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1. Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function

Author: Sarah Meulebrouck, Judith Merrheim, Gurvan Queniat, Cyril Bourouh, Mehdi Derhourhi, Mathilde Boissel, Xiaoyan Yi, Alaa Badreddine, Raphaël Boutry, Audrey Leloire, Bénédicte Toussaint, Souhila Amanzougarene, Emmanuel Vaillant, Emmanuelle Durand, Hélène Loiselle, Marlène Huyvaert, Aurélie Dechaume, Victoria Scherrer, Piero Marchetti, Beverley Balkau, Guillaume Charpentier, Sylvia Franc, Michel Marre, Ronan Roussel, Raphaël Scharfmann, Miriam Cnop, Mickaël Canouil, Morgane Baron, Philippe Froguel, and Amélie Bonnefond
Subjects: Science
Abstract: Abstract Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes.
Published: 2024
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2. Identification of biomarkers for glycaemic deterioration in type 2 diabetes

Author: Roderick C. Slieker, Louise A. Donnelly, Elina Akalestou, Livia Lopez-Noriega, Rana Melhem, Ayşim Güneş, Frederic Abou Azar, Alexander Efanov, Eleni Georgiadou, Hermine Muniangi-Muhitu, Mahsa Sheikh, Giuseppe N. Giordano, Mikael Åkerlund, Emma Ahlqvist, Ashfaq Ali, Karina Banasik, Søren Brunak, Marko Barovic, Gerard A. Bouland, Frédéric Burdet, Mickaël Canouil, Iulian Dragan, Petra J. M. Elders, Celine Fernandez, Andreas Festa, Hugo Fitipaldi, Phillippe Froguel, Valborg Gudmundsdottir, Vilmundur Gudnason, Mathias J. Gerl, Amber A. van der Heijden, Lori L. Jennings, Michael K. Hansen, Min Kim, Isabelle Leclerc, Christian Klose, Dmitry Kuznetsov, Dina Mansour Aly, Florence Mehl, Diana Marek, Olle Melander, Anne Niknejad, Filip Ottosson, Imre Pavo, Kevin Duffin, Samreen K. Syed, Janice L. Shaw, Over Cabrera, Timothy J. Pullen, Kai Simons, Michele Solimena, Tommi Suvitaival, Asger Wretlind, Peter Rossing, Valeriya Lyssenko, Cristina Legido Quigley, Leif Groop, Bernard Thorens, Paul W. Franks, Gareth E. Lim, Jennifer Estall, Mark Ibberson, Joline W. J. Beulens, Leen M ’t Hart, Ewan R. Pearson, and Guy A. Rutter
Subjects: Science
Abstract: Abstract We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
Published: 2023
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3. Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Author: Lisa de las Fuentes, Karen L. Schwander, Michael R. Brown, Amy R. Bentley, Thomas W. Winkler, Yun Ju Sung, Patricia B. Munroe, Clint L. Miller, Hugo Aschard, Stella Aslibekyan, Traci M. Bartz, Lawrence F. Bielak, Jin Fang Chai, Ching-Yu Cheng, Rajkumar Dorajoo, Mary F. Feitosa, Xiuqing Guo, Fernando P. Hartwig, Andrea Horimoto, Ivana Kolčić, Elise Lim, Yongmei Liu, Alisa K. Manning, Jonathan Marten, Solomon K. Musani, Raymond Noordam, Sandosh Padmanabhan, Tuomo Rankinen, Melissa A. Richard, Paul M. Ridker, Albert V. Smith, Dina Vojinovic, Alan B. Zonderman, Maris Alver, Mathilde Boissel, Kaare Christensen, Barry I. Freedman, Chuan Gao, Franco Giulianini, Sarah E. Harris, Meian He, Fang-Chi Hsu, Brigitte Kühnel, Federica Laguzzi, Xiaoyin Li, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Alaitz Poveda, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Tamar Sofer, Fumihiko Takeuchi, Bamidele O. Tayo, Peter J. van der Most, Niek Verweij, Erin B. Ware, Stefan Weiss, Wanqing Wen, Lisa R. Yanek, Yiqiang Zhan, Najaf Amin, Dan E. Arking, Christie Ballantyne, Eric Boerwinkle, Jennifer A. Brody, Ulrich Broeckel, Archie Campbell, Mickaël Canouil, Xiaoran Chai, Yii-Der Ida Chen, Xu Chen, Kumaraswamy Naidu Chitrala, Maria Pina Concas, Ulf de Faire, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ahn Do, Jessica D. Faul, Virginia Fisher, James S. Floyd, Terrence Forrester, Yechiel Friedlander, Giorgia Girotto, C. Charles Gu, Göran Hallmans, Sami Heikkinen, Chew-Kiat Heng, Georg Homuth, Steven Hunt, M. Arfan Ikram, David R. Jacobs, Maryam Kavousi, Chiea Chuen Khor, Tuomas O. Kilpeläinen, Woon-Puay Koh, Pirjo Komulainen, Carl D. Langefeld, Jingjing Liang, Kiang Liu, Jianjun Liu, Kurt Lohman, Reedik Mägi, Ani W. Manichaikul, Colin A. McKenzie, Thomas Meitinger, Yuri Milaneschi, Matthias Nauck, Christopher P. Nelson, Jeffrey R. O’Connell, Nicholette D. Palmer, Alexandre C. Pereira, Thomas Perls, Annette Peters, Ozren Polašek, Olli T. Raitakari, Kenneth Rice, Treva K. Rice, Stephen S. Rich, Charumathi Sabanayagam, Pamela J. Schreiner, Xiao-Ou Shu, Stephen Sidney, Mario Sims, Jennifer A. Smith, John M. Starr, Konstantin Strauch, E. Shyong Tai, Kent D. Taylor, Michael Y. Tsai, André G. Uitterlinden, Diana van Heemst, Melanie Waldenberger, Ya-Xing Wang, Wen-Bin Wei, Gregory Wilson, Deng Xuan, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Diane M. Becker, Amélie Bonnefond, Donald W. Bowden, Richard S. Cooper, Ian J. Deary, Jasmin Divers, Tõnu Esko, Paul W. Franks, Philippe Froguel, Christian Gieger, Jost B. Jonas, Norihiro Kato, Timo A. Lakka, Karin Leander, Terho Lehtimäki, Patrik K. E. Magnusson, Kari E. North, Ioanna Ntalla, Brenda Penninx, Nilesh J. Samani, Harold Snieder, Beatrice Spedicati, Pim van der Harst, Henry Völzke, Lynne E. Wagenknecht, David R. Weir, Mary K. Wojczynski, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Claude Bouchard, Daniel I. Chasman, Michele K. Evans, Ervin R. Fox, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Sharon L. R. Kardia, Jose Eduardo Krieger, Dennis O. Mook-Kanamori, Patricia A. Peyser, Michael M. Province, Bruce M. Psaty, Igor Rudan, Xueling Sim, Blair H. Smith, Rob M. van Dam, Cornelia M. van Duijn, Tien Yin Wong, Donna K. Arnett, Dabeeru C. Rao, James Gauderman, Ching-Ti Liu, Alanna C. Morrison, Jerome I. Rotter, and Myriam Fornage
Subjects: educational attainment, lipids, cholesterol, triglycerides, genome-wide association study, meta-analysis, Genetics, QH426-470
Abstract: Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.
Published: 2023
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4. Elevated circulating follistatin associates with an increased risk of type 2 diabetes

