successful in detecting type 2 diabetes putative susceptibility genes. Although several positive reports have emerged (1,2), few [...]

Published
2006

30. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author

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

Abstract

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

Published
2017
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31. 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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32. KLB is associated with alcohol drinking, and its gene product beta-Klotho is necessary for FGF21 regulation of alcohol preference

Author

Schumann, Gunter, Liu, Chunyu, O'Reilly, Paul, Gao, He, Song, Parkyong, Xu, Bing, Ruggeri, Barbara, Amin, Najaf, Jia, Tianye, Preis, Sarah, Lepe, Marcelo Segura, Akira, Shizuo, Barbieri, Caterina, Baumeister, Sebastian, Cauchi, Stephane, Clarke, Toni-Kim, Enroth, Stefan, Fischer, Krista, Hallfors, Jenni, Harris, Sarah E., Hieber, Saskia, Hofer, Edith, Hottenga, Jouke-Jan, Johansson, Åsa, Joshi, PeterK., Kaartinen, Niina, Laitinen, Jaana, Lemaitre, Rozenn, Loukola, Anu, Luan, Jian'an, Lyytikainen, Leo-Pekka, Mangino, Massimo, Manichaikul, Ani, Mbarek, Hamdi, Milaneschi, Yuri, Moayyeri, Alireza, Mukamal, Kenneth, Nelson, Christopher, Nettleton, Jennifer, Partinen, Eemil, Rawal, Rajesh, Robino, Antonietta, Rose, Lynda, Sala, Cinzia, Satoh, Takashi, Schmidt, Reinhold, Schrautz, Katharina, Scott, Robert, Smith, Albert Vernon, Starr, John M., Teumer, Alexander, Trompet, Stella, Uitterlinden, Andre G., Venturini, Cristina, Vergnaud, Anne-Claire, Verweij, Niek, Vitart, Veronique, Vuckovic, Dragana, Wedenoja, Juho, Yengo, Loic, Yu, Bing, Zhang, Weihua, Zhao, Jing Hua, Boomsma, Dorret I., Chambers, John, Chasman, Daniel I., Daniela, Toniolo, de Geus, Eco, Deary, Ian, Eriksson, Johan G., Esko, Tonu, Eulenburg, Volker, Franco, Oscar H., Froguel, Philippe, Gieger, Christian, Grabe, Hans J., Gudnason, Vilmundur, Gyllensten, Ulf B., Harris, Tamara B., Hartikainen, Anna-Liisa, Heath, Andrew C., Hocking, Lynne, Hofman, Albert, Huth, Cornelia, Jarvelin, Marjo-Riitta, Jukema, J. Wouter, Kaprio, Jaakko, Kooner, Jaspal S., Kutalik, Zoltan, Lahti, Jari, Langenberg, Claudia, Lehtimaki, Terho, Liu, Yongmei, Madden, Pamela A. F., Martin, Nicholas, Morrison, Alanna, Penninx, Brenda, Pirastu, Nicola, Psaty, Bruce, Raitakari, Olli, Ridker, Paul, Rose, Richard, Rotter, Jerome I., Samani, Nilesh J., Schmidt, Helena, Spector, Tim D., Stott, David, Strachan, David, Tzoulaki, Ioanna, van der Harst, Pim, van Duijn, Cornelia M., Marques-Vidal, Pedro, Vollenweider, Peter, Wareham, Nicholas J., Whitfield, John B., Wilson, James, Wolffenbuttel, Bruce, Bakalkin, Georgy, Evangelou, Evangelos, Liu, Yun, Rice, Kenneth M., Desrivieres, Sylvane, Kliewer, Steven A., Mangelsdorf, David J., Muller, Christian P., Levy, Daniel, Elliott, Paul, Schumann, Gunter, Liu, Chunyu, O'Reilly, Paul, Gao, He, Song, Parkyong, Xu, Bing, Ruggeri, Barbara, Amin, Najaf, Jia, Tianye, Preis, Sarah, Lepe, Marcelo Segura, Akira, Shizuo, Barbieri, Caterina, Baumeister, Sebastian, Cauchi, Stephane, Clarke, Toni-Kim, Enroth, Stefan, Fischer, Krista, Hallfors, Jenni, Harris, Sarah E., Hieber, Saskia, Hofer, Edith, Hottenga, Jouke-Jan, Johansson, Åsa, Joshi, PeterK., Kaartinen, Niina, Laitinen, Jaana, Lemaitre, Rozenn, Loukola, Anu, Luan, Jian'an, Lyytikainen, Leo-Pekka, Mangino, Massimo, Manichaikul, Ani, Mbarek, Hamdi, Milaneschi, Yuri, Moayyeri, Alireza, Mukamal, Kenneth, Nelson, Christopher, Nettleton, Jennifer, Partinen, Eemil, Rawal, Rajesh, Robino, Antonietta, Rose, Lynda, Sala, Cinzia, Satoh, Takashi, Schmidt, Reinhold, Schrautz, Katharina, Scott, Robert, Smith, Albert Vernon, Starr, John M., Teumer, Alexander, Trompet, Stella, Uitterlinden, Andre G., Venturini, Cristina, Vergnaud, Anne-Claire, Verweij, Niek, Vitart, Veronique, Vuckovic, Dragana, Wedenoja, Juho, Yengo, Loic, Yu, Bing, Zhang, Weihua, Zhao, Jing Hua, Boomsma, Dorret I., Chambers, John, Chasman, Daniel I., Daniela, Toniolo, de Geus, Eco, Deary, Ian, Eriksson, Johan G., Esko, Tonu, Eulenburg, Volker, Franco, Oscar H., Froguel, Philippe, Gieger, Christian, Grabe, Hans J., Gudnason, Vilmundur, Gyllensten, Ulf B., Harris, Tamara B., Hartikainen, Anna-Liisa, Heath, Andrew C., Hocking, Lynne, Hofman, Albert, Huth, Cornelia, Jarvelin, Marjo-Riitta, Jukema, J. Wouter, Kaprio, Jaakko, Kooner, Jaspal S., Kutalik, Zoltan, Lahti, Jari, Langenberg, Claudia, Lehtimaki, Terho, Liu, Yongmei, Madden, Pamela A. F., Martin, Nicholas, Morrison, Alanna, Penninx, Brenda, Pirastu, Nicola, Psaty, Bruce, Raitakari, Olli, Ridker, Paul, Rose, Richard, Rotter, Jerome I., Samani, Nilesh J., Schmidt, Helena, Spector, Tim D., Stott, David, Strachan, David, Tzoulaki, Ioanna, van der Harst, Pim, van Duijn, Cornelia M., Marques-Vidal, Pedro, Vollenweider, Peter, Wareham, Nicholas J., Whitfield, John B., Wilson, James, Wolffenbuttel, Bruce, Bakalkin, Georgy, Evangelou, Evangelos, Liu, Yun, Rice, Kenneth M., Desrivieres, Sylvane, Kliewer, Steven A., Mangelsdorf, David J., Muller, Christian P., Levy, Daniel, and Elliott, Paul

Abstract

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified beta-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 x 10(-12)). beta-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific beta-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

Published
2016
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33. Coffee and tea consumption, genotype- based CYP1A2 and NAT2 activity and colorectal cancer risk- Results from the EPIC cohort study

Author

Dik, Vincent K. Bueno-de-Mesquita, H. B(as) Van Oijen, Martijn G. H. Siersema, Peter D. Uiterwaal, Cuno S. P. M. Van Gils, Carla H. Van Duijnhoven, Fraenzel J. B. Cauchi, Stephane and Yengo, Loic Froguel, Philippe Overvad, Kim Bech, Bodil H. and Tjonneland, Anne Olsen, Anja Boutron-Ruault, Marie-Christine and Racine, Antoine Fagherazzi, Guy Kuehn, Tilman Campa, Daniele Boeing, Heiner Aleksandrova, Krasimira Trichopoulou, Antonia Peppa, Eleni Oikonomou, Eleni Palli, Domenico and Grioni, Sara Vineis, Paolo Tumino, Rosaria Panico, Salvatore and Peeters, Petra H. M. Weiderpass, Elisabete Engeset, Dagrun and Braaten, Tonje Dorronsoro, Miren Chirlaque, Maria-Dolores and Sanchez, Maria-Jose Barricarte, Aurelio Zamora-Ros, Raul and Argueelles, Marcial Jirstroem, Karin Wallstroem, Peter and Nilsson, Lena M. Ljuslinder, Ingrid Travis, Ruth C. Khaw, Kay-Tee Wareham, Nick Freisling, Heinz Licaj, Idlir and Jenab, Mazda Gunter, Marc J. Murphy, Neil Romaguera-Bosch, Dora Riboli, Elio

Abstract

Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC). We investigated the association between coffee and tea consumption and CRC risk and studied potential effect modification by CYP1A2 and NAT2 genotypes, enzymes involved in the metabolization of caffeine. Data from 477,071 participants (70.2% female) of the European Investigation into Cancer and Nutrition (EPIC) cohort study were analyzed. At baseline (1992-2000) habitual (total, caffeinated and decaffeinated) coffee and tea consumption was assessed with dietary questionnaires. Cox proportional hazards models were used to estimate adjusted hazard ratio’s (HR) and 95% confidence intervals (95% CI). Potential effect modification by genotype-based CYP1A2 and NAT2 activity was studied in a nested case-control set of 1,252 cases and 2,175 controls. After a median follow-up of 11.6 years, 4,234 participants developed CRC (mean age 64.78.3 years). Total coffee consumption (high vs. non/low) was not associated with CRC risk (HR 1.06, 95% CI 0.95-1.18) or subsite cancers, and no significant associations were found for caffeinated (HR 1.10, 95% CI 0.97-1.26) and decaffeinated coffee (HR 0.96, 95% CI 0.84-1.11) and tea (HR 0.97, 95% CI 0.86-1.09). High coffee and tea consuming subjects with slow CYP1A2 or NAT2 activity had a similar CRC risk compared to non/low coffee and tea consuming subjects with a fast CYP1A2 or NAT2 activity, which suggests that caffeine metabolism does not affect the link between coffee and tea consumption and CRC risk. This study shows that coffee and tea consumption is not likely to be associated with overall CRC. What’s new? Coffee and tea contain numerous compounds that may protect against colorectal cancer (CRC). In this study of more than 475,000 participants over more than a decade, the authors investigated whether coffee or tea consumption is associated with an altered risk of developing CRC. They also asked whether genetic variations in two enzymes involved in caffeine metabolism (CYP1A2 and NAT2) might affect this risk. They conclude that neither consumption patterns, nor genetic differences in caffeine metabolism, appear to have a significant impact on CRC risk.

