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Florez, Jose

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Florez

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Jose

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Florez, Jose
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    Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
    (Nature Pub. Group, 2015) Wessel, Jennifer; Chu, Audrey Y; Willems, Sara M; Wang, Shuai; Yaghootkar, Hanieh; Brody, Jennifer A; Dauriz, Marco; Hivert, Marie-France; Raghavan, Sridharan; Lipovich, Leonard; Hidalgo, Bertha; Fox, Keolu; Huffman, Jennifer E; An, Ping; Lu, Yingchang; Rasmussen-Torvik, Laura J; Grarup, Niels; Ehm, Margaret G; Li, Li; Baldridge, Abigail S; Stančáková, Alena; Abrol, Ravinder; Besse, Céline; Boland, Anne; Bork-Jensen, Jette; Fornage, Myriam; Freitag, Daniel F; Garcia, Melissa E; Guo, Xiuqing; Hara, Kazuo; Isaacs, Aaron; Jakobsdottir, Johanna; Lange, Leslie A; Layton, Jill C; Li, Man; Hua Zhao, Jing; Meidtner, Karina; Morrison, Alanna C; Nalls, Mike A; Peters, Marjolein J; Sabater-Lleal, Maria; Schurmann, Claudia; Silveira, Angela; Smith, Albert V; Southam, Lorraine; Stoiber, Marcus H; Strawbridge, Rona J; Taylor, Kent D; Varga, Tibor V; Allin, Kristine H; Amin, Najaf; Aponte, Jennifer L; Aung, Tin; Barbieri, Caterina; Bihlmeyer, Nathan A; Boehnke, Michael; Bombieri, Cristina; Bowden, Donald W; Burns, Sean; Chen, Yuning; Chen, Yii-DerI; Cheng, Ching-Yu; Correa, Adolfo; Czajkowski, Jacek; Dehghan, Abbas; Ehret, Georg B; Eiriksdottir, Gudny; Escher, Stefan A; Farmaki, Aliki-Eleni; Frånberg, Mattias; Gambaro, Giovanni; Giulianini, Franco; Goddard, William A; Goel, Anuj; Gottesman, Omri; Grove, Megan L; Gustafsson, Stefan; Hai, Yang; Hallmans, Göran; Heo, Jiyoung; Hoffmann, Per; Ikram, Mohammad K; Jensen, Richard A; Jørgensen, Marit E; Jørgensen, Torben; Karaleftheri, Maria; Khor, Chiea C; Kirkpatrick, Andrea; Kraja, Aldi T; Kuusisto, Johanna; Lange, Ethan M; Lee, I T; Lee, Wen-Jane; Leong, Aaron; Liao, Jiemin; Liu, Chunyu; Liu, Yongmei; Lindgren, Cecilia M; Linneberg, Allan; Malerba, Giovanni; Mamakou, Vasiliki; Marouli, Eirini; Maruthur, Nisa M; Matchan, Angela; McKean-Cowdin, Roberta; McLeod, Olga; Metcalf, Ginger A; Mohlke, Karen L; Muzny, Donna M; Ntalla, Ioanna; Palmer, Nicholette D; Pasko, Dorota; Peter, Andreas; Rayner, Nigel W; Renström, Frida; Rice, Ken; Sala, Cinzia F; Sennblad, Bengt; Serafetinidis, Ioannis; Smith, Jennifer A; Soranzo, Nicole; Speliotes, Elizabeth K; Stahl, Eli A; Stirrups, Kathleen; Tentolouris, Nikos; Thanopoulou, Anastasia; Torres, Mina; Traglia, Michela; Tsafantakis, Emmanouil; Javad, Sundas; Yanek, Lisa R; Zengini, Eleni; Becker, Diane M; Bis, Joshua C; Brown, James B; Adrienne Cupples, L; Hansen, Torben; Ingelsson, Erik; Karter, Andrew J; Lorenzo, Carlos; Mathias, Rasika A; Norris, Jill M; Peloso, Gina M; Sheu, Wayne H.-H.; Toniolo, Daniela; Vaidya, Dhananjay; Varma, Rohit; Wagenknecht, Lynne E; Boeing, Heiner; Bottinger, Erwin P; Dedoussis, George; Deloukas, Panos; Ferrannini, Ele; Franco, Oscar H; Franks, Paul W; Gibbs, Richard A; Gudnason, Vilmundur; Hamsten, Anders; Harris, Tamara B; Hattersley, Andrew T; Hayward, Caroline; Hofman, Albert; Jansson, Jan-Håkan; Langenberg, Claudia; Launer, Lenore J; Levy, Daniel; Oostra, Ben A; O'Donnell, Christopher; O'Rahilly, Stephen; Padmanabhan, Sandosh; Pankow, James S; Polasek, Ozren; Province, Michael