Author: Chuanyan Wu, Yan Borné, Rui Gao, Maykel López Rodriguez, William C. Roell, Jonathan M. Wilson, Ajit Regmi, Cheng Luan, Dina Mansour Aly, Andreas Peter, Jürgen Machann, Harald Staiger, Andreas Fritsche, Andreas L. Birkenfeld, Rongya Tao, Robert Wagner, Mickaël Canouil, Mun-Gwan Hong, Jochen M. Schwenk, Emma Ahlqvist, Minna U. Kaikkonen, Peter Nilsson, Angela C. Shore, Faisel Khan, Andrea Natali, Olle Melander, Marju Orho-Melander, Jan Nilsson, Hans-Ulrich Häring, Erik Renström, Claes B. Wollheim, Gunnar Engström, Jianping Weng, Ewan R. Pearson, Paul W. Franks, Morris F. White, Kevin L. Duffin, Allan Arthur Vaag, Markku Laakso, Norbert Stefan, Leif Groop, and Yang De Marinis
Subjects: Science
Abstract: Follistatin promotes in type 2 diabetes (T2D) pathogenesis in model animals and is elevated in patients with T2D. Here the authors report that plasma follistatin associates with increased risk of incident T2D in two longitudinal cohorts, and show that follistatin regulates insulin-induced suppression lipolysis in cultured human adipocytes.
Published: 2021
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5. Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes

Author: Amna Khamis, Mickaël Canouil, Afshan Siddiq, Hutokshi Crouch, Mario Falchi, Manon von Bulow, Florian Ehehalt, Lorella Marselli, Marius Distler, Daniela Richter, Jürgen Weitz, Krister Bokvist, Ioannis Xenarios, Bernard Thorens, Anke M. Schulte, Mark Ibberson, Amelie Bonnefond, Piero Marchetti, Michele Solimena, and Philippe Froguel
Subjects: Internal medicine, RC31-1245
Abstract: Objective: Genome wide association studies (GWAS) for type 2 diabetes (T2D) have identified genetic loci that often localise in non-coding regions of the genome, suggesting gene regulation effects. We combined genetic and transcriptomic analysis from human islets obtained from brain-dead organ donors or surgical patients to detect expression quantitative trait loci (eQTLs) and shed light into the regulatory mechanisms of these genes. Methods: Pancreatic islets were isolated either by laser capture microdissection (LCM) from surgical specimens of 103 metabolically phenotyped pancreatectomized patients (PPP) or by collagenase digestion of pancreas from 100 brain-dead organ donors (OD). Genotyping (> 8.7 million single nucleotide polymorphisms) and expression (> 47,000 transcripts and splice variants) analyses were combined to generate cis-eQTLs. Results: After applying genome-wide false discovery rate significance thresholds, we identified 1,173 and 1,021 eQTLs in samples of OD and PPP, respectively. Among the strongest eQTLs shared between OD and PPP were CHURC1 (OD p-value=1.71 × 10-24; PPP p-value = 3.64 × 10–24) and PSPH (OD p-value = 3.92 × 10−26; PPP p-value = 3.64 × 10−24). We identified eQTLs in linkage-disequilibrium with GWAS loci T2D and associated traits, including TTLL6, MLX and KIF9 loci, which do not implicate the nearest gene. We found in the PPP datasets 11 eQTL genes, which were differentially expressed in T2D and two genes (CYP4V2 and TSEN2) associated with HbA1c but none in the OD samples. Conclusions: eQTL analysis of LCM islets from PPP led us to identify novel genes which had not been previously linked to islet biology and T2D. The understanding gained from eQTL approaches, especially using surgical samples of living patients, provides a more accurate 3-dimensional representation than those from genetic studies alone. Keywords: Type 2 diabetes, eQTLs, Genetics, Islets, Laser capture microdissection
Published: 2019
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6. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author: Tuomas O. Kilpeläinen, Amy R. Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W. Winkler, Hermina Jakupović, Daniel I. Chasman, Alisa Manning, Ioanna Ntalla, Hugues Aschard, Michael R. Brown, Lisa de las Fuentes, Nora Franceschini, Xiuqing Guo, Dina Vojinovic, Stella Aslibekyan, Mary F. Feitosa, Minjung Kho, Solomon K. Musani, Melissa Richard, Heming Wang, Zhe Wang, Traci M. Bartz, Lawrence F. Bielak, Archie Campbell, Rajkumar Dorajoo, Virginia Fisher, Fernando P. Hartwig, Andrea R. V. R. Horimoto, Changwei Li, Kurt K. Lohman, Jonathan Marten, Xueling Sim, Albert V. Smith, Salman M. Tajuddin, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Evangelos Evangelou, Chuan Gao, Mariaelisa Graff, Sarah E. Harris, Meian He, Fang-Chi Hsu, Anne U. Jackson, Jing Hua Zhao, Aldi T. Kraja, Brigitte Kühnel, Federica Laguzzi, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Rico Rueedi, Heather M. Stringham, Fumihiko Takeuchi, Peter J. van der Most, Tibor V. Varga, Niek Verweij, Erin B. Ware, Wanqing Wen, Xiaoyin Li, Lisa R. Yanek, Najaf Amin, Donna K. Arnett, Eric Boerwinkle, Marco Brumat, Brian Cade, Mickaël Canouil, Yii-Der Ida Chen, Maria Pina Concas, John Connell, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ayşe Demirkan, Jingzhong Ding, Charles B. Eaton, Jessica D. Faul, Yechiel Friedlander, Kelley P. Gabriel, Mohsen Ghanbari, Franco Giulianini, Chi Charles Gu, Dongfeng Gu, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Steven C. Hunt, M. Arfan Ikram, Jost B. Jonas, Woon-Puay Koh, Pirjo Komulainen, Jose E. Krieger, Stephen B. Kritchevsky, Zoltán Kutalik, Johanna Kuusisto, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Karin Leander, Rozenn N. Lemaitre, Cora E. Lewis, Jingjing Liang, Lifelines Cohort Study, Jianjun Liu, Reedik Mägi, Ani Manichaikul, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Karen L. Mohlke, Thomas H. Mosley, Alison D. Murray, Mike A. Nalls, Ei-Ei Khaing Nang, Christopher P. Nelson, Sotoodehnia Nona, Jill M. Norris, Chiamaka Vivian Nwuba, Jeff O’Connell, Nicholette D. Palmer, George J. Papanicolau, Raha Pazoki, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, David J. Porteous, Alaitz Poveda, Olli T. Raitakari, Stephen S. Rich, Neil Risch, Jennifer G. Robinson, Lynda M. Rose, Igor Rudan, Pamela J. Schreiner, Robert A. Scott, Stephen S. Sidney, Mario Sims, Jennifer A. Smith, Harold Snieder, Tamar Sofer, John M. Starr, Barbara Sternfeld, Konstantin Strauch, Hua Tang, Kent D. Taylor, Michael Y. Tsai, Jaakko Tuomilehto, André G. Uitterlinden, M. Yldau van der Ende, Diana van Heemst, Trudy Voortman, Melanie Waldenberger, Patrik Wennberg, Gregory Wilson, Yong-Bing Xiang, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, Ulf de Faire, Ian J. Deary, Paul Elliott, Tõnu Esko, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Norihiro Kato, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Patrik K. E. Magnusson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Nilesh J. Samani, Xiao-Ou Shu, Pim van der Harst, Jana V. Van Vliet-Ostaptchouk, Peter Vollenweider, Lynne E. Wagenknecht, Ya X. Wang, Nicholas J. Wareham, David R. Weir, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Michele K. Evans, Paul W. Franks, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Tanika N. Kelly, Yongmei Liu, Kari E. North, Alexandre C. Pereira, Paul M. Ridker, E. Shyong Tai, Rob M. van Dam, Ervin R. Fox, Sharon L. R. Kardia, Ching-Ti Liu, Dennis O. Mook-Kanamori, Michael A. Province, Susan Redline, Cornelia M. van Duijn, Jerome I. Rotter, Charles B. Kooperberg, W. James Gauderman, Bruce M. Psaty, Kenneth Rice, Patricia B. Munroe, Myriam Fornage, L. Adrienne Cupples, Charles N. Rotimi, Alanna C. Morrison, Dabeeru C. Rao, and Ruth J. F. Loos
Subjects: Science
Abstract: GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.
Published: 2019
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7. Epigenetic and Transcriptomic Programming of HSC Quiescence Signaling in Large for Gestational Age Neonates