Published
2014

34. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author

Gaulton, Kyle J., Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Maegi, Reedik, Reschen, Michael E., Mahajan, Anubha, Locke, Adam, Rayner, N. William, Robertson, Neil, Scott, Robert A., Prokopenko, Inga, Scott, Laura J., Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Franberg, Mattias, Strawbridge, Rona J., Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C., van Leeuwen, Elisabeth M., Willems, Sara M., Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K., Rundle, Jana K., Beer, Nicola L., van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F., Abecasis, Goncalo R., Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blueher, Matthias, Boeing, Heiner, Bonnycastle, Lori L., Bottinger, Erwin P., Burtt, Noel P., Carey, Jason, Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn C., Couper, David J., Crenshaw, Andrew T., van Dam, Rob M., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G., Esko, Tonu, Eury, Elodie, Fadista, Joao, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W., Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B., Grarup, Niels, Groves, Christopher J., Hassinen, Maija, Have, Christian T., Herder, Christian, Holmen, Oddgeir L., Hreidarsson, Astradur B., Humphries, Steve E., Hunter, David J., Jackson, Anne U., Jonsson, Anna, Jorgensen, Marit E., Jorgensen, Torben, Kao, Wen-Hong L., Kerrison, Nicola D., Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Leander, Karin, Liang, Liming, Lichtner, Peter, Lindgren, Cecilia M., Lindholm, Eero, Linneberg, Allan, Liu, Ching-Ti, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Mannisto, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Muehleisen, Thomas W., Mueller-Nurasyid, Martina, Navarro, Carmen, Noethen, Markus M., Oskolkov, Nikolay N., Owen, Katharine R., Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John R. B., Platou, Carl G. P., Roden, Michael, Ruderfer, Douglas, Rybin, Denis, van der Schouw, Yvonne T., Sennblad, Bengt, Sigurdsson, Gunnar, Stancakova, Alena, Steinbach, Gerald, Storm, Petter, Strauch, Konstantin, Stringham, Heather M., Sun, Qi, Thorand, Barbara, Tikkanen, Emmi, Tonjes, Anke, Trakalo, Joseph, Tremoli, Elena, Tuomi, Tiinamaija, Wennauer, Roman, Wiltshire, Steven, Wood, Andrew R., Zeggini, Eleftheria, Dunham, Ian, Birney, Ewan, Pasquali, Lorenzo, Ferrer, Jorge, Loos, Ruth J. F., Dupuis, Josee, Florez, Jose C., Boerwinkle, Eric, Pankow, James S., van Duijn, Cornelia, Sijbrands, Eric, Meigs, James B., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Lakka, Timo A., Rauramaa, Rainer, Stumvoll, Michael, Pedersen, Nancy L., Lind, Lars, Keinanen-Kiukaanniemi, Sirkka M., Korpi-Hyovalti, Eeva, Saaristo, Timo E., Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Joecke, Karl-Heinz, Moebus, Susanne, Ripatti, Samuli, Salomaa, Veikko, Ingelsson, Erik, Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Koistinen, Heikki, Tuomilehto, Jaakko, Hveem, Kristian, Njolstad, Inger, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., de Faire, Ulf, Hamsten, Anders, Illig, Thomas, Peters, Annette, Cauchi, Stephane, Sladek, Rob, Froguel, Philippe, Hansen, Torben, Pedersen, Oluf, Morris, Andrew D., Palmer, Collin N. A., Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M., Groop, Leif C., Barroso, Ines, Langenberg, Claudia, Wareham, Nicholas J., O'Callaghan, Christopher A., Gloyn, Anna L., Altshuler, David, Boehnke, Michael, Teslovich, Tanya M., McCarthy, Mark I., Morris, Andrew P., Gaulton, Kyle J., Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Maegi, Reedik, Reschen, Michael E., Mahajan, Anubha, Locke, Adam, Rayner, N. William, Robertson, Neil, Scott, Robert A., Prokopenko, Inga, Scott, Laura J., Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Franberg, Mattias, Strawbridge, Rona J., Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C., van Leeuwen, Elisabeth M., Willems, Sara M., Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K., Rundle, Jana K., Beer, Nicola L., van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F., Abecasis, Goncalo R., Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blueher, Matthias, Boeing, Heiner, Bonnycastle, Lori L., Bottinger, Erwin P., Burtt, Noel P., Carey, Jason, Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn C., Couper, David J., Crenshaw, Andrew T., van Dam, Rob M., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G., Esko, Tonu, Eury, Elodie, Fadista, Joao, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W., Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B., Grarup, Niels, Groves, Christopher J., Hassinen, Maija, Have, Christian T., Herder, Christian, Holmen, Oddgeir L., Hreidarsson, Astradur B., Humphries, Steve E., Hunter, David J., Jackson, Anne U., Jonsson, Anna, Jorgensen, Marit E., Jorgensen, Torben, Kao, Wen-Hong L., Kerrison, Nicola D., Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Leander, Karin, Liang, Liming, Lichtner, Peter, Lindgren, Cecilia M., Lindholm, Eero, Linneberg, Allan, Liu, Ching-Ti, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Mannisto, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Muehleisen, Thomas W., Mueller-Nurasyid, Martina, Navarro, Carmen, Noethen, Markus M., Oskolkov, Nikolay N., Owen, Katharine R., Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John R. B., Platou, Carl G. P., Roden, Michael, Ruderfer, Douglas, Rybin, Denis, van der Schouw, Yvonne T., Sennblad, Bengt, Sigurdsson, Gunnar, Stancakova, Alena, Steinbach, Gerald, Storm, Petter, Strauch, Konstantin, Stringham, Heather M., Sun, Qi, Thorand, Barbara, Tikkanen, Emmi, Tonjes, Anke, Trakalo, Joseph, Tremoli, Elena, Tuomi, Tiinamaija, Wennauer, Roman, Wiltshire, Steven, Wood, Andrew R., Zeggini, Eleftheria, Dunham, Ian, Birney, Ewan, Pasquali, Lorenzo, Ferrer, Jorge, Loos, Ruth J. F., Dupuis, Josee, Florez, Jose C., Boerwinkle, Eric, Pankow, James S., van Duijn, Cornelia, Sijbrands, Eric, Meigs, James B., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Lakka, Timo A., Rauramaa, Rainer, Stumvoll, Michael, Pedersen, Nancy L., Lind, Lars, Keinanen-Kiukaanniemi, Sirkka M., Korpi-Hyovalti, Eeva, Saaristo, Timo E., Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Joecke, Karl-Heinz, Moebus, Susanne, Ripatti, Samuli, Salomaa, Veikko, Ingelsson, Erik, Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Koistinen, Heikki, Tuomilehto, Jaakko, Hveem, Kristian, Njolstad, Inger, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., de Faire, Ulf, Hamsten, Anders, Illig, Thomas, Peters, Annette, Cauchi, Stephane, Sladek, Rob, Froguel, Philippe, Hansen, Torben, Pedersen, Oluf, Morris, Andrew D., Palmer, Collin N. A., Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M., Groop, Leif C., Barroso, Ines, Langenberg, Claudia, Wareham, Nicholas J., O'Callaghan, Christopher A., Gloyn, Anna L., Altshuler, David, Boehnke, Michael, Teslovich, Tanya M., McCarthy, Mark I., and Morris, Andrew P.

Abstract

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

Published
2015
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35. Genetic studies of body mass index yield new insights for obesity biology

