@article {1160, title = {New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Feb}, pages = {105-16}, abstract = {

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

}, keywords = {Adolescent, Adult, Alleles, Blood Glucose, Child, Databases, Genetic, Diabetes Mellitus, Type 2, DNA Copy Number Variations, Fasting, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Reproducibility of Results}, issn = {1546-1718}, doi = {10.1038/ng.520}, author = {Dupuis, Jos{\'e}e and Langenberg, Claudia and Prokopenko, Inga and Saxena, Richa and Soranzo, Nicole and Jackson, Anne U and Wheeler, Eleanor and Glazer, Nicole L and Bouatia-Naji, Nabila and Gloyn, Anna L and Lindgren, Cecilia M and M{\"a}gi, Reedik and Morris, Andrew P and Randall, Joshua and Johnson, Toby and Elliott, Paul and Rybin, Denis and Thorleifsson, Gudmar and Steinthorsdottir, Valgerdur and Henneman, Peter and Grallert, Harald and Dehghan, Abbas and Hottenga, Jouke Jan and Franklin, Christopher S and Navarro, Pau and Song, Kijoung and Goel, Anuj and Perry, John R B and Egan, Josephine M and Lajunen, Taina and Grarup, Niels and Spars{\o}, Thomas and Doney, Alex and Voight, Benjamin F and Stringham, Heather M and Li, Man and Kanoni, Stavroula and Shrader, Peter and Cavalcanti-Proen{\c c}a, Christine and Kumari, Meena and Qi, Lu and Timpson, Nicholas J and Gieger, Christian and Zabena, Carina and Rocheleau, Ghislain and Ingelsson, Erik and An, Ping and O{\textquoteright}Connell, Jeffrey and Luan, Jian{\textquoteright}an and Elliott, Amanda and McCarroll, Steven A and Payne, Felicity and Roccasecca, Rosa Maria and Pattou, Fran{\c c}ois and Sethupathy, Praveen and Ardlie, Kristin and Ariyurek, Yavuz and Balkau, Beverley and Barter, Philip and Beilby, John P and Ben-Shlomo, Yoav and Benediktsson, Rafn and Bennett, Amanda J and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bonnefond, Am{\'e}lie and Bonnycastle, Lori L and Borch-Johnsen, Knut and B{\"o}ttcher, Yvonne and Brunner, Eric and Bumpstead, Suzannah J and Charpentier, Guillaume and Chen, Yii-Der Ida and Chines, Peter and Clarke, Robert and Coin, Lachlan J M and Cooper, Matthew N and Cornelis, Marilyn and Crawford, Gabe and Crisponi, Laura and Day, Ian N M and de Geus, Eco J C and Delplanque, Jerome and Dina, Christian and Erdos, Michael R and Fedson, Annette C and Fischer-Rosinsky, Antje and Forouhi, Nita G and Fox, Caroline S and Frants, Rune and Franzosi, Maria Grazia and Galan, Pilar and Goodarzi, Mark O and Graessler, J{\"u}rgen and Groves, Christopher J and Grundy, Scott and Gwilliam, Rhian and Gyllensten, Ulf and Hadjadj, Samy and Hallmans, G{\"o}ran and Hammond, Naomi and Han, Xijing and Hartikainen, Anna-Liisa and Hassanali, Neelam and Hayward, Caroline and Heath, Simon C and Hercberg, Serge and Herder, Christian and Hicks, Andrew A and Hillman, David R and Hingorani, Aroon D and Hofman, Albert and Hui, Jennie and Hung, Joe and Isomaa, Bo and Johnson, Paul R V and J{\o}rgensen, Torben and Jula, Antti and Kaakinen, Marika and Kaprio, Jaakko and Kesaniemi, Y Antero and Kivimaki, Mika and Knight, Beatrice and Koskinen, Seppo and Kovacs, Peter and Kyvik, Kirsten Ohm and Lathrop, G Mark and Lawlor, Debbie A and Le Bacquer, Olivier and Lecoeur, C{\'e}cile and Li, Yun and Lyssenko, Valeriya and Mahley, Robert and Mangino, Massimo and Manning, Alisa K and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and McAteer, Jarred B and McCulloch, Laura J and McPherson, Ruth and Meisinger, Christa and Melzer, David and