Author: Alexandre Pelletier, Arnaud Carrier, Yongmei Zhao, Mickaël Canouil, Mehdi Derhourhi, Emmanuelle Durand, Lionel Berberian-Ferrato, John Greally, Francine Hughes, Philippe Froguel, Amélie Bonnefond, and Fabien Delahaye
Subjects: epigenomics, single-cell, stem-cells, fetal programming, hematopoiesis, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Excessive fetal growth is associated with DNA methylation alterations in human hematopoietic stem and progenitor cells (HSPC), but their functional impact remains elusive. We implemented an integrative analysis combining single-cell epigenomics, single-cell transcriptomics, and in vitro analyses to functionally link DNA methylation changes to putative alterations of HSPC functions. We showed in hematopoietic stem cells (HSC) from large for gestational age neonates that both DNA hypermethylation and chromatin rearrangements target a specific network of transcription factors known to sustain stem cell quiescence. In parallel, we found a decreased expression of key genes regulating HSC differentiation including EGR1, KLF2, SOCS3, and JUNB. Our functional analyses showed that this epigenetic programming was associated with a decreased ability for HSCs to remain quiescent. Taken together, our multimodal approach using single-cell (epi)genomics showed that human fetal overgrowth affects hematopoietic stem cells’ quiescence signaling via epigenetic programming.
Published: 2022
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8. Persistent or Transient Human β Cell Dysfunction Induced by Metabolic Stress: Specific Signatures and Shared Gene Expression with Type 2 Diabetes

Author: Lorella Marselli, Anthony Piron, Mara Suleiman, Maikel L. Colli, Xiaoyan Yi, Amna Khamis, Gaelle R. Carrat, Guy A. Rutter, Marco Bugliani, Laura Giusti, Maurizio Ronci, Mark Ibberson, Jean-Valery Turatsinze, Ugo Boggi, Paolo De Simone, Vincenzo De Tata, Miguel Lopes, Daniela Nasteska, Carmela De Luca, Marta Tesi, Emanuele Bosi, Pratibha Singh, Daniela Campani, Anke M. Schulte, Michele Solimena, Peter Hecht, Brian Rady, Ivona Bakaj, Alessandro Pocai, Lisa Norquay, Bernard Thorens, Mickaël Canouil, Philippe Froguel, Decio L. Eizirik, Miriam Cnop, and Piero Marchetti
Subjects: type 2 diabetes, lipoglucotoxicity, glucolipotoxicity, human pancreatic islets, beta cells, damage, Biology (General), QH301-705.5
Abstract: Summary: Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination. The reversal of dysfunction occurs after washout for some, although not all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA sequencing and expression quantitative trait loci (eQTL) analysis identify specific pathways underlying β cell failure and recovery. Comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β cell lipoglucotoxicity show shared gene expression signatures. The identification of mechanisms associated with human β cell dysfunction and recovery and their overlap with T2D islet traits provide insights into T2D pathogenesis, fostering the development of improved β cell-targeted therapeutic strategies.
Published: 2020
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9. Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion

Author: Fatou K. Ndiaye, Ana Ortalli, Mickaël Canouil, Marlène Huyvaert, Clara Salazar-Cardozo, Cécile Lecoeur, Marie Verbanck, Valérie Pawlowski, Raphaël Boutry, Emmanuelle Durand, Iandry Rabearivelo, Olivier Sand, Lorella Marselli, Julie Kerr-Conte, Vikash Chandra, Raphaël Scharfmann, Odile Poulain-Godefroy, Piero Marchetti, François Pattou, Amar Abderrahmani, Philippe Froguel, and Amélie Bonnefond
Subjects: Internal medicine, RC31-1245
Abstract: Objectives: Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells. Methods: The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-βH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-βH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function. Results: We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-βH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-βH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression of Prc1, Srr, Zfand6, and Zfand3 was found in mouse pancreatic islets with altered beta-cell function. Conclusions: This study showed the ability of post-GWAS functional studies to identify new genes and pathways involved in human pancreatic beta-cell function and in T2D pathophysiology. Keywords: EndoC-βH1, Expression analysis, Genome-wide association study, Insulin secretion, RNAi screening, Type 2 diabetes
Published: 2017
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10. Jointly Modelling Single Nucleotide Polymorphisms With Longitudinal and Time-to-Event Trait: An Application to Type 2 Diabetes and Fasting Plasma Glucose