Author

Locke, Adam E., Kahali, Bratati, Berndt, Sonja I., Justice, Anne E., Pers, Tune H., Day, Felix R., Powell, Corey, Vedantam, Sailaja, Buchkovich, Martin L., Yang, Jian, Croteau-Chonka, Damien C., Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Kutalik, Zoltan, Luan, Jian'an, Maegi, Reedik, Randall, Joshua C., Winkler, Thomas W., Wood, Andrew R., Workalemahu, Tsegaselassie, Faul, Jessica D., Smith, Jennifer A., Zhao, Jing Hua, Zhao, Wei, Chen, Jin, Fehrmann, Rudolf, Hedman, Asa K., Karjalainen, Juha, Schmidt, Ellen M., Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bolton, Jennifer L., Bragg-Gresham, L., Buyske, Steven, Demirkan, Ayse, Deng, Guohong, Ehret, Georg B., Feenstra, Bjarke, Feitosa, Mary F., Fischer, Krista, Goel, Anuj, Gong, Jian, Jackson, Anne U., Kanoni, Stavroula, Kleber, Marcus E., Kristiansson, Kati, Lim, Unhee, Lotay, Vaneet, Mangino, Massimo, Leach, Irene Mateo, Medina-Gomez, Carolina, Medland, Sarah E., Nalls, Michael A., Palmer, Cameron D., Pasko, Dorota, Pechlivanis, Sonali, Peters, Marjolein J., Prokopenko, Inga, Shungin, Dmitry, Stancakova, Alena, Strawbridge, Rona J., Sung, Yun Ju, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, van der Laan, Sander W., van Settee, Jessica, Van Vliet-Ostaptchouk, Jana V., Wang, Zhaoming, Yengo, Loic, Zhang, Weihua, Isaacs, Aaron, Albrecht, Eva, Arnlov, Johan, Arscott, Gillian M., Attwood, Antony P., Bandinelli, Stefania, Barrett, Amy, Bas, Isabelita N., Bellis, Claire, Bennett, Amanda J., Berne, Christian, Blagieva, Roza, Blueher, Matthias, Bohringer, Stefan, Bonnycastle, Lori L., Boettcher, Yvonne, Boyd, Heather A., Bruinenberg, Marcel, Caspersen, Ida H., Chen, Yii-Der Ida, Clarke, Robert, Daw, E. Warwick, de Craen, Anton J. M., Delgado, Graciela, Dimitriou, Maria, Doney, Alex S. F., Eklund, Niina, Estrada, Karol, Eury, Elodie, Folkersen, Lasse, Fraser, Ross M., Garcia, Melissa E., Geller, Frank, Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S., Golay, Alain, Goodall, Alison H., Gordon, Scott D., Gorski, Mathias, Grabe, Hans-Joergen, Grallert, Harald, Grammer, Tanja B., Graessler, Jurgen, Gronberg, Henrik, Groves, Christopher J., Gusto, Gaeelle, Haessler, Jeffrey, Hall, Per, Haller, Toomas, Hallmans, Göran, Hartman, Catharina A., Hassinen, Maija, Hayward, Caroline, Heard-Costa, Nancy L., Helmer, Qinta, Hengstenberg, Christian, Holmen, Oddgeir, Hottenga, Jouke-Jan, James, Alan L., Jeff, Janina M., Johansson, Asa, Jolley, Jennifer, Juliusdottir, Thorhildur, Kinnunen, Leena, Koenig, Wolfgang, Koskenvuo, Markku, Kratzer, Wolfgang, Laitinen, Jaana, Lamina, Claudia, Leander, Karin, Lee, Nanette R., Lichtner, Peter, Lind, Lars, Lindstrom, Jaana, Lo, Ken Sin, Lobbens, Stephane, Lorbeer, Roberto, Lu, Yingchang, Mach, Francois, Magnusson, Patrik K. E., Mahajan, Anubha, McArdle, Wendy L., McLachlan, Stela, Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Moayyeri, Alireza, Monda, Keri L., Morken, Mario A., Mulas, Antonella, Mueller, Gabriele, Mueller-Nurasyid, Martina, Musk, Arthur W., Nagaraja, Ramaiah, Noethen, Markus M., Nolte, Ilja M., Pilz, Stefan, Rayner, Nigel W., Renstrom, Frida, Rettig, Rainer, Ried, Janina S., Ripke, Stephan, Robertson, Neil R., Rose, Lynda M., Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Schumacher, Fredrick R., Scott, William R., Seufferlein, Thomas, Shi, Jianxin, Smith, Albert Vernon, Smolonska, Joanna, Stanton, Alice V., Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stringham, Heather M., Sundstrom, Johan, Swertz, Morris A., Swift, Amy J., Syvanen, Ann-Christine, Tan, Sian-Tsung, Tayo, Bamidele O., Thorand, Barbara, Thorleifsson, Gudmar, Tyrer, Jonathan P., Uh, Hae-Won, Vandenput, Liesbeth, Verhulst, Frank C., Vermeulen, Sita H., Verweij, Niek, Vonk, Judith M., Waite, Lindsay L., Warren, Helen R., Waterworth, Dawn, Weedon, Michael N., Wilkens, Lynne R., Willenborg, Christina, Wilsgaard, Tom, Wojczynski, Mary K., Wong, Andrew, Wrightl, Alan F., Zhang, Qunyuan, Brennan, Eoin P., Choi, Murim, Dastani, Zari, Drong, Alexander W., Eriksson, Per, Franco-Cereceda, Anders, Gadin, Jesper R., Gharavi, Ali G., Goddard, Michael E., Handsaker, Robert E., Huang, Jinyan, Karpe, Fredrik, Kathiresan, Sekar, Keildson, Sarah, Kiryluk, Krzysztof, Kubo, Michiaki, Lee, Jong-Young, Liang, Liming, Lifton, Richard P., Ma, Baoshan, McCarroll, Steven A., McKnight, Amy J., Min, Josine L., Moffatt, Miriam F., Montgomery, Grant W., Murabito, Joanne M., Nicholson, George, Nyholt, Dale R., Okada, Yukinori, Perry, John R. B., Dorajoo, Rajkumar, Reinmaa, Eva, Salem, Rany M., Sandholm, Niina, Scott, Robert A., Stolk, Lisette, Takahashi, Atsushi, Tanaka, Toshihiro, van 't Hooft, Ferdinand M., Vinkhuyzen, Anna A. E., Westra, Harm-Jan, Zheng, Wei, Zondervan, Krina T., Heath, Andrew C., Arveiler, Dominique, Bakker, Stephan J. L., Beilby, John, Bergman, Richard N., Blangero, John, Bovet, Pascal, Campbell, Harry, Caulfield, Mark J., Cesana, Giancarlo, Chakravarti, Aravinda, Chasman, Daniel I., Chines, Peter S., Collins, Francis S., Crawford, Dana C., Cupples, L. 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Eline, Snieder, Harold, Spector, Tim D., Thorsteinsdottir, Unnu R., Stumvoll, Michael, Tuomilehto, Jaakko, Uitterlinden, Andre G., Uusitupa, Matti, van der Harst, Pim, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wichmann, H-Erich, Wilson, James F., Zanen, Pieter, Borecki, Ingrid B., Deloukas, Panos, Fox, Caroline S., Heid, Iris M., O'Connell, Jeffrey R., Strachan, David P., Stefansson, Kari, van Duijri, Cornelia M., Abecasis, Goncalo R., Franke, Lude, Frayling, Timothy M., McCarthy, Mark I., Visscher, Peter M., Scherag, Andre, Willer, Cristen J., Boehnke, Michael, Mohlke, Karen L., Lindgren, Cecilia M., Beckmann, Jacques S., Barroso, Ines, North, Kari E., Ingelsson, Erik, Hirschhorn, Joel N., Loos, Ruth J. F., Speliotes, Elizabeth K., Locke, Adam E., Kahali, Bratati, Berndt, Sonja I., Justice, Anne E., Pers, Tune H., Day, Felix R., Powell, Corey, Vedantam, Sailaja, Buchkovich, Martin L., Yang, Jian, Croteau-Chonka, Damien C., Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Kutalik, Zoltan, Luan, Jian'an, Maegi, Reedik, Randall, Joshua C., Winkler, Thomas W., Wood, Andrew R., Workalemahu, Tsegaselassie, Faul, Jessica D., Smith, Jennifer A., Zhao, Jing Hua, Zhao, Wei, Chen, Jin, Fehrmann, Rudolf, Hedman, Asa K., Karjalainen, Juha, Schmidt, Ellen M., Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bolton, Jennifer L., Bragg-Gresham, L., Buyske, Steven, Demirkan, Ayse, Deng, Guohong, Ehret, Georg B., Feenstra, Bjarke, Feitosa, Mary F., Fischer, Krista, Goel, Anuj, Gong, Jian, Jackson, Anne U., Kanoni, Stavroula, Kleber, Marcus E., Kristiansson, Kati, Lim, Unhee, Lotay, Vaneet, Mangino, Massimo, Leach, Irene Mateo, Medina-Gomez, Carolina, Medland, Sarah E., Nalls, Michael A., Palmer, Cameron D., Pasko, Dorota, Pechlivanis, Sonali, Peters, Marjolein J., Prokopenko, Inga, Shungin, Dmitry, Stancakova, Alena, Strawbridge, Rona J., Sung, Yun Ju, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, van der Laan, Sander W., van Settee, Jessica, Van Vliet-Ostaptchouk, Jana V., Wang, Zhaoming, Yengo, Loic, Zhang, Weihua, Isaacs, Aaron, Albrecht, Eva, Arnlov, Johan, Arscott, Gillian M., Attwood, Antony P., Bandinelli, Stefania, Barrett, Amy, Bas, Isabelita N., Bellis, Claire, Bennett, Amanda J., Berne, Christian, Blagieva, Roza, Blueher, Matthias, Bohringer, Stefan, Bonnycastle, Lori L., Boettcher, Yvonne, Boyd, Heather A., Bruinenberg, Marcel, Caspersen, Ida H., Chen, Yii-Der Ida, Clarke, Robert, Daw, E. Warwick, de Craen, Anton J. M., Delgado, Graciela, Dimitriou, Maria, Doney, Alex S. F., Eklund, Niina, Estrada, Karol, Eury, Elodie, Folkersen, Lasse, Fraser, Ross M., Garcia, Melissa E., Geller, Frank, Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S., Golay, Alain, Goodall, Alison H., Gordon, Scott D., Gorski, Mathias, Grabe, Hans-Joergen, Grallert, Harald, Grammer, Tanja B., Graessler, Jurgen, Gronberg, Henrik, Groves, Christopher J., Gusto, Gaeelle, Haessler, Jeffrey, Hall, Per, Haller, Toomas, Hallmans, Göran, Hartman, Catharina A., Hassinen, Maija, Hayward, Caroline, Heard-Costa, Nancy L., Helmer, Qinta, Hengstenberg, Christian, Holmen, Oddgeir, Hottenga, Jouke-Jan, James, Alan L., Jeff, Janina M., Johansson, Asa, Jolley, Jennifer, Juliusdottir, Thorhildur, Kinnunen, Leena, Koenig, Wolfgang, Koskenvuo, Markku, Kratzer, Wolfgang, Laitinen, Jaana, Lamina, Claudia, Leander, Karin, Lee, Nanette R., Lichtner, Peter, Lind, Lars, Lindstrom, Jaana, Lo, Ken Sin, Lobbens, Stephane, Lorbeer, Roberto, Lu, Yingchang, Mach, Francois, Magnusson, Patrik K. E., Mahajan, Anubha, McArdle, Wendy L., McLachlan, Stela, Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Moayyeri, Alireza, Monda, Keri L., Morken, Mario A., Mulas, Antonella, Mueller, Gabriele, Mueller-Nurasyid, Martina, Musk, Arthur W., Nagaraja, Ramaiah, Noethen, Markus M., Nolte, Ilja M., Pilz, Stefan, Rayner, Nigel W., Renstrom, Frida, Rettig, Rainer, Ried, Janina S., Ripke, Stephan, Robertson, Neil R., Rose, Lynda M., Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Schumacher, Fredrick R., Scott, William R., Seufferlein, Thomas, Shi, Jianxin, Smith, Albert Vernon, Smolonska, Joanna, Stanton, Alice V., Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stringham, Heather M., Sundstrom, Johan, Swertz, Morris A., Swift, Amy J., Syvanen, Ann-Christine, Tan, Sian-Tsung, Tayo, Bamidele O., Thorand, Barbara, Thorleifsson, Gudmar, Tyrer, Jonathan P., Uh, Hae-Won, Vandenput, Liesbeth, Verhulst, Frank C., Vermeulen, Sita H., Verweij, Niek, Vonk, Judith M., Waite, Lindsay L., Warren, Helen R., Waterworth, Dawn, Weedon, Michael N., Wilkens, Lynne R., Willenborg, Christina, Wilsgaard, Tom, Wojczynski, Mary K., Wong, Andrew, Wrightl, Alan F., Zhang, Qunyuan, Brennan, Eoin P., Choi, Murim, Dastani, Zari, Drong, Alexander W., Eriksson, Per, Franco-Cereceda, Anders, Gadin, Jesper R., Gharavi, Ali G., Goddard, Michael E., Handsaker, Robert E., Huang, Jinyan, Karpe, Fredrik, Kathiresan, Sekar, Keildson, Sarah, Kiryluk, Krzysztof, Kubo, Michiaki, Lee, Jong-Young, Liang, Liming, Lifton, Richard P., Ma, Baoshan, McCarroll, Steven A., McKnight, Amy J., Min, Josine L., Moffatt, Miriam F., Montgomery, Grant W., Murabito, Joanne M., Nicholson, George, Nyholt, Dale R., Okada, Yukinori, Perry, John R. B., Dorajoo, Rajkumar, Reinmaa, Eva, Salem, Rany M., Sandholm, Niina, Scott, Robert A., Stolk, Lisette, Takahashi, Atsushi, Tanaka, Toshihiro, van 't Hooft, Ferdinand M., Vinkhuyzen, Anna A. E., Westra, Harm-Jan, Zheng, Wei, Zondervan, Krina T., Heath, Andrew C., Arveiler, Dominique, Bakker, Stephan J. L., Beilby, John, Bergman, Richard N., Blangero, John, Bovet, Pascal, Campbell, Harry, Caulfield, Mark J., Cesana, Giancarlo, Chakravarti, Aravinda, Chasman, Daniel I., Chines, Peter S., Collins, Francis S., Crawford, Dana C., Cupples, L. Adrienne, Cusi, Daniele, Danesh, John, de Faire, Ulf, den Ruijter, Hester M., Dominiczak, Anna F., Erbel, Raimund, Erdmann, Jeanette, Eriksson, Johan G., Farrall, Martin, Felix, Stephan B., Ferrannini, Ele, Ferrieres, Jean, Ford, Ian, Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Gansevoort, Ron T., Gejman, Pablo V., Gieger, Christian, Gottesman, Omri, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Alistair S., Harris, Tamara B., Hattersley, Andrew T., Hicks, Andrew A., Hindorff, Lucia A., Hingorani, Aroon D., Hofman, Albert, Homuth, Georg, Hovingh, G. Kees, Humphries, Steve E., Hunt, Steven C., Hypponen, Elina, Illig, Thomas, Jacobs, Kevin B., Jarvelin, Marjo-Riitta, Joeckel, Karl-Heinz, Johansen, Berit, Jousilahti, Pekka, Jukema, J. Wouter, Jula, Antti M., Kaprio, Jaakko, Kastelein, John J. P., Keinanen-Kiukaanniemi, Sirkka M., Kiemeney, Lambertus A., Knekt, Paul, Kooner, Jaspal S., Kooperberg, Charles, Kovacs, Peter, Kraja, Aldi T., Kumari, Meena, Kuusisto, Johanna, Lakka, Timo A., Langenberg, Claudia, Le Marchand, Laic, Lehtimaki, Terho, Lyssenko, Valeriya, Mannisto, Satu, Marette, Andre, Matise, Tara C., McKenzie, Colin A., McKnight, Barbara, Moll, Frans L., Morris, Andrew D., Morris, Andrew P., Murray, Jeffrey C., Nelis, Mari, Ohlsson, Claes, Oldehinkel, Albertine J., Ong, Ken K., Madden, Pamela A. F., Pasterkamp, Gerard, Peden, John F., Peters, Annette, Postma, Dirkje S., Pramstaller, Peter P., Price, Jackie F., Qi, Lu, Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rice, Treva K., Ridker, Paul M., Rioux, John D., Ritchie, Marylyn D., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Saramines, Jouko, Sarzynski, Mark A., Schunkert, Heribert, Schwarz, Peter E. H., Sever, Peter, Shuldiner, Alan R., Sinisalo, Juha, Stolk, Ronald P., Strauch, Konstantin, Toenjes, Anke, Tregouet, David-Alexandre, Tremblay, Angelo, Tremoli, Elena, Virtamo, Jarmo, Vohl, Marie-Claude, Voelker, Uwe, Waeber, Gerard, Willemsen, Gonneke, Witteman, Jacqueline C., Zillikens, M. Carola, Adair, Linda S., Amouyel, Philippe, Asselbergs, Folkert W., Assimes, Themistocles L., Bochud, Murielle, Boehm, Bernhard O., Boerwinkle, Eric, Bornstein, Stefan R., Bottinger, Erwin P., Bouchard, Claude, Cauchi, Stephane, Chambers, John C., Chanock, Stephen J., Cooper, Richard S., de Bakker, Paul I. W., Dedoussis, George, Ferrucci, Luigi, Franks, Paul W., Froguel, Philippe, Groop, Leif C., Haiman, Christopher A., Hamsten, Anders, Hui, Jennie, Hunter, David J., Hveem, Kristian, Kaplan, Robert C., Kivimaki, Mika, Kuh, Diana, Laakso, Markku, Liu, Yongmei, Martin, Nicholas G., Maerz, Winfried, Melbve, Mads, Metspalu, Andres, Moebus, Susanne, Munroe, Patricia B., Njolstad, Inger, Oostra, Ben A., Palmer, Colin N. A., Pedersen, Nancy L., Perola, Markus, Perusse, Louis, Peters, Ulrike, Power, Chris, Quertermous, Thomas, Rauramaa, Rainer, Rivadeneira, Fernando, Saaristo, Timo E., Saleheen, Danish, Sattar, Naveed, Schadt, Eric E., Schlessinger, David, Slagboom, P. Eline, Snieder, Harold, Spector, Tim D., Thorsteinsdottir, Unnu R., Stumvoll, Michael, Tuomilehto, Jaakko, Uitterlinden, Andre G., Uusitupa, Matti, van der Harst, Pim, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wichmann, H-Erich, Wilson, James F., Zanen, Pieter, Borecki, Ingrid B., Deloukas, Panos, Fox, Caroline S., Heid, Iris M., O'Connell, Jeffrey R., Strachan, David P., Stefansson, Kari, van Duijri, Cornelia M., Abecasis, Goncalo R., Franke, Lude, Frayling, Timothy M., McCarthy, Mark I., Visscher, Peter M., Scherag, Andre, Willer, Cristen J., Boehnke, Michael, Mohlke, Karen L., Lindgren, Cecilia M., Beckmann, Jacques S., Barroso, Ines, North, Kari E., Ingelsson, Erik, Hirschhorn, Joel N., Loos, Ruth J. F., and Speliotes, Elizabeth K.

