18 results on '"Crenshaw, Andrew T"'
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2. Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection
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Ferar, Kathleen, Hall, Taryn O., Crawford, Dana C., Rowley, Robb, Satterfield, Benjamin A., Li, Rongling, Gragert, Loren, Karlson, Elizabeth W., de Andrade, Mariza, Kullo, Iftikhar J., McCarty, Catherine A., Kho, Abel, Hayes, M. Geoffrey, Ritchie, Marylyn D., Crane, Paul K., Mirel, Daniel B., Carlson, Christopher, Connolly, John J., Hakonarson, Hakon, Crenshaw, Andrew T., Carrell, David, Luo, Yuan, Dikilitas, Ozan, Denny, Joshua C., Jarvik, Gail P., and Crosslin, David R.
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- 2023
- Full Text
- View/download PDF
3. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
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Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, 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, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blüher, Matthias, Boeing, Heiner, Bonnycastle, Lori L, Bottinger, Erwin P, Burtt, Noël P, Carey, Jason, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Doney, Alex SF, Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G, Esko, Tonu, Eury, Elodie, Fadista, João, 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, Jørgensen, Marit E, Jørgensen, Torben, Kao, Wen-Hong L, Kerrison, Nicola D, Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, and Langford, Cordelia
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Biological Sciences ,Genetics ,Liver Disease ,Diabetes ,Human Genome ,Digestive Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Binding Sites ,Case-Control Studies ,Chromatin Immunoprecipitation ,Chromosome Mapping ,Diabetes Mellitus ,Type 2 ,Gene Expression Regulation ,Genetic Loci ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genomics ,Hepatocyte Nuclear Factor 3-beta ,Humans ,Islets of Langerhans ,Liver ,Molecular Sequence Annotation ,Polymorphism ,Single Nucleotide ,Receptor ,Melatonin ,MT2 ,DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - 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.
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- 2015
4. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility
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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
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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.
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- 2014
5. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
- Author
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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
6. Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico
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Williams, Amy L, Jacobs, Suzanne BR, Moreno-Macías, Hortensia, Huerta-Chagoya, Alicia, Churchhouse, Claire, Márquez-Luna, Carla, García-Ortíz, Humberto, José Gómez-Vázquez, María, Burtt, Noël P, Aguilar-Salinas, Carlos A, González-Villalpando, Clicerio, Florez, Jose C, Orozco, Lorena, Haiman, Christopher A, Tusié-Luna, Teresa, Altshuler, David, Ripke, Stephan, Manning, Alisa K, Neale, Benjamin, Reich, David, Stram, Daniel O, Fernández-López, Juan Carlos, Romero-Hidalgo, Sandra, Patterson, Nick, Aguilar-Delfín, Irma, Martínez-Hernández, Angélica, Centeno-Cruz, Federico, Mendoza-Caamal, Elvia, Revilla-Monsalve, Cristina, Islas-Andrade, Sergio, Córdova, Emilio, Rodríguez-Arellano, Eunice, Soberón, Xavier, González-Villalpando, María Elena, Henderson, Brian E, Monroe, Kristine, Wilkens, Lynne, Kolonel, Laurence N, Le Marchand, Loic, Riba, Laura, Ordóñez-Sánchez, María Luisa, Rodríguez-Guillén, Rosario, Cruz-Bautista, Ivette, Rodríguez-Torres, Maribel, Muñoz-Hernández, Linda Liliana, Sáenz, Tamara, Gómez, Donají, Alvirde, Ulices, Onofrio, Robert C, Brodeur, Wendy M, Gage, Diane, Murphy, Jacquelyn, Franklin, Jennifer, Mahan, Scott, Ardlie, Kristin, Crenshaw, Andrew T, Winckler, Wendy, Prüfer, Kay, Shunkov, Michael V, Sawyer, Susanna, Stenzel, Udo, Kelso, Janet, Lek, Monkol, Sankararaman, Sriram, MacArthur, Daniel G, Derevianko, Anatoli P, Pääbo, Svante, Gopal, Shuba, Grammatikos, James A, Smith, Ian C, Bullock, Kevin H, Deik, Amy A, Souza, Amanda L, Pierce, Kerry A, Clish, Clary B, Fennell, Timothy, and Farjoun, Yossi
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Nutrition ,Diabetes ,Prevention ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Alleles ,Animals ,Asian People ,Black People ,Cohort Studies ,Diabetes Mellitus ,Type 2 ,Endoplasmic Reticulum ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Haplotypes ,HeLa Cells ,Humans ,Indians ,North American ,Lipid Metabolism ,Liver ,Male ,Mexico ,Monocarboxylic Acid Transporters ,Neanderthals ,Polymorphism ,Single Nucleotide ,RNA ,Messenger ,Triglycerides ,White People ,SIGMA Type 2 Diabetes Consortium ,Hela Cells ,General Science & Technology - Abstract
Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.