Author: Mickaël Canouil, Beverley Balkau, Ronan Roussel, Philippe Froguel, and Ghislain Rocheleau
Subjects: joint modelling, survival analysis, longitudinal biomarker, genetic, diabetes, glycaemia, Genetics, QH426-470
Abstract: In observational cohorts, longitudinal data are collected with repeated measurements at predetermined time points for many biomarkers, along with other variables measured at baseline. In these cohorts, time until a certain event of interest occurs is reported and very often, a relationship will be observed between some biomarker repeatedly measured over time and that event. Joint models were designed to efficiently estimate statistical parameters describing this relationship by combining a mixed model for the longitudinal biomarker trajectory and a survival model for the time until occurrence of the event, using a set of random effects to account for the relationship between the two types of data. In this paper, we discuss the implementation of joint models in genetic association studies. First, we check model consistency based on different simulation scenarios, by varying sample sizes, minor allele frequencies and number of repeated measurements. Second, using genotypes assayed with the Metabochip DNA arrays (Illumina) from about 4,500 individuals recruited in the French cohort D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance syndrome), we assess the feasibility of implementing the joint modelling approach in a real high-throughput genomic dataset. An alternative model approximating the joint model, called the Two-Step approach (TS), is also presented. Although the joint model shows more precise and less biased estimators than its alternative counterpart, the TS approach results in much reduced computational times, and could thus be used for testing millions of SNPs at the genome-wide scale.
Published: 2018
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11. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

Author: Mary F Feitosa, Aldi T Kraja, Daniel I Chasman, Yun J Sung, Thomas W Winkler, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K Musani, Changwei Li, Amy R Bentley, Michael R Brown, Karen Schwander, Melissa A Richard, Raymond Noordam, Hugues Aschard, Traci M Bartz, Lawrence F Bielak, Rajkumar Dorajoo, Virginia Fisher, Fernando P Hartwig, Andrea R V R Horimoto, Kurt K Lohman, Alisa K Manning, Tuomo Rankinen, Albert V Smith, Salman M Tajuddin, Mary K Wojczynski, Maris Alver, Mathilde Boissel, Qiuyin Cai, Archie Campbell, Jin Fang Chai, Xu Chen, Jasmin Divers, Chuan Gao, Anuj Goel, Yanick Hagemeijer, Sarah E Harris, Meian He, Fang-Chi Hsu, Anne U Jackson, Mika Kähönen, Anuradhani Kasturiratne, Pirjo Komulainen, Brigitte Kühnel, Federica Laguzzi, Jian'an Luan, Nana Matoba, Ilja M Nolte, Sandosh Padmanabhan, Muhammad Riaz, Rico Rueedi, Antonietta Robino, M Abdullah Said, Robert A Scott, Tamar Sofer, Alena Stančáková, Fumihiko Takeuchi, Bamidele O Tayo, Peter J van der Most, Tibor V Varga, Veronique Vitart, Yajuan Wang, Erin B Ware, Helen R Warren, Stefan Weiss, Wanqing Wen, Lisa R Yanek, Weihua Zhang, Jing Hua Zhao, Saima Afaq, Najaf Amin, Marzyeh Amini, Dan E Arking, Tin Aung, Eric Boerwinkle, Ingrid Borecki, Ulrich Broeckel, Morris Brown, Marco Brumat, Gregory L Burke, Mickaël Canouil, Aravinda Chakravarti, Sabanayagam Charumathi, Yii-Der Ida Chen, John M Connell, Adolfo Correa, Lisa de Las Fuentes, Renée de Mutsert, H Janaka de Silva, Xuan Deng, Jingzhong Ding, Qing Duan, Charles B Eaton, Georg Ehret, Ruben N Eppinga, Evangelos Evangelou, Jessica D Faul, Stephan B Felix, Nita G Forouhi, Terrence Forrester, Oscar H Franco, Yechiel Friedlander, Ilaria Gandin, He Gao, Mohsen Ghanbari, Bruna Gigante, C Charles Gu, Dongfeng Gu, Saskia P Hagenaars, Göran Hallmans, Tamara B Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Makoto Hirata, Barbara V Howard, M Arfan Ikram, InterAct Consortium, Ulrich John, Tomohiro Katsuya, Chiea Chuen Khor, Tuomas O Kilpeläinen, Woon-Puay Koh, José E Krieger, Stephen B Kritchevsky, Michiaki Kubo, Johanna Kuusisto, Timo A Lakka, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Benjamin Lehne, Cora E Lewis, Yize Li, Shiow Lin, Jianjun Liu, Jingmin Liu, Marie Loh, Tin Louie, Reedik Mägi, Colin A McKenzie, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Lili Milani, Karen L Mohlke, Yukihide Momozawa, Mike A Nalls, Christopher P Nelson, Nona Sotoodehnia, Jill M Norris, Jeff R O'Connell, Nicholette D Palmer, Thomas Perls, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Neil Poulter, Leslie J Raffel, Olli T Raitakari, Kathryn Roll, Lynda M Rose, Frits R Rosendaal, Jerome I Rotter, Carsten O Schmidt, Pamela J Schreiner, Nicole Schupf, William R Scott, Peter S Sever, Yuan Shi, Stephen Sidney, Mario Sims, Colleen M Sitlani, Jennifer A Smith, Harold Snieder, John M Starr, Konstantin Strauch, Heather M Stringham, Nicholas Y Q Tan, Hua Tang, Kent D Taylor, Yik Ying Teo, Yih Chung Tham, Stephen T Turner, André G Uitterlinden, Peter Vollenweider, Melanie Waldenberger, Lihua Wang, Ya Xing Wang, Wen Bin Wei, Christine Williams, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B Zonderman, Diane M Becker, Michael Boehnke, Donald W Bowden, John C Chambers, Ian J Deary, Tõnu Esko, Martin Farrall, Paul W Franks, Barry I Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Jost Bruno Jonas, Yoichiro Kamatani, Norihiro Kato, Jaspal S Kooner, Zoltán Kutalik, Markku Laakso, Cathy C Laurie, Karin Leander, Terho Lehtimäki, Lifelines Cohort Study, Patrik K E Magnusson, Albertine J Oldehinkel, Brenda W J H Penninx, Ozren Polasek, David J Porteous, Rainer Rauramaa, Nilesh J Samani, James Scott, Xiao-Ou Shu, Pim van der Harst, Lynne E Wagenknecht, Nicholas J Wareham, Hugh Watkins, David R Weir, Ananda R Wickremasinghe, Tangchun Wu, Wei Zheng, Claude Bouchard, Kaare Christensen, Michele K Evans, Vilmundur Gudnason, Bernardo L Horta, Sharon L R Kardia, Yongmei Liu, Alexandre C Pereira, Bruce M Psaty, Paul M Ridker, Rob M van Dam, W James Gauderman, Xiaofeng Zhu, Dennis O Mook-Kanamori, Myriam Fornage, Charles N Rotimi, L Adrienne Cupples, Tanika N Kelly, Ervin R Fox, Caroline Hayward, Cornelia M van Duijn, E Shyong Tai, Tien Yin Wong, Charles Kooperberg, Walter Palmas, Kenneth Rice, Alanna C Morrison, Paul Elliott, Mark J Caulfield, Patricia B Munroe, Dabeeru C Rao, Michael A Province, and Daniel Levy
Subjects: Medicine, Science
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
Published: 2018
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12. Low-dose exposure to bisphenols A, F and S of human primary adipocyte impacts coding and non-coding RNA profiles.