Abstract

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for similar to 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous systemin obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Published
2015
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36. New genetic loci link adipose and insulin biology to body fat distribution

Author

Shungin, Dmitry, Winkler, Thomas W., Croteau-Chonka, Damien C., Ferreira, Teresa, Lockes, Adam E., Maegi, Reedik, Strawbridge, Rona J., Pers, Tune H., Fischer, Krista, Justice, Anne E., Workalemahu, Tsegaselassie, Wu, Joseph M. W., Buchkovich, Martin L., Heard-Costa, Nancy L., Roman, Tamara S., Drong, Alexander W., Song, Ci, Gustafsson, Stefan, Day, Felix R., Esko, Tonu, Fall, Tove, Kutalik, Zoltan, Luan, Jian'an, Randall, Joshua C., Scherag, Andre, Vedantam, Sailaja, Wood, Andrew R., Chen, Jin, Fehrmann, Rudolf, Karjalainen, Juha, Kahali, Bratati, Liu, Ching-Ti, Schmidt, Ellen M., Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bragg-Gresham, Jennifer L., Buyske, Steven, Demirkan, Ayse, Ehret, Georg B., Feitosa, Mary F., Goel, Anuj, Jackson, Anne U., Johnson, Toby, Kleber, Marcus E., Kristiansson, Kati, Mangino, Massimo, Leach, Irene Mateo, Medina-Gomez, Carolina, Palmer, Cameron D., Pasko, Dorota, Pechlivaniss, Sonali, Peters, Marjolein J., Prokopenko, Inga, Stancakova, Alena, Sung, Yun Ju, Tanakam, Toshiko, Teumer, Alexander, Van Vliet-Ostaptchouk, Jana V., Yengo, Loic, Zhang, Weihua, Albrecht, Eva, Arnlov, Johan, Arscott, Gillian M., Bandinelli, Stefania, Barrett, Amy, Bellis, Claire, Bennett, Amanda J., Berne, Christian, Blueher, Matthias, Buhringer, Stefan, Bonnet, Fabrice, Boettcher, Yvonne, Bruinenberg, Marcel, Carba, Delia B., Caspersen, Ida H., Clarke, Robert, Daw, E. Warwick, Deelen, Joris, Deelman, Ewa, Delgado, Graciela, Doney, Alex S. F., Eklund, Niina, Erdos, Michael R., Estrada, Karol, Eury, Elodie, Friedrichs, Nele, Garcia, Melissa E., Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S., Golay, Alain, Grallert, Harald, Grammer, Tanja B., Graessler, Juergen, Grewal, Jagvir, Groves, Christopher J., Haller, Toomas, Hallmans, Göran, Hartman, Catharina A., Hassinen, Maija, Hayward, Caroline, Heikkila, Kauko, Herzig, Karl-Heinz, Helmer, Quinta, Hillege, Hans L., Holmen, Oddgeir, Hunt, Steven C., Isaacs, Aaron, Ittermann, Till, James, Alan L., Johansson, Ingegerd, Juliusdottir, Thorhildur, Kalafati, Ioanna-Panagiota, Kinnunen, Leena, Koenig, Wolfgang, Kooner, Ishminder K., Kratzer, Wolfgang, Lamina, Claudia, Leander, Karin, Lee, Nanette R., Lichtner, Peter, Lind, Lars, Lindstrom, Jaana, Lobbens, Stephane, Lorentzon, Mattias, Mach, Francois, Magnusson, Patrik K. E., Mahajan, Anubha, McArdle, Wendy L., Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Moayyeri, Alireza, Monda, Ken L., Mooijaart, Simon P., Muehleisen, Thomas W., Mulas, Antonella, Mueller, Gabriele, Mueller-Nurasyid, Martina, Nagaraja, Ramaiah, Nalls, Michael A., Narisu, Narisu, Glorioso, Nicola, Nolte, Ilja M., Olden, Matthias, Rayner, Nigel W., Renstrom, Frida, Ried, Janina S., Robertson, Neil R., Rose, Lynda M., Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Sennblad, Bengt, Seufferlein, Thomas, Sitlani, Colleen M., Smith, Albert Vernon, Stirrups, Kathleen, Stringham, Heather M., Sundstrom, Johan, Swertz, Morris A., Swift, Amy J., Syvanen, Ann-Christine, Tayo, Bamidele O., Thorand, Barbara, Thorleifsson, Gudmar, Tomaschitz, Andreas, Troffa, Chiara, van Oort, Floor V. A., Verweij, Niek, Vonk, Judith M., Waite, Lindsay L., Wennauer, Roman, Wilsgaard, Tom, Wojczynski, Mary K., Wong, Andrew, Zhang, Qunyuan, Zhao, Jing Hua, Brennan, Eoin P., Choi, Murim, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Gharavi, Ali G., Hedman, Asa K., Hivert, Marie-France, Huang, Jinyan, Kanoni, Stavroula, Karpe, Fredrik, Keildson, Sarah, Kiryluk, Krzysztof, Liang, Liming, Lifton, Richard P., Ma, Baoshan, McKnight, Amy J., McPherson, Ruth, Metspalu, Andres, Min, Josine L., Moffatt, Miriam F., Montgomery, Grant W., Murabito, Joanne M., Nicholson, George, Nyholt, Dale R., Olsson, Christian, Perry, John R. B., Reinmaa, Eva, Salem, Rany M., Sandholm, Niina, Schadt, Eric E., Scott, Robert A., Stolk, Lisette, Vallejo, Edgar E., Westra, Harm-Jan, Zondervan, Krina T., Amouyel, Philippe, Arveiler, Dominique, Bakker, Stephan J. L., Beilby, John, Bergman, Richard N., Blangero, John, Brown, Morris J., Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chiness, Peter S., Claudi-Boehmi, Simone, Collins, Francis S., Crawford, Dana C., Danesh, John, de Faire, Ulf, de Geusl, Eco J. 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Carola, McCarthy, Mark I., Speliotes, Elizabeth K., North, Kari E., Fox, Caroline S., Barroso, Ines, Franks, Paul W., Ingelsson, Erik, Heid, Iris M., Loos, Ruth J. F., Cupples, L. Adrienne, Morris, Andrew P., Lindgren, Cecilia M., and Mohlke, Karen L.