Meyre, David and Mitchell, Braxton D and Morken, Mario A and Mukherjee, Sutapa and Naitza, Silvia and Narisu, Narisu and Neville, Matthew J and Oostra, Ben A and Orr{\`u}, Marco and Pakyz, Ruth and Palmer, Colin N A and Paolisso, Giuseppe and Pattaro, Cristian and Pearson, Daniel and Peden, John F and Pedersen, Nancy L and Perola, Markus and Pfeiffer, Andreas F H and Pichler, Irene and Polasek, Ozren and Posthuma, Danielle and Potter, Simon C and Pouta, Anneli and Province, Michael A and Psaty, Bruce M and Rathmann, Wolfgang and Rayner, Nigel W and Rice, Kenneth and Ripatti, Samuli and Rivadeneira, Fernando and Roden, Michael and Rolandsson, Olov and Sandbaek, Annelli and Sandhu, Manjinder and Sanna, Serena and Sayer, Avan Aihie and Scheet, Paul and Scott, Laura J and Seedorf, Udo and Sharp, Stephen J and Shields, Beverley and Sigurethsson, Gunnar and Sijbrands, Eric J G and Silveira, Angela and Simpson, Laila and Singleton, Andrew and Smith, Nicholas L and Sovio, Ulla and Swift, Amy and Syddall, Holly and Syv{\"a}nen, Ann-Christine and Tanaka, Toshiko and Thorand, Barbara and Tichet, Jean and T{\"o}njes, Anke and Tuomi, Tiinamaija and Uitterlinden, Andr{\'e} G and van Dijk, Ko Willems and van Hoek, Mandy and Varma, Dhiraj and Visvikis-Siest, Sophie and Vitart, Veronique and Vogelzangs, Nicole and Waeber, G{\'e}rard and Wagner, Peter J and Walley, Andrew and Walters, G Bragi and Ward, Kim L and Watkins, Hugh and Weedon, Michael N and Wild, Sarah H and Willemsen, Gonneke and Witteman, Jaqueline C M and Yarnell, John W G and Zeggini, Eleftheria and Zelenika, Diana and Zethelius, Bj{\"o}rn and Zhai, Guangju and Zhao, Jing Hua and Zillikens, M Carola and Borecki, Ingrid B and Loos, Ruth J F and Meneton, Pierre and Magnusson, Patrik K E and Nathan, David M and Williams, Gordon H and Hattersley, Andrew T and Silander, Kaisa and Salomaa, Veikko and Smith, George Davey and Bornstein, Stefan R and Schwarz, Peter and Spranger, Joachim and Karpe, Fredrik and Shuldiner, Alan R and Cooper, Cyrus and Dedoussis, George V and Serrano-R{\'\i}os, Manuel and Morris, Andrew D and Lind, Lars and Palmer, Lyle J and Hu, Frank B and Franks, Paul W and Ebrahim, Shah and Marmot, Michael and Kao, W H Linda and Pankow, James S and Sampson, Michael J and Kuusisto, Johanna and Laakso, Markku and Hansen, Torben and Pedersen, Oluf and Pramstaller, Peter Paul and Wichmann, H Erich and Illig, Thomas and Rudan, Igor and Wright, Alan F and Stumvoll, Michael and Campbell, Harry and Wilson, James F and Bergman, Richard N and Buchanan, Thomas A and Collins, Francis S and Mohlke, Karen L and Tuomilehto, Jaakko and Valle, Timo T and Altshuler, David and Rotter, Jerome I and Siscovick, David S and Penninx, Brenda W J H and Boomsma, Dorret I and Deloukas, Panos and Spector, Timothy D and Frayling, Timothy M and Ferrucci, Luigi and Kong, Augustine and Thorsteinsdottir, Unnur and Stefansson, Kari and van Duijn, Cornelia M and Aulchenko, Yurii S and Cao, Antonio and Scuteri, Angelo and Schlessinger, David and Uda, Manuela and Ruokonen, Aimo and Jarvelin, Marjo-Riitta and Waterworth, Dawn M and Vollenweider, Peter and Peltonen, Leena and Mooser, Vincent and Abecasis, Goncalo R and Wareham, Nicholas J and Sladek, Robert and Froguel, Philippe and Watanabe, Richard M and Meigs, James B and Groop, Leif and Boehnke, Michael and McCarthy, Mark I and Florez, Jose C and Barroso, In{\^e}s} } @article {1378, title = {Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002607}, abstract = {