A; Rich, Stephen S; Ridker, Paul; Rudan, Igor; Schulze, Matthias B; Smith, Blair H; Uitterlinden, André G; Walker, Mark; Watkins, Hugh; Wong, Tien Y; Zeggini, Eleftheria; Sharp, Stephen J; Forouhi, Nita G; Kerrison, Nicola D; Lucarelli, Debora ME; Sims, Matt; Barroso, Inês; McCarthy, Mark I; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Gonzalez, Carlos; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J; Navarro, Carmen; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sánchez, María–José; Slimani, Nadia; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; Riboli, Elio; Laakso, Markku; Borecki, Ingrid B; Chasman, Daniel; Pedersen, Oluf; Psaty, Bruce M; Shyong Tai, E; van Duijn, Cornelia M; Wareham, Nicholas J; Waterworth, Dawn M; Boerwinkle, Eric; Linda Kao, W H; Florez, Jose; Loos, Ruth J.F.; Wilson, James G; Frayling, Timothy M; Siscovick, David S; Dupuis, Josée; Rotter, Jerome I; Meigs, James; Scott, Robert A; Goodarzi, Mark O
    Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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    Analysis of protein-coding genetic variation in 60,706 humans
    (2016) Lek, Monkol; Karczewski, Konrad; Minikel, Eric; Samocha, Kaitlin E.; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H; Ware, James S; Hill, Andrew J; Cummings, Beryl; Tukiainen, Taru; Birnbaum, Daniel P; Kosmicki, Jack; Duncan, Laramie E; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hoffman, Emma; Berghout, Joanne; Cooper, David N; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja; Moonshine, Ami Levy; Natarajan, Pradeep; Orozco, Lorena; Peloso, Gina M; Poplin, Ryan; Rivas, Manuel A; Ruano-Rubio, Valentin; Rose, Samuel A; Ruderfer, Douglas M; Shakir, Khalid; Stenson, Peter D; Stevens, Christine; Thomas, Brett P; Tiao, Grace; Tusie-Luna, Maria T; Weisburd, Ben; Won, Hong-Hee; Yu, Dongmei; Altshuler, David; Ardissino, Diego; Boehnke, Michael; Danesh, John; Donnelly, Stacey; Elosua, Roberto; Florez, Jose; Gabriel, Stacey B; Getz, Gad; Glatt, Stephen J; Hultman, Christina M; Kathiresan, Sekar; Laakso, Markku; McCarroll, Steven; McCarthy, Mark I; McGovern, Dermot; McPherson, Ruth; Neale, Benjamin; Palotie, Aarno; Purcell, Shaun M; Saleheen, Danish; Scharf, Jeremiah; Sklar, Pamela; Sullivan, Patrick F; Tuomilehto, Jaakko; Tsuang, Ming T; Watkins, Hugh C; Wilson, James G; Daly, Mark; MacArthur, Daniel
    Summary Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes.
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    Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes
    (Nature Publishing Group UK, 2018) Bonàs-Guarch, Sílvia; Guindo-Martínez, Marta; Miguel-Escalada, Irene; Grarup, Niels; Sebastian, David; Rodriguez-Fos, Elias; Sánchez, Friman; Planas-Fèlix, Mercè; Cortes-Sánchez, Paula; González, Santi; Timshel, Pascal; Pers, Tune H.; Morgan, Claire C.; Moran, Ignasi; Atla, Goutham; González, Juan R.; Puiggros, Montserrat; Martí, Jonathan; Andersson, Ehm A.; Díaz, Carlos; Badia, Rosa M.; Udler, Miriam; Leong, Aaron; Kaur, Varindepal; Flannick, Jason; Jørgensen, Torben; Linneberg, Allan; Jørgensen, Marit E.; Witte, Daniel R.; Christensen, Cramer; Brandslund, Ivan; Appel, Emil V.; Scott, Robert A.; Luan, Jian’an; Langenberg, Claudia; Wareham, Nicholas J.; Pedersen, Oluf; Zorzano, Antonio; Florez, Jose; Hansen, Torben; Ferrer, Jorge; Mercader, Josep Maria; Torrents, David
    The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.