Abstract

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Published
2015
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37. Alcohol consumption and risk of type 2 diabetes in European men and women:Influence of beverage type and body sizeThe EPIC-InterAct study

Author

Beulens, Joline Wj, van der Schouw, Yvonne T, Bergmann, Manuela M, Rohrmann, Sabine, Schulze, Matthias B, Buijsse, Brian, Grobbee, Diederick E, Arriola, Larraitz, Cauchi, Stephane, Tormo, Maria-Jose, Allen, Naomi E, van der, Daphne L, Balkau, Beverly, Boeing, Heiner, Clavel-Chapelon, Françoise, de Lauzon-Guillan, Blandine, Franks, Paul, Froguel, Phillipe, Gonzales, Carlos, Halkjaer, Jytte, Huerta, Jose Maria, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay Tee, Krogh, Vittorio, Molina-Montes, Esther, Nilsson, Peter, Overvad, Kim, Palli, Domenico, Panico, Salvatore, Quirós, Jose Ramón, Ronaldsson, Olov, Romieu, Isabelle, Romaguera, Dora, Sacerdote, Carlotta, Sánchez, María-José, Spijkerman, Annemieke Mw, Teucher, Birgit, Tjonneland, Anne, Tumino, Rosario, Sharpe, Stephen, Forouhi, Nita G, Langenberg, Claudia, Feskens, Edith Jm, Riboli, Elio, Wareham, Nicholas J, Epidemiology and Data Science, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, and APH - Health Behaviors & Chronic Diseases

Abstract

Objective: To investigate the association between alcohol consumption and type 2 diabetes, and determine whether this is modified by sex, body mass index (BMI) and beverage type. Design: Multicentre prospective case-cohort study. Setting: Eight countries from the European Prospective Investigation into Cancer and Nutrition cohort. Subjects: A representative baseline sample of 16154 participants and 12403 incident cases of type 2 diabetes. Interventions: Alcohol consumption assessed using validated dietary questionnaires. Main outcome measures: Occurrence of type 2 diabetes based on multiple sources (mainly self-reports), verified against medical information. Results: Amongst men, moderate alcohol consumption was nonsignificantly associated with a lower incidence of diabetes with a hazard ratio (HR) of 0.90 (95% CI: 0.78-1.05) for 6.1-12.0 versus 0.1-6.0gday-1, adjusted for dietary and diabetes risk factors. However, the lowest risk was observed at higher intakes of 24.1-96.0gday-1 with an HR of 0.86 (95% CI: 0.75-0.98). Amongst women, moderate alcohol consumption was associated with a lower incidence of diabetes with a hazard ratio of 0.82 (95% CI: 0.72-0.92) for 6.1-12.0gday-1 (P interaction gender

Published
2012

38. A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans

Author

Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, DIAGRAM Consortium, MAGIC Investigators, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie CY, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, Van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, 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Center for Liver, Digestive and Metabolic Diseases (CLDM), Palmer, Nd, Mcdonough, Cw, Hicks, Pj, Roh, Bh, Wing, Mr, An, S, Hester, Jm, Cooke, Jn, Bostrom, Ma, Rudock, Me, Talbert, Me, Lewis, Jp, Diagram, Consortium, Magic, Investigator, Ferrara, A, Lu, L, Ziegler, Jt, Sale, Mm, Divers, J, Shriner, D, Adeyemo, A, Rotimi, Cn, Ng, Mc, Langefeld, Cd, Freedman, Bi, Bowden, Dw, Voight, Bf, Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Langenberg, C, Hofmann, Om, Dupuis, J, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Couper, Dj, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Perry, Jr, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, Nj, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Meigs, Jb, Pankow, J, Pedersen, O, Wichmann, He, Barroso, I, Florez, Jc, Frayling, Tm, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Johnson, T, Elliott, P, Rybin, D, Henneman, P, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Egan, Jm, Lajunen, T, Kanoni, S, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Frants, R, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hicks, Aa, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Jula, A, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Manning, Ak, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Oostra, Ba, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Perola, M, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Psaty, Bm, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tanaka, T, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Borecki, Ib, Loos, Rj, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Salomaa, V, Smith, Gd, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Dedoussis, Gv, Serrano Ríos, M, Lind, L, Palmer, Lj, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Buchanan, Ta, Valle, Tt, Rotter, Ji, Siscovick, D, Penninx, Bw, Boomsma, Di, Deloukas, P, Spector, Td, Ferrucci, L, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Waterworth, Dm, Vollenweider, P, Peltonen, L, Mooser, V, Sladek, R., Medical Research Council (MRC), Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, Langenberg, Claudia [0000-0002-5017-7344], Griffin, Simon [0000-0002-2157-4797], Wareham, Nicholas [0000-0003-1422-2993], Soranzo, Nicole [0000-0003-1095-3852], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Apollo - University of Cambridge Repository, DIAGRAM Consortium, MAGIC Investigators, Johnson, T., Bergman, S., Bochud, M., Waeber, G., and Vollenweider, P.

Subjects
Netherlands Twin Register (NTR), Male, Adult, African Americans/genetics, Aged, Case-Control Studies, Cohort Studies, Diabetes Mellitus, Type 2/ethnology, Diabetes Mellitus, Type 2/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Validation Studies as Topic, Medicin och hälsovetenskap, Linkage disequilibrium, Genetic Screens, endocrine system diseases, lcsh:Medicine, Genome-wide association study, Medical and Health Sciences, 0302 clinical medicine, Endocrinology, Genome Sequencing, lcsh:Science, Medicine(all), Genetics, African Americans, 0303 health sciences, education.field_of_study, INSULIN-RESISTANCE, Multidisciplinary, Agricultural and Biological Sciences(all), LARGE-SCALE ASSOCIATION, STAGE RENAL-DISEASE, COMMON VARIANTS, Genomics, Medicine, Research Article, SUSCEPTIBILITY LOCI, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, DIAGRAM Consortium, 03 medical and health sciences, MAGIC Investigators, SDG 3 - Good Health and Well-being, Genetic linkage, MD Multidisciplinary, Genome-Wide Association Studies, SNP, ddc:610, education, Genotyping, 030304 developmental biology, Diabetic Endocrinology, LINKAGE ANALYSIS, Biochemistry, Genetics and Molecular Biology(all), lcsh:R, TCF7L2 GENE, Case-control study, Computational Biology, nutritional and metabolic diseases, Human Genetics, Diabetes Mellitus Type 2, Stage renal-disease, large-scale association, Susceptibility loci, Insulin-resistance, Fasting glucose, Tissue factor, Homeodomain protein, Linkage analysis, Common variants, TCF7L2 gene, Black or African American, Diabetes Mellitus, Type 2, TISSUE FACTOR, Genetics of Disease, HOMEODOMAIN PROTEIN, Genetic Polymorphism, lcsh:Q, Genome Expression Analysis, 030217 neurology & neurosurgery, Population Genetics, FASTING GLUCOSE
Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Published
2012

39. Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

Author

Dimas, Antigone S., Lagou, Vasiliki, Barker, Adam, Knowles, Joshua W., Maegi, Reedik, Hivert, Marie-France, Benazzo, Andrea, Rybin, Denis, Jackson, Anne U., Stringham, Heather M., Song, Ci, Fischer-Rosinsky, Antje, Boesgaard, Trine Wellov, Grarup, Niels, Abbasi, Fahim A., Assimes, Themistocles L., Hao, Ke, Yang, Xia, Lecoeur, Cecile, Barroso, Ines, Bonnycastle, Lori L., Boettcher, Yvonne, Bumpstead, Suzannah, Chines, Peter S., Erdos, Michael R., Graessler, Jurgen, Kovacs, Peter, Morken, Mario A., Narisu, Narisu, Payne, Felicity, Stancakova, Alena, Swift, Amy J., Toenjes, Anke, Bornstein, Stefan R., Cauchi, Stephane, Froguel, Philippe, Meyre, David, Schwarz, Peter E. H., Haering, Hans-Ulrich, Smith, Ulf, Boehnke, Michael, Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Quertemous, Thomas, Lind, Lars, Hansen, Torben, Pedersen, Oluf, Walker, Mark, Pfeiffer, Andreas F. H., Spranger, Joachim, Stumvoll, Michael, Meigs, James B., Wareham, Nicholas J., Kuusisto, Johanna, Laakso, Markku, Langenberg, Claudia, Dupuis, Josee, Watanabe, Richard M., Florez, Jose C., Ingelsson, Erik, McCarthy, Mark I., Prokopenko, Inga, Dimas, Antigone S., Lagou, Vasiliki, Barker, Adam, Knowles, Joshua W., Maegi, Reedik, Hivert, Marie-France, Benazzo, Andrea, Rybin, Denis, Jackson, Anne U., Stringham, Heather M., Song, Ci, Fischer-Rosinsky, Antje, Boesgaard, Trine Wellov, Grarup, Niels, Abbasi, Fahim A., Assimes, Themistocles L., Hao, Ke, Yang, Xia, Lecoeur, Cecile, Barroso, Ines, Bonnycastle, Lori L., Boettcher, Yvonne, Bumpstead, Suzannah, Chines, Peter S., Erdos, Michael R., Graessler, Jurgen, Kovacs, Peter, Morken, Mario A., Narisu, Narisu, Payne, Felicity, Stancakova, Alena, Swift, Amy J., Toenjes, Anke, Bornstein, Stefan R., Cauchi, Stephane, Froguel, Philippe, Meyre, David, Schwarz, Peter E. H., Haering, Hans-Ulrich, Smith, Ulf, Boehnke, Michael, Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Quertemous, Thomas, Lind, Lars, Hansen, Torben, Pedersen, Oluf, Walker, Mark, Pfeiffer, Andreas F. H., Spranger, Joachim, Stumvoll, Michael, Meigs, James B., Wareham, Nicholas J., Kuusisto, Johanna, Laakso, Markku, Langenberg, Claudia, Dupuis, Josee, Watanabe, Richard M., Florez, Jose C., Ingelsson, Erik, McCarthy, Mark I., and Prokopenko, Inga

Abstract

Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF712, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition., De fem sista författarna delar sistaförfattarskapet.