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5{\texttimes}10(-8)-1.2{\texttimes}10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3{\texttimes}10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3{\texttimes}10(-3), n = 22,044), increased triglycerides (p = 2.6{\texttimes}10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8{\texttimes}10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4{\texttimes}10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5{\texttimes}10(-13), n = 96,748) and decreased BMI (p = 1.4{\texttimes}10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

}, keywords = {Adiponectin, African Americans, Asian Continental Ancestry Group, Cholesterol, HDL, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002607}, author = {Dastani, Zari and Hivert, Marie-France and Timpson, Nicholas and Perry, John R B and Yuan, Xin and Scott, Robert A and Henneman, Peter and Heid, Iris M and Kizer, Jorge R and Lyytik{\"a}inen, Leo-Pekka and Fuchsberger, Christian and Tanaka, Toshiko and Morris, Andrew P and Small, Kerrin and Isaacs, Aaron and Beekman, Marian and Coassin, Stefan and Lohman, Kurt and Qi, Lu and Kanoni, Stavroula and Pankow, James S and Uh, Hae-Won and Wu, Ying and Bidulescu, Aurelian and Rasmussen-Torvik, Laura J and Greenwood, Celia M T and Ladouceur, Martin and Grimsby, Jonna and Manning, Alisa K and Liu, Ching-Ti and Kooner, Jaspal and Mooser, Vincent E and Vollenweider, Peter and Kapur, Karen A and Chambers, John and Wareham, Nicholas J and Langenberg, Claudia and Frants, Rune and Willems-Vandijk, Ko and Oostra, Ben A and Willems, Sara M and Lamina, Claudia and Winkler, Thomas W and Psaty, Bruce M and Tracy, Russell P and Brody, Jennifer and Chen, Ida and Viikari, Jorma and K{\"a}h{\"o}nen, Mika and Pramstaller, Peter P and Evans, David M and St Pourcain, Beate and Sattar, Naveed and Wood, Andrew R and Bandinelli, Stefania and Carlson, Olga D and Egan, Josephine M and B{\"o}hringer, Stefan and van Heemst, Diana and Kedenko, Lyudmyla and Kristiansson, Kati and Nuotio, Marja-Liisa and Loo, Britt-Marie and Harris, Tamara and Garcia, Melissa and Kanaya, Alka and Haun, Margot and Klopp, Norman and Wichmann, H-Erich and Deloukas, Panos and Katsareli, Efi and Couper, David J and Duncan, Bruce B and Kloppenburg, Margreet and Adair, Linda S and Borja, Judith B and Wilson, James G and Musani, Solomon and Guo, Xiuqing and Johnson, Toby and Semple, Robert and Teslovich, Tanya M and Allison, Matthew A and Redline, Susan and Buxbaum, Sarah G and Mohlke, Karen L and Meulenbelt, Ingrid and Ballantyne, Christie M and Dedoussis, George V and Hu, Frank B and Liu, Yongmei and Paulweber, Bernhard and Spector, Timothy D and Slagboom, P Eline and Ferrucci, Luigi and Jula, Antti and Perola, Markus and Raitakari, Olli and Florez, Jose C and Salomaa, Veikko and Eriksson, Johan G and Frayling, Timothy M and Hicks, Andrew A and Lehtim{\"a}ki, Terho and Smith, George Davey and Siscovick, David S and Kronenberg, Florian and van Duijn, Cornelia and Loos, Ruth J F and Waterworth, Dawn M and Meigs, James B and Dupuis, Jos{\'e}e and Richards, J Brent and Voight, Benjamin F and Scott, Laura J and Steinthorsdottir, Valgerdur and Dina, Christian and Welch, Ryan P and Zeggini, Eleftheria and Huth, Cornelia and Aulchenko, Yurii S and Thorleifsson, Gudmar and McCulloch, Laura J and Ferreira, Teresa and Grallert, Harald and Amin, Najaf and Wu, Guanming and Willer, Cristen J and Raychaudhuri, Soumya and McCarroll, Steve A and Hofmann, Oliver M and Segr{\`e}, Ayellet V and van Hoek, Mandy and Navarro, Pau and Ardlie, Kristin and Balkau, Beverley and Benediktsson, Rafn and Bennett, Amanda J and Blagieva, Roza and Boerwinkle, Eric and Bonnycastle, Lori L and Bostr{\"o}m, Kristina Bengtsson and Bravenboer, Bert and Bumpstead, Suzannah and Burtt, Noel P and Charpentier, Guillaume and Chines, Peter S and Cornelis, Marilyn and Crawford, Gabe and Doney, Alex S F and Elliott, Katherine S and Elliott, Amanda L and Erdos, Michael R and Fox, Caroline S and Franklin, Christopher S and Ganser, Martha and Gieger, Christian and Grarup, Niels and Green, Todd and Griffin, Simon and Groves, Christopher J and Guiducci, Candace and Hadjadj, Samy and Hassanali, Neelam and Herder, Christian