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    The Genetic Basis of Type 2 Diabetes in Hispanics and Latin Americans: Challenges and Opportunities
    (Frontiers Media S.A., 2017) Mercader, Josep M.; Florez, Jose
    Type 2 diabetes (T2D) affects 415 million people worldwide, and has a much higher prevalence in Hispanics (16.9%), compared to non-Hispanic whites (10.2%). Genome-wide association studies and whole-genome and whole-exome sequencing studies have discovered more than 100 genetic regions associated with modified risk for T2D. However, the identified genetic factors explain a very small fraction of the estimated heritability. Until recently, little attention has been put in studying other non European populations that suffer from a higher burden of T2D, such as Hispanics/Latinos. In the past few years, genetic studies in Hispanic populations have started to provide new insights into the genetic architecture of T2D in this ancestry group. Of note, several genetic variants that are absent or very rare in non-Hispanic populations but more common in Hispanics have shown from moderate to strong association with T2D and have provided new insights into the biology of T2D, which may be ultimately useful for developing novel therapeutic strategies applicable to all populations. Studying diverse populations can also improve the ability to find the causal variants in known T2D loci by a multi-ancestry fine-mapping approach, which leverages the different patterns of linkage disequilibrium between the causal and the ascertained genetic variants. In this mini-review, we summarize the main genetic findings discovered in Hispanics and discuss the limitations and challenges of performing genetic studies in these populations. Finally, we present possible next steps to make studies in Latino populations more valuable in providing a deeper understanding of T2D and anticipate their future application to the development of predictive and preventive medicine and personalized therapies.
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    Publisher Correction: Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes
    (Nature Publishing Group UK, 2018) Bonàs-Guarch, Sílvia; Guindo-Martínez, Marta; Miguel-Escalada, Irene; Grarup, Niels; Sebastian, David; Rodriguez-Fos, Elias; Sánchez, Friman; Planas-Fèlix, Mercè; Cortes-Sánchez, Paula; González, Santi; Timshel, Pascal; Pers, Tune H.; Morgan, Claire C.; Moran, Ignasi; Atla, Goutham; González, Juan R.; Puiggros, Montserrat; Martí, Jonathan; Andersson, Ehm A.; Díaz, Carlos; Badia, Rosa M.; Udler, Miriam; Leong, Aaron; Kaur, Varindepal; Flannick, Jason; Jørgensen, Torben; Linneberg, Allan; Jørgensen, Marit E.; Witte, Daniel R.; Christensen, Cramer; Brandslund, Ivan; Appel, Emil V.; Scott, Robert A.; Luan, Jian’an; Langenberg, Claudia; Wareham, Nicholas J.; Pedersen, Oluf; Zorzano, Antonio; Florez, Jose; Hansen, Torben; Ferrer, Jorge; Mercader, Josep Maria; Torrents, David
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    Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci
    (American Diabetes Association, 2016) Walford, Geoffrey A.; Gustafsson, Stefan; Rybin, Denis; Stančáková, Alena; Chen, Han; Liu, Ching-Ti; Hong, Jaeyoung; Jensen, Richard A.; Rice, Ken; Morris, Andrew P.; Mägi, Reedik; Tönjes, Anke; Prokopenko, Inga; Kleber, Marcus E.; Delgado, Graciela; Silbernagel, Günther; Jackson, Anne U.; Appel, Emil V.; Grarup, Niels; Lewis, Joshua P.; Montasser, May E.; Landenvall, Claes; Staiger, Harald; Luan, Jian’an; Frayling, Timothy M.; Weedon, Michael N.; Xie, Weijia; Morcillo, Sonsoles; Martínez-Larrad, María Teresa; Biggs, Mary L.; Chen, Yii-Der Ida; Corbaton-Anchuelo, Arturo; Færch, Kristine; Gómez-Zumaquero, Juan Miguel; Goodarzi, Mark O.; Kizer, Jorge R.; Koistinen, Heikki A.; Leong, Aaron; Lind, Lars; Lindgren, Cecilia; Machicao, Fausto; Manning, Alisa; Martín-Núñez, Gracia María; Rojo-Martínez, Gemma; Rotter, Jerome I.; Siscovick, David S.; Zmuda, Joseph M.; Zhang, Zhongyang; Serrano-Rios, Manuel; Smith, Ulf; Soriguer, Federico; Hansen, Torben; Jørgensen, Torben J.; Linnenberg, Allan; Pedersen, Oluf; Walker, Mark; Langenberg, Claudia; Scott, Robert A.; Wareham, Nicholas J.; Fritsche, Andreas; Häring, Hans-Ulrich; Stefan, Norbert; Groop, Leif; O’Connell, Jeff R.; Boehnke, Michael; Bergman, Richard N.; Collins, Francis S.; Mohlke, Karen L.; Tuomilehto, Jaakko; März, Winfried; Kovacs, Peter; Stumvoll, Michael; Psaty, Bruce M.; Kuusisto, Johanna; Laakso, Markku; Meigs, James; Dupuis, Josée; Ingelsson, Erik; Florez, Jose
    Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
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    Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
    (Nature Publishing Group UK, 2018) Gusarova, Viktoria; O’Dushlaine, Colm; Teslovich, Tanya M.; Benotti, Peter N.; Mirshahi, Tooraj; Gottesman, Omri; Van Hout, Cristopher V.; Murray, Michael F.; Mahajan, Anubha; Nielsen, Jonas B.; Fritsche, Lars; Wulff, Anders Berg; Gudbjartsson, Daniel F.; Sjögren, Marketa; Emdin, Connor A.; Scott, Robert A.; Lee, Wen-Jane; Small, Aeron; Kwee, Lydia C.; Dwivedi, Om Prakash; Prasad, Rashmi B.; Bruse, Shannon; Lopez, Alexander E.; Penn, John; Marcketta, Anthony; Leader, Joseph B.; Still, Christopher D.; Kirchner, H. Lester; Mirshahi, Uyenlinh L.; Wardeh, Amr H.; Hartle, Cassandra M.; Habegger, Lukas; Fetterolf, Samantha N.; Tusie-Luna, Teresa; Morris, Andrew P.; Holm, Hilma; Steinthorsdottir, Valgerdur; Sulem, Patrick; Thorsteinsdottir, Unnur; Rotter, Jerome I.; Chuang, Lee-Ming; Damrauer, Scott; Birtwell, David; Brummett, Chad M.; Khera, Amit; Natarajan, Pradeep; Orho-Melander, Marju; Flannick, Jason; Lotta, Luca A.; Willer, Cristen J.; Holmen, Oddgeir L.; Ritchie, Marylyn D.; Ledbetter, David H.; Murphy, Andrew J.; Borecki, Ingrid B.; Reid, Jeffrey G.; Overton, John D.; Hansson, Ola; Groop, Leif; Shah, Svati H.; Kraus, William E.; Rader, Daniel J.; Chen, Yii-Der I.; Hveem, Kristian; Wareham, Nicholas J.; Kathiresan, Sekar; Melander, Olle; Stefansson, Kari; Nordestgaard, Børge G.; Tybjærg-Hansen, Anne; Abecasis, Goncalo R.; Altshuler, David; Florez, Jose; Boehnke, Michael; McCarthy, Mark I.; Yancopoulos, George D.; Carey, David J.; Shuldiner, Alan R.; Baras, Aris; Dewey, Frederick E.; Gromada, Jesper
    Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.