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- 2014
7. Supplementary Table 1 from Evaluating Genetic Risk for Prostate Cancer among Japanese and Latinos
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Cheng, Iona, primary, Chen, Gary K., primary, Nakagawa, Hidewaki, primary, He, Jing, primary, Wan, Peggy, primary, Laurie, Cathy C., primary, Shen, Jess, primary, Sheng, Xin, primary, Pooler, Loreall C., primary, Crenshaw, Andrew T., primary, Mirel, Daniel B., primary, Takahashi, Atsushi, primary, Kubo, Michiaki, primary, Nakamura, Yusuke, primary, Al Olama, Ali Amin, primary, Benlloch, Sara, primary, Donovan, Jenny L., primary, Guy, Michelle, primary, Hamdy, Freddie C., primary, Kote-Jarai, Zsofia, primary, Neal, David E., primary, Wilkens, Lynne R., primary, Monroe, Kristine R., primary, Stram, Daniel O., primary, Muir, Kenneth, primary, Eeles, Rosalind A., primary, Easton, Douglas F., primary, Kolonel, Laurence N., primary, Henderson, Brian E., primary, Le Marchand, Loïc, primary, and Haiman, Christopher A., primary
- Published
- 2023
- Full Text
- View/download PDF
8. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
- Author
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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
- Full Text
- View/download PDF
9. Variants in Interferon-α Pathway Genes and Response to Pegylated-Interferon-α2a plus Ribavirin for Treatment of Chronic HCV Infection in the HALT-C Trial
- Author
-
Welzel, Tania Mara, Morgan, Timothy R., Bonkovsky, Herbert L., Naishadham, Deepa, Pfeiffer, Ruth M., Wright, Elizabeth C., Hutchinson, Amy A., Crenshaw, Andrew T., Bashirova, Arman, Carrington, Mary, Dotrang, Myhanh, Sterling, Richard K., Lindsay, Karen L., Fontana, Robert J., Lee, William M., Di Bisceglie, Adrian M., Ghany, Marc G., Gretch, David R., Chanock, Stephen J., Chung, Raymond T., and O’Brien, Thomas R.
- Subjects
virus diseases ,Article - Abstract
Combination treatment with pegylated-interferon-α and ribavirin, the current recommended therapy for chronic hepatitis C virus (HCV) infection, results in a sustained virological response (SVR) in only about half of patients. Because genes involved in the interferon-α pathway may affect anti-viral responses, we analyzed the relationship between variants in these genes and SVR among participants in the HALT-C trial. Patients had advanced chronic hepatitis C and had previously failed to respond to interferon-based treatment. Participants were treated with peginterferon-α2a and ribavirin during the trial. Subjects with undetectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered non-responders. We used TaqMan assays to genotype 56 polymorphisms found in 13 genes in the interferon-α pathway. This analysis compares genotypes for participants with an SVR to non-responders. The primary analysis was restricted to European American participants because a priori statistical power was low among the small number (n=131) of African American patients. We used logistic regression to control the effect of other variables that are associated with treatment response. Among 581 European American patients, SVR was associated with IFNAR1 IVS1-22G (adjusted odds ratio [aOR], 0.57; p=0.02); IFNAR2 Ex2-33C (aOR, 2.09; p=0.02); JAK1 IVS22+112T (aOR, 1.66; p=0.04); and ADAR Ex9+14A (aOR, 1.67; p=0.03). For the TYK2 -2256A promoter region variant a borderline association was present among European American participants (OR, 1.51; p=0.05) and a strong relationship among African American patients; all 10 with SVR who were genotyped for TYK2-2256 carried the A variant compared to 68/120 (57%) non-responders (p=0.006). In conclusion, genetic polymorphisms in the interferon-α pathway may affect responses to antiviral therapy of chronic hepatitis C.