and Isomaa, Bo and Jackson, Anne U and Johnson, Paul R V and J{\o}rgensen, Torben and Kao, Wen H L and Kong, Augustine and Kraft, Peter and Kuusisto, Johanna and Lauritzen, Torsten and Li, Man and Lieverse, Aloysius and Lindgren, Cecilia M and Lyssenko, Valeriya and Marre, Michel and Meitinger, Thomas and Midthjell, Kristian and Morken, Mario A and Narisu, Narisu and Nilsson, Peter and Owen, Katharine R and Payne, Felicity and Petersen, Ann-Kristin and Platou, Carl and Proen{\c c}a, Christine and Prokopenko, Inga and Rathmann, Wolfgang and Rayner, N William and Robertson, Neil R and Rocheleau, Ghislain and Roden, Michael and Sampson, Michael J and Saxena, Richa and Shields, Beverley M and Shrader, Peter and Sigurdsson, Gunnar and Spars{\o}, Thomas and Strassburger, Klaus and Stringham, Heather M and Sun, Qi and Swift, Amy J and Thorand, Barbara and Tichet, Jean and Tuomi, Tiinamaija and van Dam, Rob M and van Haeften, Timon W and van Herpt, Thijs and van Vliet-Ostaptchouk, Jana V and Walters, G Bragi and Weedon, Michael N and Wijmenga, Cisca and Witteman, Jacqueline and Bergman, Richard N and Cauchi, Stephane and Collins, Francis S and Gloyn, Anna L and Gyllensten, Ulf and Hansen, Torben and Hide, Winston A and Hitman, Graham A and Hofman, Albert and Hunter, David J and Hveem, Kristian and Laakso, Markku and Morris, Andrew D and Palmer, Colin N A and Rudan, Igor and Sijbrands, Eric and Stein, Lincoln D and Tuomilehto, Jaakko and Uitterlinden, Andre and Walker, Mark and Watanabe, Richard M and Abecasis, Goncalo R and Boehm, Bernhard O and Campbell, Harry and Daly, Mark J and Hattersley, Andrew T and Pedersen, Oluf and Barroso, In{\^e}s and Groop, Leif and Sladek, Rob and Thorsteinsdottir, Unnur and Wilson, James F and Illig, Thomas and Froguel, Philippe and van Duijn, Cornelia M and Stefansson, Kari and Altshuler, David and Boehnke, Michael and McCarthy, Mark I and Soranzo, Nicole and Wheeler, Eleanor and Glazer, Nicole L and Bouatia-Naji, Nabila and M{\"a}gi, Reedik and Randall, Joshua and Elliott, Paul and Rybin, Denis and Dehghan, Abbas and Hottenga, Jouke Jan and Song, Kijoung and Goel, Anuj and Lajunen, Taina and Doney, Alex and Cavalcanti-Proen{\c c}a, Christine and Kumari, Meena and Timpson, Nicholas J and Zabena, Carina and Ingelsson, Erik and An, Ping and O{\textquoteright}Connell, Jeffrey and Luan, Jian{\textquoteright}an and Elliott, Amanda and McCarroll, Steven A and Roccasecca, Rosa Maria and Pattou, Fran{\c c}ois and Sethupathy, Praveen and Ariyurek, Yavuz and Barter, Philip and Beilby, John P and Ben-Shlomo, Yoav and Bergmann, Sven and Bochud, Murielle and Bonnefond, Am{\'e}lie and Borch-Johnsen, Knut and B{\"o}ttcher, Yvonne and Brunner, Eric and Bumpstead, Suzannah J and Chen, Yii-Der Ida and Chines, Peter and Clarke, Robert and Coin, Lachlan J M and Cooper, Matthew N and Crisponi, Laura and Day, Ian N M and de Geus, Eco J C and Delplanque, Jerome and Fedson, Annette C and Fischer-Rosinsky, Antje and Forouhi, Nita G and Franzosi, Maria Grazia and Galan, Pilar and Goodarzi, Mark O and Graessler, J{\"u}rgen and Grundy, Scott and Gwilliam, Rhian and Hallmans, G{\"o}ran and Hammond, Naomi and Han, Xijing and Hartikainen, Anna-Liisa and Hayward, Caroline and Heath, Simon C and Hercberg, Serge and Hillman, David R and Hingorani, Aroon D and Hui, Jennie and Hung, Joe and Kaakinen, Marika and Kaprio, Jaakko and Kesaniemi, Y Antero and Kivimaki, Mika and Knight, Beatrice and Koskinen, Seppo and Kovacs, Peter and Kyvik, Kirsten Ohm and Lathrop, G Mark and Lawlor, Debbie A and Le Bacquer, Olivier and Lecoeur, C{\'e}cile and Li, Yun and Mahley, Robert and Mangino, Massimo and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and McAteer, Jarred B and McPherson, Ruth and Meisinger, Christa and Melzer, David and Meyre, David and Mitchell, Braxton D and Mukherjee, Sutapa and Naitza, Silvia and Neville, Matthew J and Orr{\`u}, Marco and Pakyz, Ruth and Paolisso, Giuseppe and Pattaro, Cristian and Pearson, Daniel and Peden, John F and Pedersen, Nancy L and Pfeiffer, Andreas F H and Pichler, Irene and Polasek, Ozren and Posthuma, Danielle and Potter, Simon C and Pouta, Anneli and Province, Michael A and Rayner, Nigel W and Rice, Kenneth and Ripatti, Samuli and