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    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
    (Public Library of Science, 2017) Wheeler, Eleanor; Leong, Aaron; Liu, Ching-Ti; Hivert, Marie-France; Strawbridge, Rona J.; Podmore, Clara; Li, Man; Yao, Jie; Sim, Xueling; Hong, Jaeyoung; Chu, Audrey Y.; Zhang, Weihua; Wang, Xu; Chen, Peng; Maruthur, Nisa M.; Porneala, Bianca C.; Sharp, Stephen J.; Jia, Yucheng; Kabagambe, Edmond K.; Chang, Li-Ching; Chen, Wei-Min; Elks, Cathy E.; Evans, Daniel S.; Fan, Qiao; Giulianini, Franco; Go, Min Jin; Hottenga, Jouke-Jan; Hu, Yao; Jackson, Anne U.; Kanoni, Stavroula; Kim, Young Jin; Kleber, Marcus E.; Ladenvall, Claes; Lecoeur, Cecile; Lim, Sing-Hui; Lu, Yingchang; Mahajan, Anubha; Marzi, Carola; Nalls, Mike A.; Navarro, Pau; Nolte, Ilja M.; Rose, Lynda M.; Rybin, Denis V.; Sanna, Serena; Shi, Yuan; Stram, Daniel O.; Takeuchi, Fumihiko; Tan, Shu Pei; van der Most, Peter J.; Van Vliet-Ostaptchouk, Jana V.; Wong, Andrew; Yengo, Loic; Zhao, Wanting; Goel, Anuj; Martinez Larrad, Maria Teresa; Radke, Dörte; Salo, Perttu; Tanaka, Toshiko; van Iperen, Erik P. A.; Abecasis, Goncalo; Afaq, Saima; Alizadeh, Behrooz Z.; Bertoni, Alain G.; Bonnefond, Amelie; Böttcher, Yvonne; Bottinger, Erwin P.; Campbell, Harry; Carlson, Olga D.; Chen, Chien-Hsiun; Cho, Yoon Shin; Garvey, W. Timothy; Gieger, Christian; Goodarzi, Mark O.; Grallert, Harald; Hamsten, Anders; Hartman, Catharina A.; Herder, Christian; Hsiung, Chao Agnes; Huang, Jie; Igase, Michiya; Isono, Masato; Katsuya, Tomohiro; Khor, Chiea-Chuen; Kiess, Wieland; Kohara, Katsuhiko; Kovacs, Peter; Lee, Juyoung; Lee, Wen-Jane; Lehne, Benjamin; Li, Huaixing; Liu, Jianjun; Lobbens, Stephane; Luan, Jian'an; Lyssenko, Valeriya; Meitinger, Thomas; Miki, Tetsuro; Miljkovic, Iva; Moon, Sanghoon; Mulas, Antonella; Müller, Gabriele; Müller-Nurasyid, Martina; Nagaraja, Ramaiah; Nauck, Matthias; Pankow, James S.; Polasek, Ozren; Prokopenko, Inga; Ramos, Paula S.; Rasmussen-Torvik, Laura; Rathmann, Wolfgang; Rich, Stephen S.; Robertson, Neil R.; Roden, Michael; Roussel, Ronan; Rudan, Igor; Scott, Robert A.; Scott, William R.; Sennblad, Bengt; Siscovick, David S.; Strauch, Konstantin; Sun, Liang; Swertz, Morris; Tajuddin, Salman M.; Taylor, Kent D.; Teo, Yik-Ying; Tham, Yih Chung; Tönjes, Anke; Wareham, Nicholas J.; Willemsen, Gonneke; Wilsgaard, Tom; Hingorani, Aroon D.; Egan, Josephine; Ferrucci, Luigi; Hovingh, G. Kees; Jula, Antti; Kivimaki, Mika; Kumari, Meena; Njølstad, Inger; Palmer, Colin N. A.; Serrano Ríos, Manuel; Stumvoll, Michael; Watkins, Hugh; Aung, Tin; Blüher, Matthias; Boehnke, Michael; Boomsma, Dorret I.; Bornstein, Stefan R.; Chambers, John C.; Chasman, Daniel; Chen, Yii-Der Ida; Chen, Yduan-Tsong; Cheng, Ching-Yu; Cucca, Francesco; de Geus, Eco J. C.; Deloukas, Panos; Evans, Michele K.; Fornage, Myriam; Friedlander, Yechiel; Froguel, Philippe; Groop, Leif; Gross, Myron D.; Harris, Tamara B.; Hayward, Caroline; Heng, Chew-Kiat; Ingelsson, Erik; Kato, Norihiro; Kim, Bong-Jo; Koh, Woon-Puay; Kooner, Jaspal S.; Körner, Antje; Kuh, Diana; Kuusisto, Johanna; Laakso, Markku; Lin, Xu; Liu, Yongmei; Loos, Ruth J. F.; Magnusson, Patrik K. E.; März, Winfried; McCarthy, Mark I.; Oldehinkel, Albertine J.; Ong, Ken K.; Pedersen, Nancy L.; Pereira, Mark A.; Peters, Annette; Ridker, Paul; Sabanayagam, Charumathi; Sale, Michele; Saleheen, Danish; Saltevo, Juha; Schwarz, Peter EH.; Sheu, Wayne H. H.; Snieder, Harold; Spector, Timothy D.; Tabara, Yasuharu; Tuomilehto, Jaakko; van Dam, Rob M.; Wilson, James G.; Wilson, James F.; Wolffenbuttel, Bruce H. R.; Wong, Tien Yin; Wu, Jer-Yuarn; Yuan, Jian-Min; Zonderman, Alan B.; Soranzo, Nicole; Guo, Xiuqing; Roberts, David J.; Florez, Jose; Sladek, Robert; Dupuis, Josée; Morris, Andrew P.; Tai, E-Shyong; Selvin, Elizabeth; Rotter, Jerome I.; Langenberg, Claudia; Barroso, Inês; Meigs, James
    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 × 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.