- Published
- 2009
10. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes
- Author
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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
- Full Text
- View/download PDF
11. Variants in interferon-alpha pathway genes and response to pegylated interferon-Alpha2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis C antiviral long-term treatment against cirrhosis trial
- Author
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Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, Division of Gastroenterology, University of California - Irvine, Irvine, CA, and Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, CA, Departments of Medicine and The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Farmington, CT, and Carolinas Medical Center, Charlotte, NC, New England Research Institutes, Watertown, MA, Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, Core Genotyping Facility, NCI/Division of Cancer Epidemiology and Genetics, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, Department of Medicine, Johns Hopkins University, Baltimore, MD, Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick Inc., NCI-Frederick Inc., Frederick, MD, Computer Sciences Corp., Rockville, MD, Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, Virology Division, Department of Laboratory Medicine, University of Washington, Seattle, WA, Gastrointestinal Unit, Medical Services, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School, Boston, MA, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD ; fax: 301-480-1917. ; 6120 Executive Boulevard, Room 6111, MSC 7246, Rockville, MD 20892, Welzel, Tania Mara, Morgan, Timothy R., Bonkovsky, Herbert L., Naishadham, Deepa, Pfeiffer, Ruth M., Wright, Elizabeth C., Hutchinson, Amy A., Crenshaw, Andrew T., Bashirova, Arman, Carrington, Mary, Dotrang, Myhanh, Sterling, Richard K., Lindsay, Karen L., Fontana, Robert J., Lee, William M., Di Bisceglie, Adrian M., Ghany, Marc G., Gretch, David R., Chanock, Stephen J., Chung, Raymond T., O'Brien, Thomas R., Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, Division of Gastroenterology, University of California - Irvine, Irvine, CA, and Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, CA, Departments of Medicine and The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Farmington, CT, and Carolinas Medical Center, Charlotte, NC, New England Research Institutes, Watertown, MA, Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, Core Genotyping Facility, NCI/Division of Cancer Epidemiology and Genetics, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, Department of Medicine, Johns Hopkins University, Baltimore, MD, Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick Inc., NCI-Frederick Inc., Frederick, MD, Computer Sciences Corp., Rockville, MD, Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, Virology Division, Department of Laboratory Medicine, University of Washington, Seattle, WA, Gastrointestinal Unit, Medical Services, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School, Boston, MA, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD ; fax: 301-480-1917. ; 6120 Executive Boulevard, Room 6111, MSC 7246, Rockville, MD 20892, Welzel, Tania Mara, Morgan, Timothy R., Bonkovsky, Herbert L., Naishadham, Deepa, Pfeiffer, Ruth M., Wright, Elizabeth C., Hutchinson, Amy A., Crenshaw, Andrew T., Bashirova, Arman, Carrington, Mary, Dotrang, Myhanh, Sterling, Richard K., Lindsay, Karen L., Fontana, Robert J., Lee, William M., Di Bisceglie, Adrian M., Ghany, Marc G., Gretch, David R., Chanock, Stephen J., Chung, Raymond T., and O'Brien, Thomas R.