Published
2014
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41. Leveraging Cross-Species Transcription Factor Binding Site Patterns: From Diabetes Risk Loci to Disease Mechanisms

Author

Claussnitzer, Melina, primary, Dankel, Simon N., additional, Klocke, Bernward, additional, Grallert, Harald, additional, Glunk, Viktoria, additional, Berulava, Tea, additional, Lee, Heekyoung, additional, Oskolkov, Nikolay, additional, Fadista, Joao, additional, Ehlers, Kerstin, additional, Wahl, Simone, additional, Hoffmann, Christoph, additional, Qian, Kun, additional, Rönn, Tina, additional, Riess, Helene, additional, Müller-Nurasyid, Martina, additional, Bretschneider, Nancy, additional, Schroeder, Timm, additional, Skurk, Thomas, additional, Horsthemke, Bernhard, additional, Spieler, Derek, additional, Klingenspor, Martin, additional, Seifert, Martin, additional, Kern, Michael J., additional, Mejhert, Niklas, additional, Dahlman, Ingrid, additional, Hansson, Ola, additional, Hauck, Stefanie M., additional, Blüher, Matthias, additional, Arner, Peter, additional, Groop, Leif, additional, Illig, Thomas, additional, Suhre, Karsten, additional, Hsu, Yi-Hsiang, additional, Mellgren, Gunnar, additional, Hauner, Hans, additional, Laumen, Helmut, additional, Voight, Benjamin F., additional, Scott, Laura J., additional, Steinthorsdottir, Valgerdur, additional, Morris, Andrew P., additional, Dina, Christian, additional, Welch, Ryan P., additional, Zeggini, Eleftheria, additional, Huth, Cornelia, additional, Aulchenko, Yurii S., additional, Thorleifsson, Gudmar, additional, McCulloch, Laura J., additional, Ferreira, Teresa, additional, Amin, Najaf, additional, Wu, Guanming, additional, Willer, Cristen J., additional, Raychaudhuri, Soumya, additional, McCarroll, Steve A., additional, Langenberg, Claudia, additional, Hofmann, Oliver M., additional, Dupuis, Josée, additional, Qi, Lu, additional, Segrè, Ayellet V., additional, van Hoek, Mandy, additional, Navarro, Pau, additional, Ardlie, Kristin, additional, Balkau, Beverley, additional, Benediktsson, Rafn, additional, Bennett, Amanda J., additional, Blagieva, Roza, additional, Boerwinkle, Eric, additional, Bonnycastle, Lori L., additional, Boström, Kristina Bengtsson, additional, Bravenboer, Bert, additional, Bumpstead, Suzannah, additional, Burtt, Noël P., additional, Charpentier, Guillaume, additional, Chines, Peter S., additional, Cornelis, Marilyn, additional, Couper, David J., additional, Crawford, Gabe, additional, Doney, Alex S.F., additional, Elliott, Katherine S., additional, Elliott, Amanda L., additional, Erdos, Michael R., additional, Fox, Caroline S., additional, Franklin, Christopher S., additional, Ganser, Martha, additional, Gieger, Christian, additional, Grarup, Niels, additional, Green, Todd, additional, Griffin, Simon, additional, Groves, Christopher J., additional, Guiducci, Candace, additional, Hadjadj, Samy, additional, Hassanali, Neelam, additional, Herder, Christian, additional, Isomaa, Bo, additional, Jackson, Anne U., additional, Johnson, Paul R.V., additional, Jørgensen, Torben, additional, Kao, Wen H.L., additional, Klopp, Norman, additional, Kong, Augustine, additional, Kraft, Peter, additional, Kuusisto, Johanna, additional, Lauritzen, Torsten, additional, Li, Man, additional, Lieverse, Aloysius, additional, Lindgren, Cecilia M., additional, Lyssenko, Valeriya, additional, Marre, Michel, additional, Meitinger, Thomas, additional, Midthjell, Kristian, additional, Morken, Mario A., additional, Narisu, Narisu, additional, Nilsson, Peter, additional, Owen, Katharine R., additional, Payne, Felicity, additional, Perry, John R.B., additional, Petersen, Ann-Kristin, additional, Platou, Carl, additional, Proença, Christine, additional, Prokopenko, Inga, additional, Rathmann, Wolfgang, additional, Rayner, N. William, additional, Robertson, Neil R., additional, Rocheleau, Ghislain, additional, Roden, Michael, additional, Sampson, Michael J., additional, Saxena, Richa, additional, Shields, Beverley M., additional, Shrader, Peter, additional, Sigurdsson, Gunnar, additional, Sparsø, Thomas, additional, Strassburger, Klaus, additional, Stringham, Heather M., additional, Sun, Qi, additional, Swift, Amy J., additional, Thorand, Barbara, additional, Tichet, Jean, additional, Tuomi, Tiinamaija, additional, van Dam, Rob M., additional, van Haeften, Timon W., additional, van Herpt, Thijs, additional, van Vliet-Ostaptchouk, Jana V., additional, Walters, G. Bragi, additional, Weedon, Michael N., additional, Wijmenga, Cisca, additional, Witteman, Jacqueline, additional, Bergman, Richard N., additional, Cauchi, Stephane, additional, Collins, Francis S., additional, Gloyn, Anna L., additional, Gyllensten, Ulf, additional, Hansen, Torben, additional, Hide, Winston A., additional, Hitman, Graham A., additional, Hofman, Albert, additional, Hunter, David J., additional, Hveem, Kristian, additional, Laakso, Markku, additional, Mohlke, Karen L., additional, Morris, Andrew D., additional, Palmer, Colin N.A., additional, Pramstaller, Peter P., additional, Rudan, Igor, additional, Sijbrands, Eric, additional, Stein, Lincoln D., additional, Tuomilehto, Jaakko, additional, Uitterlinden, Andre, additional, Walker, Mark, additional, Wareham, Nicholas J., additional, Watanabe, Richard M., additional, Abecasis, Goncalo R., additional, Boehm, Bernhard O., additional, Campbell, Harry, additional, Daly, Mark J., additional, Hattersley, Andrew T., additional, Hu, Frank B., additional, Meigs, James B., additional, Pankow, James S., additional, Pedersen, Oluf, additional, Wichmann, H.-Erich, additional, Barroso, Inês, additional, Florez, Jose C., additional, Frayling, Timothy M., additional, Sladek, Rob, additional, Thorsteinsdottir, Unnur, additional, Wilson, James F., additional, Froguel, Philippe, additional, van Duijn, Cornelia M., additional, Stefansson, Kari, additional, Altshuler, David, additional, Boehnke, Michael, additional, and McCarthy, Mark I., additional

Published
2014
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42. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Author