Author: Marie Verbanck, Mickaël Canouil, Audrey Leloire, Véronique Dhennin, Xavier Coumoul, Loïc Yengo, Philippe Froguel, and Odile Poulain-Godefroy
Subjects: Medicine, Science
Abstract: Bisphenol A (BPA) exposure has been suspected to be associated with deleterious effects on health including obesity and metabolically-linked diseases. Although bisphenols F (BPF) and S (BPS) are BPA structural analogs commonly used in many marketed products as a replacement for BPA, only sparse toxicological data are available yet. Our objective was to comprehensively characterize bisphenols gene targets in a human primary adipocyte model, in order to determine whether they may induce cellular dysfunction, using chronic exposure at two concentrations: a "low-dose" similar to the dose usually encountered in human biological fluids and a higher dose. Therefore, BPA, BPF and BPS have been added at 10 nM or 10 μM during the differentiation of human primary adipocytes from subcutaneous fat of three non-diabetic Caucasian female patients. Gene expression (mRNA/lncRNA) arrays and microRNA arrays, have been used to assess coding and non-coding RNA changes. We detected significantly deregulated mRNA/lncRNA and miRNA at low and high doses. Enrichment in "cancer" and "organismal injury and abnormalities" related pathways was found in response to the three products. Some long intergenic non-coding RNAs and small nucleolar RNAs were differentially expressed suggesting that bisphenols may also activate multiple cellular processes and epigenetic modifications. The analysis of upstream regulators of deregulated genes highlighted hormones or hormone-like chemicals suggesting that BPS and BPF can be suspected to interfere, just like BPA, with hormonal regulation and have to be considered as endocrine disruptors. All these results suggest that as BPA, its substitutes BPS and BPF should be used with the same restrictions.
Published: 2017
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13. Contribution of heterozygous PCSK1 variants to obesity and implications for precision medicine: a case-control study

Author: Lise Folon, Morgane Baron, Bénédicte Toussaint, Emmanuel Vaillant, Mathilde Boissel, Victoria Scherrer, Hélène Loiselle, Audrey Leloire, Alaa Badreddine, Beverley Balkau, Guillaume Charpentier, Sylvia Franc, Michel Marre, Soulaimane Aboulouard, Michel Salzet, Mickaël Canouil, Mehdi Derhourhi, Philippe Froguel, and Amélie Bonnefond
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Internal Medicine
Published: 2023

14. NACHO: an R package for quality control of NanoString nCounter data.

Author: Mickaël Canouil, Gerard A. Bouland, Amélie Bonnefond, Philippe Froguel, Leen M. 't Hart, and Roderick C. Slieker
Published: 2020
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15. High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor

Author: Sadia Saeed, Roohia Khanam, Qasim M. Janjua, Jaida Manzoor, Lijiao Ning, Sharoon Hanook, Mickaël Canouil, Muhammad Ali, Hina Ayesha, Waqas I. Khan, I. Sadaf Farooqi, Giles S.H. Yeo, Stephen O’Rahilly, Amélie Bonnefond, Taeed A. Butt, Muhammad Arslan, and Philippe Froguel
Abstract: BACKGROUNDBiallelic pathogenic mutations inLEP, LEPRandMC4Rgenes controlling central leptin-melanocortin signalling cause early onset severe obesity. However, the long-term clinical outcomes of leptin signalling deficiency are unknown.DESIGN AND OBJECTIVESWe carried out a retrospective cross-sectional clinical investigation of a large cohort of children withLEP, LEPRorMC4Rdeficiency, to evaluate the progression of the disease and its impact on morbidity and mortality.PARTICIPANTSSeverely obese children from 454 consanguineous families of Pakistani origin were screened for mutations in the three genes using Sanger and exome sequencing. We identified 132 probands and 13 affected family members with homozygous pathogenic mutations inLEP, LEPRorMC4R.MAIN OUTCOME MEASURESWeight, height, and head circumference were measured by trained technicians using standardized protocols. WHO-anthro and anthroplus were used to assess BMI-standard deviation score. All affected individuals underwent detailed physical and clinical investigations by expert paediatric endocrinologist. Metabolic and oxidative stress biomarkers were measured in serum.RESULTSWe report a very high mortality in children withLEP(26%) andLEPR-deficiency (9%), mainly due to recurrent pulmonary and gastro-intestinal infections. In addition, 40% ofLEP- orLEPR-deficient surviving children experienced life-threatening episodes of pulmonary or gastro-intestinal infections. Oxidative stress as assessed by biomarkers, was significantly higher inLEPdeficiency compared to the other two mutant groups.CONCLUSIONSChildren with congenital deficiency of leptin or its receptor suffer a high mortality rate, and severe morbidity. Although effective therapies are available for both but as yet(orto-date) are not accessible in Pakistan. An appreciation of the severe impact of leptin or leptin receptor deficiency on educational attainment, morbidity and early mortality risks should spur efforts to deliver available life-saving drugs to these children as a matter of urgency.
Published: 2023

16. Epigenetics ofPNLIPRP1in human pancreas reveals a molecular path between type 2 diabetes and pancreatic cancer

Author: Lucas Maurin, Lorella Marselli, Lijiao Ning, Mathilde Boissel, Raphael Boutry, Mara Suleiman, Audrey Leloire, Vincent Pascat, Jared Maina, Bénédicte Toussaint, Souhila Amanzougarene, Alaa Badreddine, Mehdi Derhourhi, Inga Prokopenko, Anne Jörns, Sigurd Lenzen, François Pattou, Julie Kerr-Conte, Mickaël Canouil, Amélie Bonnefond, Piero Marchetti, Philippe Froguel, and Amna Khamis
Abstract: BackgroundType 2 diabetes (T2D) increases the risk of pancreatic ductal adenocarcinoma (PDAC), which could be due to an epigenetic mechanism.MethodsWe explored the association between T2D and whole pancreas methylation in 141 individuals, of which 28 had T2D, using Illumina MethylationEPIC 850K BeadChip arrays. We performed downstream functional assessment in the rat acinar pancreas cell line AR42J. To further understand the role of our candidate gene in humans, we tested whether null variants were associated with T2D and related traits using the UK biobank.ResultsMethylation analysis identified one significant CpG associated with T2D: hypermethylation in an enhancer inPNLIPRP1, an acinar-specific gene.PNLIPRP1expression was decreased in T2D individuals. Using a rat acinar cell line, we 1/ confirmed decreasedPnliprp1in response to a diabetogenic treatment, and 2/ inPnliprp1knockdown, an up-regulation of cholesterol biosynthesis, cell cycle down-regulation, decreased expression of acinar markers and increased expression of ductal markers pointing towards acinar-to-ductal metaplasia (ADM), a hallmark of PDAC initiation. Using exome data from UK Biobank, we show that rarePNLIPRP1null variants associated with increased glucose, BMI and LDL-cholesterol.Conclusions/interpretationWe present evidence that an epigenetically-regulated gene associates with T2D risk, and might promote ADM and PDAC progression, opening new insights into early prevention of PDAC.
Published: 2022