- Abstract
Combination treatment with pegylated-interferon-alpha (PEG IFN-??) and ribavirin, the current recommended therapy for chronic hepatitis C virus (HCV) infection, results in a sustained virological response (SVR) in only about half of patients. Because genes involved in the interferon-alpha pathway may affect antiviral responses, we analyzed the relationship between variants in these genes and SVR among participants in the Hepatitis C Antiviral Long-Term treatment Against Cirrhosis (HALT-C) trial. Patients had advanced chronic hepatitis C that had previously failed to respond to interferon-based treatment. Participants were treated with peginterferon-??2a and ribavirin during the trial. Subjects with undetectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered nonresponders. We used TaqMan assays to genotype 56 polymorphisms found in 13 genes in the interferon-alpha pathway. This analysis compares genotypes for participants with an SVR to nonresponders. The primary analysis was restricted to European American participants because a priori statistical power was low among the small number (n = 131) of African American patients. We used logistic regression to control the effect of other variables that are associated with treatment response. Among 581 European American patients, SVR was associated with IFNAR1 IVS1-22G (adjusted odds ratio, 0.57; P = 0.02); IFNAR2 Ex2-33C (adjusted odds ratio, 2.09; P = 0.02); JAK1 IVS22+112T (adjusted odds ratio, 1.66; P = 0.04); and ADAR Ex9+14A (adjusted odds ratio, 1.67; P = 0.03). For the TYK2 -2256A promoter region variant, a borderline association was present among European American participants (OR, 1.51; P = 0.05) and a strong relationship among African American patients; all 10 with SVR who were genotyped for TYK2 -2256 carried the A variant compared with 68 of 120 (57%) nonresponders ( P = 0.006). Conclusion: Genetic polymorphisms in the interferon-?? pathway may
- Published
- 2009
12. Evaluating Genetic Risk for Prostate Cancer among Japanese and Latinos
- Author
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Cheng, Iona, primary, Chen, Gary K., additional, Nakagawa, Hidewaki, additional, He, Jing, additional, Wan, Peggy, additional, Laurie, Cathy C., additional, Shen, Jess, additional, Sheng, Xin, additional, Pooler, Loreall C., additional, Crenshaw, Andrew T., additional, Mirel, Daniel B., additional, Takahashi, Atsushi, additional, Kubo, Michiaki, additional, Nakamura, Yusuke, additional, Al Olama, Ali Amin, additional, Benlloch, Sara, additional, Donovan, Jenny L., additional, Guy, Michelle, additional, Hamdy, Freddie C., additional, Kote-Jarai, Zsofia, additional, Neal, David E., additional, Wilkens, Lynne R., additional, Monroe, Kristine R., additional, Stram, Daniel O., additional, Muir, Kenneth, additional, Eeles, Rosalind A., additional, Easton, Douglas F., additional, Kolonel, Laurence N., additional, Henderson, Brian E., additional, Le Marchand, Loïc, additional, and Haiman, Christopher A., additional
- Published
- 2012
- Full Text
- View/download PDF
13. Pitfalls of merging GWAS data: lessons learned in the eMERGE network and quality control procedures to maintain high data quality
- Author
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Zuvich, Rebecca L., primary, Armstrong, Loren L., additional, Bielinski, Suzette J., additional, Bradford, Yuki, additional, Carlson, Christopher S., additional, Crawford, Dana C., additional, Crenshaw, Andrew T., additional, de Andrade, Mariza, additional, Doheny, Kimberly F., additional, Haines, Jonathan L., additional, Hayes, M. Geoffrey, additional, Jarvik, Gail P., additional, Jiang, Lan, additional, Kullo, Iftikhar J., additional, Li, Rongling, additional, Ling, Hua, additional, Manolio, Teri A., additional, Matsumoto, Martha E., additional, McCarty, Catherine A., additional, McDavid, Andrew N., additional, Mirel, Daniel B., additional, Olson, Lana M., additional, Paschall, Justin E., additional, Pugh, Elizabeth W., additional, Rasmussen, Luke V., additional, Rasmussen-Torvik, Laura J., additional, Turner, Stephen D., additional, Wilke, Russell A., additional, and Ritchie, Marylyn D., additional
- Published
- 2011
- Full Text
- View/download PDF
14. Quality Control Procedures for Genome‐Wide Association Studies
- Author
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Turner, Stephen, primary, Armstrong, Loren L., additional, Bradford, Yuki, additional, Carlson, Christopher S., additional, Crawford, Dana C., additional, Crenshaw, Andrew T., additional, de Andrade, Mariza, additional, Doheny, Kimberly F., additional, Haines, Jonathan L., additional, Hayes, Geoffrey, additional, Jarvik, Gail, additional, Jiang, Lan, additional, Kullo, Iftikhar J., additional, Li, Rongling, additional, Ling, Hua, additional, Manolio, Teri A., additional, Matsumoto, Martha, additional, McCarty, Catherine A., additional, McDavid, Andrew N., additional, Mirel, Daniel B., additional, Paschall, Justin E., additional, Pugh, Elizabeth W., additional, Rasmussen, Luke V., additional, Wilke, Russell A., additional, Zuvich, Rebecca L., additional, and Ritchie, Marylyn D., additional
- Published
- 2011
- Full Text
- View/download PDF
15. Variants in interferon-alpha pathway genes and response to pegylated interferon-Alpha2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis C antiviral long-term treatment against cirrhosis trial.