Morris, Andrew P., Voight, Benjamin F., Teslovich, Tanya M., Ferreira, Teresa, Segre, Ayellet V., Steinthorsdottir, Valgerdur, Strawbridge, Rona J., Khan, Hassan, Grallert, Harald, Mahajan, Anubha, Prokopenko, Inga, Kang, Hyun Min, Dina, Christian, Esko, Tonu, Fraser, Ross M., Kanoni, Stavroula, Kumar, Ashish, Lagou, Vasiliki, Langenberg, Claudia, Luan, Jian'an, Lindgren, Cecilia M., Mueller-Nurasyid, Martina, Pechlivanis, Sonali, Rayner, N. William, Scott, Laura J., Wiltshire, Steven, Yengo, Loic, Kinnunen, Leena, Rossin, Elizabeth J., Raychaudhuri, Soumya, Johnson, Andrew D., Dimas, Antigone S., Loos, Ruth J. F., Vedantam, Sailaja, Chen, Han, Florez, Jose C., Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Couper, David J., Kao, Wen Hong L., Li, Man, Cornelis, Marilyn C., Kraft, Peter, Sun, Qi, van Dam, Rob M., Stringham, Heather M., Chines, Peter S., Fischer, Krista, Fontanillas, Pierre, Holmen, Oddgeir L., Hunt, Sarah E., Jackson, Anne U., Kong, Augustine, Lawrence, Robert, Meyer, Julia, Perry, John R. B., Platou, Carl G. P., Potter, Simon, Rehnberg, Emil, Robertson, Neil, Sivapalaratnam, Suthesh, Stancakova, Alena, Stirrups, Kathleen, Thorleifsson, Gudmar, Tikkanen, Emmi, Wood, Andrew R., Almgren, Peter, Atalay, Mustafa, Benediktsson, Rafn, Bonnycastle, Lori L., Burtt, Noel, Carey, Jason, Charpentier, Guillaume, Crenshaw, Andrew T., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Emilsson, Valur, Eury, Elodie, Forsen, Tom, Gertow, Karl, Gigante, Bruna, Grant, George B., Groves, Christopher J., Guiducci, Candace, Herder, Christian, Hreidarsson, Astradur B., Hui, Jennie, James, Alan, Jonsson, Anna, Rathmann, Wolfgang, Klopp, Norman, Kravic, Jasmina, Krjutskov, Kaarel, Langford, Cordelia, Leander, Karin, Lindholm, Eero, Lobbens, Stephane, Mannisto, Satu, Mirza, Ghazala, Muehleisen, Thomas W., Musk, Bill, Parkin, Melissa, Rallidis, Loukianos, Saramies, Jouko, Sennblad, Bengt, Shah, Sonia, Sigurdsson, Gunnar, Silveira, Angela, Steinbach, Gerald, Thorand, Barbara, Trakalo, Joseph, Veglia, Fabrizio, Wennauer, Roman, Winckler, Wendy, Zabaneh, Delilah, Campbell, Harry, van Duijn, Cornelia, Uitterlinden, Andre G., Hofman, Albert, Sijbrands, Eric, Abecasis, Goncalo R., Owen, Katharine R., Zeggini, Eleftheria, Trip, Mieke D., Forouhi, Nita G., Syvänen, Ann-Christine, Eriksson, Johan G., Peltonen, Leena, Noethen, Markus M., Balkau, Beverley, Palmer, Colin N. A., Lyssenko, Valeriya, Tuomi, Tiinamaija, Isomaa, Bo, Hunter, David J., Qi, Lu, Shuldiner, Alan R., Roden, Michael, Barroso, Ines, Wilsgaard, Tom, Beilby, John, Hovingh, Kees, Price, Jackie F., Wilson, James F., Rauramaa, Rainer, Lakka, Timo A., Lind, Lars, Dedoussis, George, Njolstad, Inger, Pedersen, Nancy L., Khaw, Kay-Tee, Wareham, Nicholas J., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Korpi-Hyovalti, Eeva, Saltevo, Juha, Laakso, Markku, Kuusisto, Johanna, Metspalu, Andres, Collins, Francis S., Mohlke, Karen L., Bergman, Richard N., Tuomilehto, Jaakko, Boehm, Bernhard O., Gieger, Christian, Hveem, Kristian, Cauchi, Stephane, Froguel, Philippe, Baldassarre, Damiano, Tremoli, Elena, Humphries, Steve E., Saleheen, Danish, Danesh, John, Ingelsson, Erik, Ripatti, Samuli, Salomaa, Veikko, Erbel, Raimund, Joeckel, Karl-Heinz, Moebus, Susanne, Peters, Annette, Illig, Thomas, de Faire, Ulf, Hamsten, Anders, Morris, Andrew D., Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., Boerwinkle, Eric, Melander, Olle, Kathiresan, Sekar, Nilsson, Peter M., Deloukas, Panos, Thorsteinsdottir, Unnur, Groop, Leif C., Stefansson, Kari, Hu, Frank, Pankow, James S., Dupuis, Josee, Meigs, James B., Altshuler, David, Boehnke, Michael, McCarthy, Mark I., Morris, Andrew P., Voight, Benjamin F., Teslovich, Tanya M., Ferreira, Teresa, Segre, Ayellet V., Steinthorsdottir, Valgerdur, Strawbridge, Rona J., Khan, Hassan, Grallert, Harald, Mahajan, Anubha, Prokopenko, Inga, Kang, Hyun Min, Dina, Christian, Esko, Tonu, Fraser, Ross M., Kanoni, Stavroula, Kumar, Ashish, Lagou, Vasiliki, Langenberg, Claudia, Luan, Jian'an, Lindgren, Cecilia M., Mueller-Nurasyid, Martina, Pechlivanis, Sonali, Rayner, N. William, Scott, Laura J., Wiltshire, Steven, Yengo, Loic, Kinnunen, Leena, Rossin, Elizabeth J., Raychaudhuri, Soumya, Johnson, Andrew D., Dimas, Antigone S., Loos, Ruth J. F., Vedantam, Sailaja, Chen, Han, Florez, Jose C., Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Couper, David J., Kao, Wen Hong L., Li, Man, Cornelis, Marilyn C., Kraft, Peter, Sun, Qi, van Dam, Rob M., Stringham, Heather M., Chines, Peter S., Fischer, Krista, Fontanillas, Pierre, Holmen, Oddgeir L., Hunt, Sarah E., Jackson, Anne U., Kong, Augustine, Lawrence, Robert, Meyer, Julia, Perry, John R. B., Platou, Carl G. P., Potter, Simon, Rehnberg, Emil, Robertson, Neil, Sivapalaratnam, Suthesh, Stancakova, Alena, Stirrups, Kathleen, Thorleifsson, Gudmar, Tikkanen, Emmi, Wood, Andrew R., Almgren, Peter, Atalay, Mustafa, Benediktsson, Rafn, Bonnycastle, Lori L., Burtt, Noel, Carey, Jason, Charpentier, Guillaume, Crenshaw, Andrew T., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Emilsson, Valur, Eury, Elodie, Forsen, Tom, Gertow, Karl, Gigante, Bruna, Grant, George B., Groves, Christopher J., Guiducci, Candace, Herder, Christian, Hreidarsson, Astradur B., Hui, Jennie, James, Alan, Jonsson, Anna, Rathmann, Wolfgang, Klopp, Norman, Kravic, Jasmina, Krjutskov, Kaarel, Langford, Cordelia, Leander, Karin, Lindholm, Eero, Lobbens, Stephane, Mannisto, Satu, Mirza, Ghazala, Muehleisen, Thomas W., Musk, Bill, Parkin, Melissa, Rallidis, Loukianos, Saramies, Jouko, Sennblad, Bengt, Shah, Sonia, Sigurdsson, Gunnar, Silveira, Angela, Steinbach, Gerald, Thorand, Barbara, Trakalo, Joseph, Veglia, Fabrizio, Wennauer, Roman, Winckler, Wendy, Zabaneh, Delilah, Campbell, Harry, van Duijn, Cornelia, Uitterlinden, Andre G., Hofman, Albert, Sijbrands, Eric, Abecasis, Goncalo R., Owen, Katharine R., Zeggini, Eleftheria, Trip, Mieke D., Forouhi, Nita G., Syvänen, Ann-Christine, Eriksson, Johan G., Peltonen, Leena, Noethen, Markus M., Balkau, Beverley, Palmer, Colin N. A., Lyssenko, Valeriya, Tuomi, Tiinamaija, Isomaa, Bo, Hunter, David J., Qi, Lu, Shuldiner, Alan R., Roden, Michael, Barroso, Ines, Wilsgaard, Tom, Beilby, John, Hovingh, Kees, Price, Jackie F., Wilson, James F., Rauramaa, Rainer, Lakka, Timo A., Lind, Lars, Dedoussis, George, Njolstad, Inger, Pedersen, Nancy L., Khaw, Kay-Tee, Wareham, Nicholas J., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Korpi-Hyovalti, Eeva, Saltevo, Juha, Laakso, Markku, Kuusisto, Johanna, Metspalu, Andres, Collins, Francis S., Mohlke, Karen L., Bergman, Richard N., Tuomilehto, Jaakko, Boehm, Bernhard O., Gieger, Christian, Hveem, Kristian, Cauchi, Stephane, Froguel, Philippe, Baldassarre, Damiano, Tremoli, Elena, Humphries, Steve E., Saleheen, Danish, Danesh, John, Ingelsson, Erik, Ripatti, Samuli, Salomaa, Veikko, Erbel, Raimund, Joeckel, Karl-Heinz, Moebus, Susanne, Peters, Annette, Illig, Thomas, de Faire, Ulf, Hamsten, Anders, Morris, Andrew D., Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., Boerwinkle, Eric, Melander, Olle, Kathiresan, Sekar, Nilsson, Peter M., Deloukas, Panos, Thorsteinsdottir, Unnur, Groop, Leif C., Stefansson, Kari, Hu, Frank, Pankow, James S., Dupuis, Josee, Meigs, James B., Altshuler, David, Boehnke, Michael, and McCarthy, Mark I.

Abstract

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genomewide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

Published
2012
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43. The Interplay of Variants Near LEKR and CCNL1 and Social Stress in Relation to Birth Size

Author

Khan, Anokhi Ali, Rodriguez, Alina, Sebert, Sylvain, Kaakinen, Marika, Cauchi, Stephane, Froguel, Philippe, Hartikainen, Anna-Liisa, Pouta, Anneli, Jarvelin, Marjo-Riitta, Khan, Anokhi Ali, Rodriguez, Alina, Sebert, Sylvain, Kaakinen, Marika, Cauchi, Stephane, Froguel, Philippe, Hartikainen, Anna-Liisa, Pouta, Anneli, and Jarvelin, Marjo-Riitta

Abstract

Background: We previously identified via a genome wide association study variants near LEKR and CCNL1 and in the ADCY5 genes lead to lower birthweight. Here, we study the impact of these variants and social stress during pregnancy, defined as social adversity and neighborhood disparity, on infant birth size. We aimed to determine whether the addition of genetic variance magnified the observed associations. Methodology/Principal Findings: We analyzed data from the Northern Finland Birth Cohort 1986 (n = 5369). Social adversity was defined by young maternal age (<20 years), low maternal education (<11 years), and/or single marital status. Neighborhood social disparity was assessed by discrepancy between neighborhoods relative to personal socio-economic status. These variables are indicative of social and socioeconomic stress, but also of biological risk. The adjusted multiple regression analysis showed smaller birth size in both infants of mothers who experienced social adversity (birthweight by -40.4 g, 95% CI -61.4, -19.5; birth length -0.14 cm, 95% CI -0.23, -0.05; head circumference -0.09 cm 95% CI -0.15, -0.02) and neighborhood disparity (birthweight -28.8 g, 95% CI -47.7, -10.0; birth length -0.12 cm, 95% CI -0.20, -0.05). The birthweight-lowering risk allele (SNP rs900400 near LEKR and CCNL1) magnified this association in an additive manner. However, likely due to sample size restriction, this association was not significant for the SNP rs9883204 in ADCY5. Birth size difference due to social stress was greater in the presence of birthweight-lowering alleles. Conclusions/Significance: Social adversity, neighborhood disparity, and genetic variants have independent associations with infant birth size in the mutually adjusted analyses. If the newborn carried a risk allele rs900400 near LEKR/CCNL1, the impact of stress on birth size was stronger. These observations give support to the hypothesis that individuals with genetic or other biological risk are more v

Published
2012
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44. Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

Author

Perry, John R. B., Voight, Benjamin F., Yengo, Loic, Amin, Najaf, Dupuis, Josee, Ganser, Martha, Grallert, Harald, Navarro, Pau, Li, Man, Qi, Lu, Steinthorsdottir, Valgerdur, Scott, Robert A., Almgren, Peter, Arking, Dan E., Aulchenko, Yurii, Balkau, Beverley, Benediktsson, Rafn, Bergman, Richard N., Boerwinkle, Eric, Bonnycastle, Lori, Burtt, Noel P., Campbell, Harry, Charpentier, Guillaume, Collins, Francis S., Gieger, Christian, Green, Todd, Hadjadj, Samy, Hattersley, Andrew T., Herder, Christian, Hofman, Albert, Johnson, Andrew D., Kottgen, Anna, Kraft, Peter, Labrune, Yann, Langenberg, Claudia, Manning, Alisa K., Mohlke, Karen L., Morris, Andrew P., Oostra, Ben, Pankow, James, Petersen, Ann-Kristin, Pramstaller, Peter P., Prokopenko, Inga, Rathmann, Wolfgang, Rayner, William, Roden, Michael, Rudan, Igor, Rybin, Denis, Scott, Laura J., Sigurdsson, Gunnar, Sladek, Rob, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vivequin, Sidonie, Weedon, Michael N., Wright, Alan F., Hu, Frank B., Illig, Thomas, Kao, Linda, Meigs, James B., Wilson, James F., Stefansson, Kari, van Duijn, Cornelia, Altschuler, David, Morris, Andrew D., Boehnke, Michael, McCarthy, Mark I., Froguel, Philippe, Palmer, Colin N. A., Wareham, Nicholas J., Groop, Leif, Frayling, Timothy M., Cauchi, Stephane, Perry, John R. B., Voight, Benjamin F., Yengo, Loic, Amin, Najaf, Dupuis, Josee, Ganser, Martha, Grallert, Harald, Navarro, Pau, Li, Man, Qi, Lu, Steinthorsdottir, Valgerdur, Scott, Robert A., Almgren, Peter, Arking, Dan E., Aulchenko, Yurii, Balkau, Beverley, Benediktsson, Rafn, Bergman, Richard N., Boerwinkle, Eric, Bonnycastle, Lori, Burtt, Noel P., Campbell, Harry, Charpentier, Guillaume, Collins, Francis S., Gieger, Christian, Green, Todd, Hadjadj, Samy, Hattersley, Andrew T., Herder, Christian, Hofman, Albert, Johnson, Andrew D., Kottgen, Anna, Kraft, Peter, Labrune, Yann, Langenberg, Claudia, Manning, Alisa K., Mohlke, Karen L., Morris, Andrew P., Oostra, Ben, Pankow, James, Petersen, Ann-Kristin, Pramstaller, Peter P., Prokopenko, Inga, Rathmann, Wolfgang, Rayner, William, Roden, Michael, Rudan, Igor, Rybin, Denis, Scott, Laura J., Sigurdsson, Gunnar, Sladek, Rob, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vivequin, Sidonie, Weedon, Michael N., Wright, Alan F., Hu, Frank B., Illig, Thomas, Kao, Linda, Meigs, James B., Wilson, James F., Stefansson, Kari, van Duijn, Cornelia, Altschuler, David, Morris, Andrew D., Boehnke, Michael, McCarthy, Mark I., Froguel, Philippe, Palmer, Colin N. A., Wareham, Nicholas J., Groop, Leif, Frayling, Timothy M., and Cauchi, Stephane