Rivadeneira, Fernando and Rolandsson, Olov and Sandbaek, Annelli and Sandhu, Manjinder and Sanna, Serena and Sayer, Avan Aihie and Scheet, Paul and Seedorf, Udo and Sharp, Stephen J and Shields, Beverley and Sigur{\dh}sson, Gunnar and Sijbrands, Eric J G and Silveira, Angela and Simpson, Laila and Singleton, Andrew and Smith, Nicholas L and Sovio, Ulla and Swift, Amy and Syddall, Holly and Syv{\"a}nen, Ann-Christine and T{\"o}njes, Anke and Uitterlinden, Andr{\'e} G and van Dijk, Ko Willems and Varma, Dhiraj and Visvikis-Siest, Sophie and Vitart, Veronique and Vogelzangs, Nicole and Waeber, G{\'e}rard and Wagner, Peter J and Walley, Andrew and Ward, Kim L and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Witteman, Jaqueline C M and Yarnell, John W G and Zelenika, Diana and Zethelius, Bj{\"o}rn and Zhai, Guangju and Zhao, Jing Hua and Zillikens, M Carola and Borecki, Ingrid B and Meneton, Pierre and Magnusson, Patrik K E and Nathan, David M and Williams, Gordon H and Silander, Kaisa and Bornstein, Stefan R and Schwarz, Peter and Spranger, Joachim and Karpe, Fredrik and Shuldiner, Alan R and Cooper, Cyrus and Serrano-R{\'\i}os, Manuel and Lind, Lars and Palmer, Lyle J and Hu, Frank B and Franks, Paul W and Ebrahim, Shah and Marmot, Michael and Kao, W H Linda and Pramstaller, Peter Paul and Wright, Alan F and Stumvoll, Michael and Hamsten, Anders and Buchanan, Thomas A and Valle, Timo T and Rotter, Jerome I and Penninx, Brenda W J H and Boomsma, Dorret I and Cao, Antonio and Scuteri, Angelo and Schlessinger, David and Uda, Manuela and Ruokonen, Aimo and Jarvelin, Marjo-Riitta and Peltonen, Leena and Mooser, Vincent and Sladek, Robert and Musunuru, Kiran and Smith, Albert V and Edmondson, Andrew C and Stylianou, Ioannis M and Koseki, Masahiro and Pirruccello, James P and Chasman, Daniel I and Johansen, Christopher T and Fouchier, Sigrid W and Peloso, Gina M and Barbalic, Maja and Ricketts, Sally L and Bis, Joshua C and Feitosa, Mary F and Orho-Melander, Marju and Melander, Olle and Li, Xiaohui and Li, Mingyao and Cho, Yoon Shin and Go, Min Jin and Kim, Young Jin and Lee, Jong-Young and Park, Taesung and Kim, Kyunga and Sim, Xueling and Ong, Rick Twee-Hee and Croteau-Chonka, Damien C and Lange, Leslie A and Smith, Joshua D and Ziegler, Andreas and Zhang, Weihua and Zee, Robert Y L and Whitfield, John B and Thompson, John R and Surakka, Ida and Spector, Tim D and Smit, Johannes H and Sinisalo, Juha and Scott, James and Saharinen, Juha and Sabatti, Chiara and Rose, Lynda M and Roberts, Robert and Rieder, Mark and Parker, Alex N and Par{\'e}, Guillaume and O{\textquoteright}Donnell, Christopher J and Nieminen, Markku S and Nickerson, Deborah A and Montgomery, Grant W and McArdle, Wendy and Masson, David and Martin, Nicholas G and Marroni, Fabio and Lucas, Gavin and Luben, Robert and Lokki, Marja-Liisa and Lettre, Guillaume and Launer, Lenore J and Lakatta, Edward G and Laaksonen, Reijo and Kyvik, Kirsten O and K{\"o}nig, Inke R and Khaw, Kay-Tee and Kaplan, Lee M and Johansson, Asa and Janssens, A Cecile J W and Igl, Wilmar and Hovingh, G Kees and Hengstenberg, Christian and Havulinna, Aki S and Hastie, Nicholas D and Harris, Tamara B and Haritunians, Talin and Hall, Alistair S and Groop, Leif C and Gonzalez, Elena and Freimer, Nelson B and Erdmann, Jeanette and Ejebe, Kenechi G and D{\"o}ring, Angela and Dominiczak, Anna F and Demissie, Serkalem and Deloukas, Panagiotis and de Faire, Ulf and Crawford, Gabriel and Chen, Yii-der I and Caulfield, Mark J and Boekholdt, S Matthijs and Assimes, Themistocles L and Quertermous, Thomas and Seielstad, Mark and Wong, Tien Y and Tai, E-Shyong and Feranil, Alan B and Kuzawa, Christopher W and Taylor, Herman A and Gabriel, Stacey B and Holm, Hilma and Gudnason, Vilmundur and Krauss, Ronald M and Ordovas, Jose M and Munroe, Patricia B and Kooner, Jaspal S and Tall, Alan R and Hegele, Robert A and Kastelein, John J P and Schadt, Eric E and Strachan, David P and Reilly, Muredach P and Samani, Nilesh J and Schunkert, Heribert and Cupples, L Adrienne and Sandhu, Manjinder S and Ridker, Paul M and Rader, Daniel J and Kathiresan, Sekar} } @article {6555, title = {Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {374-382}, abstract = {