- Author
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Welzel, Tania Mara, Morgan, Timothy R., Bonkovsky, Herbert L., Naishadham, Deepa, Pfeiffer, Ruth M., Wright, Elizabeth C., Hutchinson, Amy A., Crenshaw, Andrew T., Bashirova, Arman, Carrington, Mary, Dotrang, Myhanh, Sterling, Richard K., Lindsay, Karen L., Fontana, Robert J., Lee, William M., Di Bisceglie, Adrian M., Ghany, Marc G., Gretch, David R., Chanock, Stephen J., and Chung, Raymond T.
- Published
- 2009
- Full Text
- View/download PDF
16. Genome-wide association study of Tourette Syndrome
- Author
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Scharf, Jeremiah M., Yu, Dongmei, Mathews, Carol A., Neale, Benjamin M., Stewart, S. Evelyn, Fagerness, Jesen A, Evans, Patrick, Gamazon, Eric, Edlund, Christopher K., Service, Susan, Tikhomirov, Anna, Osiecki, Lisa, Illmann, Cornelia, Pluzhnikov, Anna, Konkashbaev, Anuar, Davis, Lea K, Han, Buhm, Crane, Jacquelyn, Moorjani, Priya, Crenshaw, Andrew T., Parkin, Melissa A., Reus, Victor I., Lowe, Thomas L., Rangel-Lugo, Martha, Chouinard, Sylvain, Dion, Yves, Girard, Simon, Cath, Danielle C, Smit, Jan H, King, Robert A., Fernandez, Thomas, Leckman, James F., Kidd, Kenneth K., Kidd, Judith R., Pakstis, Andrew J., State, Matthew, Herrera, Luis Diego, Romero, Roxana, Fournier, Eduardo, Sandor, Paul, Barr, Cathy L, Phan, Nam, Gross-Tsur, Varda, Benarroch, Fortu, Pollak, Yehuda, Budman, Cathy L., Bruun, Ruth D., Erenberg, Gerald, Naarden, Allan L, Lee, Paul C, Weiss, Nicholas, Kremeyer, Barbara, Berrío, Gabriel Bedoya, Campbell, Desmond, Silgado, Julio C. Cardona, Ochoa, William Cornejo, Restrepo, Sandra C. Mesa, Muller, Heike, Duarte, Ana V. Valencia, Lyon, Gholson J, Leppert, Mark, Morgan, Jubel, Weiss, Robert, Grados, Marco A., Anderson, Kelley, Davarya, Sarah, Singer, Harvey, Walkup, John, Jankovic, Joseph, Tischfield, Jay A., Heiman, Gary A., Gilbert, Donald L., Hoekstra, Pieter J., Robertson, Mary M., Kurlan, Roger, Liu, Chunyu, Gibbs, J. Raphael, Singleton, Andrew, Hardy, John, Strengman, Eric, Ophoff, Roel, Wagner, Michael, Moessner, Rainald, Mirel, Daniel B., Posthuma, Danielle, Sabatti, Chiara, Eskin, Eleazar, Conti, David V., Knowles, James A., Ruiz-Linares, Andres, Rouleau, Guy A., Purcell, Shaun, Heutink, Peter, Oostra, Ben A., McMahon, William, Freimer, Nelson, Cox, Nancy J., and Pauls, David L.