Abstract

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4610 29, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3 x 10(-8), OR= 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2 x 10(-14). This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2 x 10(-16). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger g

Published
2012

45. Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children

Author

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

Abstract

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

Published
2011

46. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Author

Voight, Benjamin F., Scott, Laura J., Steinthorsdottir, Valgerdur, Morris, Andrew P., Dina, Christian, Welch, Ryan P., Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S., Thorleifsson, Gudmar, McCulloch, Laura J., Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J., Raychaudhuri, Soumya, McCarroll, Steve A., Langenberg, Claudia, Hofmann, Oliver M., Dupuis, Josee, Qi, Lu, Segre, Ayellet V., van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J., Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L., Bostrom, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noisel P., Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn, Couper, David J., Crawford, Gabe, Doney, Alex S. F., Elliott, Katherine S., Elliott, Amanda L., Erdos, Michael R., Fox, Caroline S., Franklin, Christopher S., Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J., Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U., Johnson, Paul R. V., Jorgensen, Torben, Kao, Wen H. L., Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M., Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A., Narisu, Narisu, Nilsson, Peter, Owen, Katharine R., Payne, Felicity, Perry, John R. B., Petersen, Ann-Kristin, Platou, Carl, Proenca, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N. William, Robertson, Neil R., Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J., Saxena, Richa, Shields, Beverley M., Shrader, Peter, Sigurdsson, Gunnar, Sparso, Thomas, Strassburger, Klaus, Stringham, Heather M., Sun, Qi, Swift, Amy J., Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, van Dam, Rob M., van Haeften, Timon W., van Herpt, Thijs, van Vliet-Ostaptchouk, Jana V., Walters, G. Bragi, Weedon, Michael N., Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N., Cauchi, Stephane, Collins, Francis S., Gloyn, Anna L., Gyllensten, Ulf, Hansen, Torben, Hide, Winston A., Hitman, Graham A., Hofman, Albert, Hunter, David J., Hveem, Kristian, Laakso, Markku, Mohlke, Karen L., Morris, Andrew D., Palmer, Colin N. A., Pramstaller, Peter P., Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D., Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J., Watanabe, Richard M., Abecasis, Goncalo R., Boehm, Bernhard O., Campbell, Harry, Daly, Mark J., Hattersley, Andrew T., Hu, Frank B., Meigs, James B., Pankow, James S., Pedersen, Oluf, Wichmann, H-Erich, Barroso, Ines, Florez, Jose C., Frayling, Timothy M., Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F., Illig, Thomas, Froguel, Philippe, van Duijn, Cornelia M., Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I., Voight, Benjamin F., Scott, Laura J., Steinthorsdottir, Valgerdur, Morris, Andrew P., Dina, Christian, Welch, Ryan P., Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S., Thorleifsson, Gudmar, McCulloch, Laura J., Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J., Raychaudhuri, Soumya, McCarroll, Steve A., Langenberg, Claudia, Hofmann, Oliver M., Dupuis, Josee, Qi, Lu, Segre, Ayellet V., van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J., Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L., Bostrom, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noisel P., Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn, Couper, David J., Crawford, Gabe, Doney, Alex S. F., Elliott, Katherine S., Elliott, Amanda L., Erdos, Michael R., Fox, Caroline S., Franklin, Christopher S., Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J., Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U., Johnson, Paul R. V., Jorgensen, Torben, Kao, Wen H. L., Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M., Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A., Narisu, Narisu, Nilsson, Peter, Owen, Katharine R., Payne, Felicity, Perry, John R. B., Petersen, Ann-Kristin, Platou, Carl, Proenca, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N. William, Robertson, Neil R., Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J., Saxena, Richa, Shields, Beverley M., Shrader, Peter, Sigurdsson, Gunnar, Sparso, Thomas, Strassburger, Klaus, Stringham, Heather M., Sun, Qi, Swift, Amy J., Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, van Dam, Rob M., van Haeften, Timon W., van Herpt, Thijs, van Vliet-Ostaptchouk, Jana V., Walters, G. Bragi, Weedon, Michael N., Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N., Cauchi, Stephane, Collins, Francis S., Gloyn, Anna L., Gyllensten, Ulf, Hansen, Torben, Hide, Winston A., Hitman, Graham A., Hofman, Albert, Hunter, David J., Hveem, Kristian, Laakso, Markku, Mohlke, Karen L., Morris, Andrew D., Palmer, Colin N. A., Pramstaller, Peter P., Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D., Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J., Watanabe, Richard M., Abecasis, Goncalo R., Boehm, Bernhard O., Campbell, Harry, Daly, Mark J., Hattersley, Andrew T., Hu, Frank B., Meigs, James B., Pankow, James S., Pedersen, Oluf, Wichmann, H-Erich, Barroso, Ines, Florez, Jose C., Frayling, Timothy M., Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F., Illig, Thomas, Froguel, Philippe, van Duijn, Cornelia M., Stefansson, Kari, Altshuler, David, Boehnke, Michael, and McCarthy, Mark I.

Abstract

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

Published
2010
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47. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B

Author

Yamauchi, Toshimasa, Hara, Kazuo, Maeda, Shiro, Yasuda, Kazuki, Takahashi, Atsushi, Horikoshi, Momoko, Nakamura, Masahiro, Fujita, Hayato, Grarup, Niels, Cauchi, Stephane, Ng, Daniel P K, Ma, Ronald C W, Tsunoda, Tatsuhiko, Kubo, Michiaki, Watada, Hirotaka, Maegawa, Hiroshi, Okada-Iwabu, Miki, Iwabu, Masato, Shojima, Nobuhiro, Shin, Hyoung Doo, Andersen, Gitte, Witte, Daniel R, Jørgensen, Torben, Lauritzen, Torsten, Sandbæk, Annelli, Hansen, Torben, Ohshige, Toshihiko, Omori, Shintaro, Saito, Ikuo, Kaku, Kohei, Hirose, Hiroshi, So, Wing-Yee, Beury, Delphine, Chan, Juliana C N, Park, Kyong Soo, Tai, E Shyong, Ito, Chikako, Tanaka, Yasushi, Kashiwagi, Atsunori, Kawamori, Ryuzo, Kasuga, Masato, Froguel, Philippe, Pedersen, Oluf, Kamatani, Naoyuki, Nakamura, Yusuke, Kadowaki, Takashi, Yamauchi, Toshimasa, Hara, Kazuo, Maeda, Shiro, Yasuda, Kazuki, Takahashi, Atsushi, Horikoshi, Momoko, Nakamura, Masahiro, Fujita, Hayato, Grarup, Niels, Cauchi, Stephane, Ng, Daniel P K, Ma, Ronald C W, Tsunoda, Tatsuhiko, Kubo, Michiaki, Watada, Hirotaka, Maegawa, Hiroshi, Okada-Iwabu, Miki, Iwabu, Masato, Shojima, Nobuhiro, Shin, Hyoung Doo, Andersen, Gitte, Witte, Daniel R, Jørgensen, Torben, Lauritzen, Torsten, Sandbæk, Annelli, Hansen, Torben, Ohshige, Toshihiko, Omori, Shintaro, Saito, Ikuo, Kaku, Kohei, Hirose, Hiroshi, So, Wing-Yee, Beury, Delphine, Chan, Juliana C N, Park, Kyong Soo, Tai, E Shyong, Ito, Chikako, Tanaka, Yasushi, Kashiwagi, Atsunori, Kawamori, Ryuzo, Kasuga, Masato, Froguel, Philippe, Pedersen, Oluf, Kamatani, Naoyuki, Nakamura, Yusuke, and Kadowaki, Takashi

Abstract

We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 × 10¿¿; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 × 10¿¿). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10¿¹4, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.

Published
2010

49. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B

Author

Yamauchi, Toshimasa, primary, Hara, Kazuo, additional, Maeda, Shiro, additional, Yasuda, Kazuki, additional, Takahashi, Atsushi, additional, Horikoshi, Momoko, additional, Nakamura, Masahiro, additional, Fujita, Hayato, additional, Grarup, Niels, additional, Cauchi, Stephane, additional, Ng, Daniel P K, additional, Ma, Ronald C W, additional, Tsunoda, Tatsuhiko, additional, Kubo, Michiaki, additional, Watada, Hirotaka, additional, Maegawa, Hiroshi, additional, Okada-Iwabu, Miki, additional, Iwabu, Masato, additional, Shojima, Nobuhiro, additional, Shin, Hyoung Doo, additional, Andersen, Gitte, additional, Witte, Daniel R, additional, Jørgensen, Torben, additional, Lauritzen, Torsten, additional, Sandbæk, Annelli, additional, Hansen, Torben, additional, Ohshige, Toshihiko, additional, Omori, Shintaro, additional, Saito, Ikuo, additional, Kaku, Kohei, additional, Hirose, Hiroshi, additional, So, Wing-Yee, additional, Beury, Delphine, additional, Chan, Juliana C N, additional, Park, Kyong Soo, additional, Tai, E Shyong, additional, Ito, Chikako, additional, Tanaka, Yasushi, additional, Kashiwagi, Atsunori, additional, Kawamori, Ryuzo, additional, Kasuga, Masato, additional, Froguel, Philippe, additional, Pedersen, Oluf, additional, Kamatani, Naoyuki, additional, Nakamura, Yusuke, additional, and Kadowaki, Takashi, additional

Published
2010
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