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.

METHODS AND RESULTS: Sequencing (mean depth, 38{\texttimes}) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9\% of which were rare (minor allele frequency <1\%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73{\texttimes}10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28{\texttimes}10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6\% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.

CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

}, keywords = {Aged, Aged, 80 and over, Aging, Blood Glucose, Chromosomes, Human, Pair 11, Cohort Studies, Death Domain Receptor Signaling Adaptor Proteins, Diabetes Mellitus, Type 2, Fasting, Female, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genomics, Guanine Nucleotide Exchange Factors, Heart Diseases, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000169}, author = {Cornes, Belinda K and Brody, Jennifer A and Nikpoor, Naghmeh and Morrison, Alanna C and Chu, Huan and Ahn, Byung Soo and Wang, Shuai and Dauriz, Marco and Barzilay, Joshua I and Dupuis, Jos{\'e}e and Florez, Jose C and Coresh, Josef and Gibbs, Richard A and Kao, W H Linda and Liu, Ching-Ti and McKnight, Barbara and Muzny, Donna and Pankow, James S and Reid, Jeffrey G and White, Charles C and Johnson, Andrew D and Wong, Tien Y and Psaty, Bruce M and Boerwinkle, Eric and Rotter, Jerome I and Siscovick, David S and Sladek, Robert and Meigs, James B} } @article {7596, title = {Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.}, journal = {PLoS Med}, volume = {14}, year = {2017}, month = {2017 Sep}, pages = {e1002383}, abstract = {

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS \& FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95\% CI 1.04-1.06, per HbA1c-raising allele, p = 3 {\texttimes} 10-29); whereas GS-E was not (OR = 1.00, 95\% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11\%) was associated with an absolute decrease in HbA1c of 0.81\%-units (95\% CI 0.66-0.96) per allele in hemizygous men, and 0.68\%-units (95\% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2\% (N = 0.65 million, 95\% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