- Subjects
Tourette Syndrome ,tics ,genetics ,GWAS ,neurodevelopmental disorder - Abstract
Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.
- Published
- 2012
- Full Text
- View/download PDF
17. Large-Scale Association Analysis Provides Insights into the Genetic Architecture and Pathophysiology of Type 2 Diabetes
- Author
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Morris, Andrew P, Voight, Benjamin F, Teslovich, Tanya M, Ferreira, Teresa, Segré, 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, Müller-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 Carlos, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Couper, David J, Kao, Wen Hong L, Li, Man, Cornelis, Marilyn, Kraft, Peter Elias, 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, Stančáková, Alena, Stirrups, Kathleen, Thorleifsson, Gudmar, Tikkanen, Emmi, Wood, Andrew R, Almgren, Peter, Atalay, Mustafa, Benediktsson, Rafn, Bonnycastle, Lori L, Burtt, Noël, 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, Krjutškov, Kaarel, Langford, Cordelia, Leander, Karin, Lindholm, Eero, Lobbens, Stéphane, Männistö, Satu, Mirza, Ghazala, Mühleisen, Thomas W, Musk, Bill, Parkin, Melissa Ann, Rallidis, Loukianos, Saramies, Jouko, Sennblad, Bengt, Shah, Sonia, Sigurðsson, 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, Nöthen, 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, Njølstad, Inger, Pedersen, Nancy L, Khaw, Kay-Tee, Wareham, Nicholas J, Keinanen-Kiukaanniemi, Sirkka M, Saaristo, Timo E, Korpi-Hyövälti, 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, Jöckel, 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 B., Pankow, James S, Dupuis, Josée, Meigs, James Benjamin, Altshuler, David Matthew, 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 involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further 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 signalling and cell cycle regulation, in diabetes pathogenesis.
- Published
- 2012
- Full Text
- View/download PDF
18. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
- Author
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Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, 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, Frånberg, 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, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blüher, Matthias, Boeing, Heiner, Bonnycastle, Lori L, Bottinger, Erwin P, Burtt, Noël P, Carey, Jason, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, Van Dam, Rob M, Doney, Alex SF, Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G, Esko, Tonu, Eury, Elodie, Fadista, João, 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, Jørgensen, Marit E, Jørgensen, 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, Stéphane, Luan, Jian'an, Lyssenko, Valeriya, Männistö, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Mühleisen, Thomas W, Müller-Nurasyid, Martina, Navarro, Carmen, Nöthen, Markus M, Oskolkov, Nikolay N, Owen, Katharine R, Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John RB, Platou, Carl GP, Roden, Michael, Ruderfer, Douglas, Rybin, Denis, Van Der Schouw, Yvonne T, Sennblad, Bengt, Sigurðsson, Gunnar, Stančáková, 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 JF, Dupuis, Josée, 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-Hyövälti, Eeva, Saaristo, Timo E, Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Jöcke, 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, Njølstad, 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 NA, Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M, Groop, Leif C, Barroso, Inês, 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, and DIAbetes Genetics Replication And Meta-Analysis (DIAGRAM) Consortium
- Subjects
endocrine system ,Chromatin Immunoprecipitation ,Binding Sites ,endocrine system diseases ,Receptor, Melatonin, MT2 ,Chromosome Mapping ,Molecular Sequence Annotation ,Genomics ,Polymorphism, Single Nucleotide ,3. Good health ,Islets of Langerhans ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Liver ,Genetic Loci ,Case-Control Studies ,Hepatocyte Nuclear Factor 3-beta ,Humans ,Genetic Predisposition to Disease ,Genome-Wide Association Study - 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.
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