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    Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure underpinning obesity
    (2018) Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E; Fine, Rebecca; Bradfield, Jonathan P; Esko, Tõnu; Giri, Ayush; Graff, Mariaelisa; Guo, Xiuqing; Hendricks, Audrey E; Karaderi, Tugce; Lempradl, Adelheid; Locke, Adam E; Mahajan, Anubha; Marouli, Eirini; Sivapalaratnam, Suthesh; Young, Kristin L; Alfred, Tamuno; Feitosa, Mary F; Masca, Nicholas GD; Manning, Alisa; Medina-Gomez, Carolina; Mudgal, Poorva; Ng, Maggie CY; Reiner, Alex P; Vedantam, Sailaja; Willems, Sara M; Winkler, Thomas W; Abecasis, Goncalo; Aben, Katja K; Alam, Dewan S; Alharthi, Sameer E; Allison, Matthew; Amouyel, Philippe; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Bang, Lia E; Barroso, Inês; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Brumat, Marco; Burt, Amber A; Butterworth, Adam S; Campbell, Peter T; Cappellani, Stefania; Carey, David J; Catamo, Eulalia; Caulfield, Mark J; Chambers, John C; Chasman, Daniel; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J; Crosslin, David S; Cuellar-Partida, Gabriel; D'Eustacchio, Angela; Danesh, John; Davies, Gail; de Bakker, Paul IW; de Groot, Mark CH; de Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; den Heijer, Martin; den Hollander, Anneke I; den Ruijter, Hester M; Dennis, Joe G; Denny, Josh C; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dubé, Marie-Pierre; Dunning, Alison M; Easton, Douglas F; Edwards, Todd L; Ellinghaus, David; Ellinor, Patrick; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Farooqi, I. Sadaf; Faul, Jessica D; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose; Ford, Ian; Fornage, Myriam; Franco, Oscar H; Franke, Andre; Franks, Paul; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E.; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans-Jörgen; Grant, Struan FA; Grarup, Niels; Griffiths, Helen L; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeff; Hakonarson, Hakon; Hammerschlag, Anke R; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Have, Christian T; Hayward, Caroline; He, Liang; Heard-Costa, Nancy L; Heath, Andrew C; Heid, Iris M; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna MM; Hu, Yao; Huang, Paul; Huffman, Jennifer E; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jia, Yucheng; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon LR; Karpe, Fredrik; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltán; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A; Lamparter, David; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia; Larson, Eric B; Lee, Nanette R; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng-Hung; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Ching-Ti; Liu, Dajiang J; Liu, Yongmei; Lo, Ken Sin; Lophatananon, Artitaya; Lotery, Andrew J; Loukola, Anu; Luan, Jian'an; Lubitz, Steven; Lyytikäinen, Leo-Pekka; Männistö, Satu; Marenne, Gaëlle; Mazul, Angela L; McCarthy, Mark I; McKean-Cowdin, Roberta; Medland, Sarah E; Meidtner, Karina; Milani, Lili; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L; Moilanen, Leena; Moitry, Marie; Montgomery, Grant W; Mook-Kanamori, Dennis O; Moore, Carmel; Mori, Trevor A; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Narisu, Narisu; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Nyholt, Dale R; O'Connel, Jeffrey R; O’Donoghue, Michelle L.; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin NA; Palmer, Nicholette D; Pasterkamp, Gerard; Patel, Aniruddh; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John RB; Pers, Tune H; Person, Thomas N; Peters, Annette; Petersen, Eva RB; Peyser, Patricia A; Pirie, Ailith; Polasek, Ozren; Polderman, Tinca J; Puolijoki, Hannu; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Renström, Frida; Rheinberger, Myriam; Ridker, Paul; Rioux, John D; Rivas, Manuel A; Roberts, David J; Robertson, Neil R; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sapkota, Yadav; Sattar, Naveed; Schoen, Robert E; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati H; Sheu, Wayne H-H; Sim, Xueling; Slater, Andrew J; Small, Kerrin S; Smith, Albert Vernon; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Stefansson, Kari; Steinthorsdottir, Valgerdur; Stirrups, Kathleen E; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; Swift, Amy J; Tada, Hayato; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Uusitupa, Matti; van der Laan, Sander W; van Duijn, Cornelia M; van Leeuwen, Nienke; van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Velez Edwards, Digna R; Vermeulen, Sita H; Veronesi, Giovanni; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Völker, Uwe; Vuckovic, Dragana; Wagenknecht, Lynne E; Walker, Mark; Wallentin, Lars; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Ware, Erin B; Wareham, Nicholas J; Warren, Helen R; Waterworth, Dawn M; Wessel, Jennifer; White, Harvey D; Willer, Cristen J; Wilson, James G; Witte, Daniel R; Wood, Andrew R; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhou, Wei; Zondervan, Krina T; Rotter, Jerome I; Pospisilik, John A; Rivadeneira, Fernando; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Lettre, Guillaume; North, Kari E; Lindgren, Cecilia M; Hirschhorn, Joel; Loos, Ruth JF
    Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, non-coding variants from which pinpointing causal genes remains challenging. Here, we combined data from 718,734 individuals to discover rare and low-frequency (MAF<5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which eight in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2, ZNF169) newly implicated in human obesity, two (MC4R, KSR2) previously observed in extreme obesity, and two variants in GIPR. Effect sizes of rare variants are ~10 times larger than of common variants, with the largest effect observed in carriers of an MC4R stop-codon (p.Tyr35Ter, MAF=0.01%), weighing ~7kg more than non-carriers. Pathway analyses confirmed enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically-supported therapeutic targets to treat obesity.
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    Genetically Driven Hyperglycemia Increases Risk of Coronary Artery Disease Separately From Type 2 Diabetes
    (American Diabetes Association, 2017) Merino, Jordi; Leong, Aaron; Posner, Daniel C.; Porneala, Bianca; Masana, Lluís; Dupuis, Josée; Florez, Jose
    OBJECTIVE This study tested the hypothesis that genetically raised hyperglycemia increases coronary artery disease (CAD) risk separately from the risk conferred by type 2 diabetes as a whole. RESEARCH DESIGN AND METHODS We conducted a Mendelian randomization (MR) analysis using summary-level statistics from the largest published meta-analyses of genome-wide association studies (GWAS) for fasting glucose (FG) (n = 133,010 participants free of diabetes) and CAD (n = 63,746 case subjects and 130,681 control subjects) of predominantly European ancestry. FG-increasing variants associated with type 2 diabetes from the largest GWAS for type 2 diabetes were excluded. Variants with pleiotropic effects on other CAD risk factors (blood lipids, blood pressure, and obesity) were excluded using summary-level data from the largest published GWAS. Data from the Framingham Heart Study were used to validate the MR instrument and to build an FG genetic risk score (GRS). RESULTS In an instrumental variable analysis comprising 12 FG-raising variants, a 1 mmol/L increase in FG revealed an effect-size estimate of 1.43 CAD odds (95% CI 1.14–1.79). The association was preserved after excluding variants for heterogeneity and pleiotropic effects on other CAD risk factors (odds ratio [OR] 1.33 [95% CI 1.02–1.73]). The 12 FG-increasing variants did not significantly increase type 2 diabetes risk (OR 1.05 [95% CI 0.91–1.23]), and its prevalence was constant across FG GRS quintiles (P = 0.72). CONCLUSIONS Our data support that genetic predisposition to hyperglycemia raises the odds of CAD separately from type 2 diabetes and other CAD risk factors. These findings suggest that modulating glycemia may provide cardiovascular benefit.