}, keywords = {Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Phenotype, Risk}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002383}, author = {Wheeler, Eleanor and Leong, Aaron and Liu, Ching-Ti and Hivert, Marie-France and Strawbridge, Rona J and Podmore, Clara and Li, Man and Yao, Jie and Sim, Xueling and Hong, Jaeyoung and Chu, Audrey Y and Zhang, Weihua and Wang, Xu and Chen, Peng and Maruthur, Nisa M and Porneala, Bianca C and Sharp, Stephen J and Jia, Yucheng and Kabagambe, Edmond K and Chang, Li-Ching and Chen, Wei-Min and Elks, Cathy E and Evans, Daniel S and Fan, Qiao and Giulianini, Franco and Go, Min Jin and Hottenga, Jouke-Jan and Hu, Yao and Jackson, Anne U and Kanoni, Stavroula and Kim, Young Jin and Kleber, Marcus E and Ladenvall, Claes and Lecoeur, C{\'e}cile and Lim, Sing-Hui and Lu, Yingchang and Mahajan, Anubha and Marzi, Carola and Nalls, Mike A and Navarro, Pau and Nolte, Ilja M and Rose, Lynda M and Rybin, Denis V and Sanna, Serena and Shi, Yuan and Stram, Daniel O and Takeuchi, Fumihiko and Tan, Shu Pei and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Wong, Andrew and Yengo, Loic and Zhao, Wanting and Goel, Anuj and Martinez Larrad, Maria Teresa and Radke, D{\"o}rte and Salo, Perttu and Tanaka, Toshiko and van Iperen, Erik P A and Abecasis, Goncalo and Afaq, Saima and Alizadeh, Behrooz Z and Bertoni, Alain G and Bonnefond, Am{\'e}lie and B{\"o}ttcher, Yvonne and Bottinger, Erwin P and Campbell, Harry and Carlson, Olga D and Chen, Chien-Hsiun and Cho, Yoon Shin and Garvey, W Timothy and Gieger, Christian and Goodarzi, Mark O and Grallert, Harald and Hamsten, Anders and Hartman, Catharina A and Herder, Christian and Hsiung, Chao Agnes and Huang, Jie and Igase, Michiya and Isono, Masato and Katsuya, Tomohiro and Khor, Chiea-Chuen and Kiess, Wieland and Kohara, Katsuhiko and Kovacs, Peter and Lee, Juyoung and Lee, Wen-Jane and Lehne, Benjamin and Li, Huaixing and Liu, Jianjun and Lobbens, Stephane and Luan, Jian{\textquoteright}an and Lyssenko, Valeriya and Meitinger, Thomas and Miki, Tetsuro and Miljkovic, Iva and Moon, Sanghoon and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nauck, Matthias and Pankow, James S and Polasek, Ozren and Prokopenko, Inga and Ramos, Paula S and Rasmussen-Torvik, Laura and Rathmann, Wolfgang and Rich, Stephen S and Robertson, Neil R and Roden, Michael and Roussel, Ronan and Rudan, Igor and Scott, Robert A and Scott, William R and Sennblad, Bengt and Siscovick, David S and Strauch, Konstantin and Sun, Liang and Swertz, Morris and Tajuddin, Salman M and Taylor, Kent D and Teo, Yik-Ying and Tham, Yih Chung and T{\"o}njes, Anke and Wareham, Nicholas J and Willemsen, Gonneke and Wilsgaard, Tom and Hingorani, Aroon D and Egan, Josephine and Ferrucci, Luigi and Hovingh, G Kees and Jula, Antti and Kivimaki, Mika and Kumari, Meena and Nj{\o}lstad, Inger and Palmer, Colin N A and Serrano R{\'\i}os, Manuel and Stumvoll, Michael and Watkins, Hugh and Aung, Tin and Bl{\"u}her, Matthias and Boehnke, Michael and Boomsma, Dorret I and Bornstein, Stefan R and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chen, Yduan-Tsong and Cheng, Ching-Yu and Cucca, Francesco and de Geus, Eco J C and Deloukas, Panos and Evans, Michele K and Fornage, Myriam and Friedlander, Yechiel and Froguel, Philippe and Groop, Leif and Gross, Myron D and Harris, Tamara B and Hayward, Caroline and Heng, Chew-Kiat and Ingelsson, Erik and Kato, Norihiro and Kim, Bong-Jo and Koh, Woon-Puay and Kooner, Jaspal S and K{\"o}rner, Antje and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lin, Xu and Liu, Yongmei and Loos, Ruth J F and Magnusson, Patrik K E and M{\"a}rz, Winfried and McCarthy, Mark I and Oldehinkel, Albertine J and Ong, Ken K and Pedersen, Nancy L and Pereira, Mark A and Peters, Annette and Ridker, Paul M and Sabanayagam, Charumathi and Sale, Michele and Saleheen, Danish and Saltevo, Juha and Schwarz, Peter Eh and Sheu, Wayne H H and Snieder, Harold and Spector, Timothy D and Tabara, Yasuharu and Tuomilehto, Jaakko and van Dam, Rob M and Wilson, James G and Wilson, James F and Wolffenbuttel, Bruce H R and Wong, Tien Yin and Wu, Jer-Yuarn and Yuan, Jian-Min and Zonderman, Alan B and Soranzo, Nicole and Guo, Xiuqing and Roberts, David J and Florez, Jose C and Sladek, Robert and Dupuis, Jos{\'e}e and Morris, Andrew P and Tai, E-Shyong and Selvin, Elizabeth and Rotter, Jerome I and Langenberg, Claudia and Barroso, In{\^e}s and Meigs, James B} } @article {9158, title = {Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 07 28}, pages = {756}, abstract = {

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI{\textquoteright}s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

}, keywords = {Diabetes Mellitus, Type 2, Fasting, Glucose, Humans, Insulin, National Heart, Lung, and Blood Institute (U.S.), Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Precision Medicine, Receptors, Immunologic, United States}, issn = {2399-3642}, doi = {10.1038/s42003-022-03702-4}, author = {DiCorpo, Daniel and Gaynor, Sheila M and Russell, Emily M and Westerman, Kenneth E and Raffield, Laura M and Majarian, Timothy D and Wu, Peitao and Sarnowski, Chloe and Highland, Heather M and Jackson, Anne and Hasbani, Natalie R and de Vries, Paul S and Brody, Jennifer A and Hidalgo, Bertha and Guo, Xiuqing and Perry, James A and O{\textquoteright}Connell, Jeffrey R and Lent, Samantha and Montasser, May E and Cade, Brian E and Jain, Deepti and Wang, Heming and D{\textquoteright}Oliveira Albanus, Ricardo and Varshney, Arushi and Yanek, Lisa R and Lange, Leslie and Palmer, Nicholette D and Almeida, Marcio and Peralta, Juan M and Aslibekyan, Stella and Baldridge, Abigail S and Bertoni, Alain G and Bielak, Lawrence F and Chen, Chung-Shiuan and Chen, Yii-Der Ida and Choi, Won Jung and Goodarzi, Mark O and Floyd, James S and Irvin, Marguerite R and Kalyani, Rita R and Kelly, Tanika N and Lee, Seonwook and Liu, Ching-Ti and Loesch, Douglas and Manson, JoAnn E and Minster, Ryan L and Naseri, Take and Pankow, James S and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Selvin, Elizabeth and Smith, Jennifer A and Weeks, Daniel E and Xu, Huichun and Yao, Jie and Zhao, Wei and Parker, Stephen and Alonso, Alvaro and Arnett, Donna K and Blangero, John and Boerwinkle, Eric and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Duggirala, Ravindranath and He, Jiang and Heckbert, Susan R and Kardia, Sharon L R and Kim, Ryan W and Kooperberg, Charles and Liu, Simin and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Morrison, Alanna C and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Shuldiner, Alan R and Taylor, Kent D and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Florez, Jose C and Wilson, James G and Sladek, Robert and Rich, Stephen S and Rotter, Jerome I and Lin, Xihong and Dupuis, Jos{\'e}e and Meigs, James B and Wessel, Jennifer and Manning, Alisa K} } @article {9450, title = {Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.}, journal = {medRxiv}, year = {2023}, month = {2023 Jul 28}, abstract = {

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.

METHODS: From 16 studies of the Cohorts for Heart \& Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.

RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2\%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0{\texttimes}10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95\% confidence interval (CI) 1.15 - 1.32, =3.6{\texttimes}10 , rs11444867 (intergenic variant near ) with HR 1.89, 95\% CI 1.52 - 2.35, =9.9{\texttimes}10 , and rs335407 (intergenic variant between and ) HR 1.25, 95\% CI 1.16 - 1.35, =1.5{\texttimes}10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95\% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0{\texttimes}10 ).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.

}, doi = {10.1101/2023.07.25.23293180}, author = {Kwak, Soo Heon and Hernandez-Cancela, Ryan B and DiCorpo, Daniel A and Condon, David E and Merino, Jordi and Wu, Peitao and Brody, Jennifer A and Yao, Jie and Guo, Xiuqing and Ahmadizar, Fariba and Meyer, Mariah and Sincan, Murat and Mercader, Josep M and Lee, Sujin and Haessler, Jeffrey and Vy, Ha My T and Lin, Zhaotong and Armstrong, Nicole D and Gu, Shaopeng and Tsao, Noah L and Lange, Leslie A and Wang, Ningyuan and Wiggins, Kerri L and Trompet, Stella and Liu, Simin and Loos, Ruth J F and Judy, Renae and Schroeder, Philip H and Hasbani, Natalie R and Bos, Maxime M and Morrison, Alanna C and Jackson, Rebecca D and Reiner, Alexander P and Manson, JoAnn E and Chaudhary, Ninad S and Carmichael, Lynn K and Chen, Yii-Der Ida and Taylor, Kent D and Ghanbari, Mohsen and van Meurs, Joyce and Pitsillides, Achilleas N and Psaty, Bruce M and Noordam, Raymond and Do, Ron and Park, Kyong Soo and Jukema, J Wouter and Kavousi, Maryam and Correa, Adolfo and Rich, Stephen S and Damrauer, Scott M and Hajek, Catherine and Cho, Nam H and Irvin, Marguerite R and Pankow, James S and Nadkarni, Girish N and Sladek, Robert and Goodarzi, Mark O and Florez, Jose C and Chasman, Daniel I and Heckbert, Susan R and Kooperberg, Charles and Dupuis, Jos{\'e}e and Malhotra, Rajeev and de Vries, Paul S and Liu, Ching-Ti and Rotter, Jerome I and Meigs, James B} }