17. Pathogenic variants in actionable MODY genes are associated with type 2 diabetes

Author: Elizabeth T. Cirulli, Nicole L. Washington, Mickaël Canouil, Guillaume Charpentier, Emmanuelle Durand, Jean-Michel Borys, Alexandre Bolze, Franck De Graeve, Aurélie Dechaume, David Le Guilcher, Beverley Balkau, Sylvia Franc, Frédéric Allegaert, Ronan Roussel, Emmanuel Vaillant, Philippe Froguel, Gai Elhanan, Stefan Gaget, Joseph J. Grzymski, Loic Yengo, Véronique Dhennin, Amélie Bonnefond, James T. Lu, M Vaxillaire, Mathilde Boissel, Michel Marre, Bénédicte Toussaint, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018)
Subjects: Male, Heterozygote, MESH: Mutation, endocrine system diseases, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Type 2 diabetes, ABCC8, Germinal Center Kinases, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Diabetes mellitus, Internal Medicine, medicine, Humans, MESH: Genetic Variation, Gene, 030304 developmental biology, Monogenic Diabetes, Genetic association, Genetics, 0303 health sciences, MESH: Humans, biology, business.industry, Computational Biology, Genetic Variation, nutritional and metabolic diseases, Cell Biology, Middle Aged, medicine.disease, Precision medicine, HNF1B, 3. Good health, Diabetes Mellitus, Type 2, Mutation, MESH: Genome-Wide Association Study, biology.protein, Female, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, MESH: Computational Biology, MESH: Diabetes Mellitus, Type 2
Abstract: International audience; Genome-wide association studies have identified 240 independent loci associated with type 2 diabetes (T2D) risk, but this knowledge has not advanced precision medicine. In contrast, the genetic diagnosis of monogenic forms of diabetes (including maturity-onset diabetes of the young (MODY)) are textbook cases of genomic medicine. Recent studies trying to bridge the gap between monogenic diabetes and T2D have been inconclusive. Here, we show a significant burden of pathogenic variants in genes linked with monogenic diabetes among people with common T2D, particularly in actionable MODY genes, thus implying that there should be a substantial change in care for carriers with T2D. We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. The carriers with T2D are leaner, which evidences a functional metabolic effect of these mutations. Pathogenic variants in actionable MODY genes are more frequent than was previously expected in common T2D. These results open avenues for future interventions assessing the clinical interest of these pathogenic mutations in precision medicine.
Published: 2020

18. Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

Author: Elmar W. Tobi, Diana L. Juvinao-Quintero, Justiina Ronkainen, Raffael Ott, Rossella Alfano, Mickaël Canouil, Madelon L. Geurtsen, Amna Khamis, Leanne K. Küpers, Ives Y. Lim, Patrice Perron, Giancarlo Pesce, Johanna Tuhkanen, Anne P. Starling, Toby Andrew, Elisabeth Binder, Robert Caiazzo, Jerry K.Y. Chan, Romy Gaillard, Peter D. Gluckman, Elina Keikkala, Neerja Karnani, Sanna Mustaniemi, Tim S. Nawrot, François Pattou, Michelle Plusquin, Violeta Raverdy, Kok Hian Tan, Evangelia Tzala, Katri Raikkonen, Christiane Winkler, Anette-G. Ziegler, Isabella Annesi-Maesano, Luigi Bouchard, Yap Seng Chong, Dana Dabelea, Janine F. Felix, Barbara Heude, Vincent W.V. Jaddoe, Jari Lahti, Brigitte Reimann, Marja Vääräsmäki, Amélie Bonnefond, Philippe Froguel, Sandra Hummel, Eero Kajantie, Marjo-Riita Jarvelin, Regine P.M. Steegers-Theunissen, Caitlin G. Howe, Marie-France Hivert, Sylvain Sebert, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Harvard Pilgrim Health Care Institute, University of Oulu, Helmholtz Zentrum München = German Research Center for Environmental Health, Klinikums rechts der Isar, Hasselt University (UHasselt), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The Generation R Study Group, Imperial College London, Bioinformatics Institute (A*STAR), Singapore Institute for Clinical Sciences [Singapour] (SICS), Agency for science, technology and research [Singapore] (A*STAR), Université de Sherbrooke (UdeS), Centre Hospitalier Universitaire de Sherbrooke, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Epidemiology of Allergic and Respiratory Diseases Department [iPlesp] (EPAR), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), TKK Helsinki University of Technology (TKK), Colorado School of Public Health [Aurora, CO, USA] (CSPH), University of Colorado Anschutz [Aurora], Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Emory University School of Medicine, Emory University [Atlanta, GA], Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), KK Women's and Children's Hospital [Singapore], Duke-NUS Medical School [Singapore], Liggins Institute, University of Auckland [Auckland], Finnish Institute for Health and Welfare [Helsinki, Finland] (FIHW), Oulu University Hospital [Oulu], Bioinformatics Institute [Singapore], Yong Loo Lin School of Medicine [Singapore], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université du Québec à Chicoutimi (UQAC), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Norwegian University of Life Sciences (NMBU), Brunel University London [Uxbridge], Geisel School of Medicine at Dartmouth, Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], Salvy-Córdoba, Nathalie, Obstetrics & Gynecology, Pediatrics, Binder, Elisabeth, Küpers, Leanne K., Geurtsen, Madelon L., Raikkonen, Katri, Tuhkanen, Johanna, Felix, Janine F., ALFANO, Rossella, Winkler, Christiane, Ott, Raffael, Dabelea, Dana, Khamis, Amna, Bouchard, Luigi, Bonnefond, Amélie, Canouil, Mickaël, Karnani, Neerja, Hummel, Sandra, Tobi, Elmar W, Sebert, Sylvain, Jarvelin, Marjo-Riita, Keikkala, Elina, Heude, Barbara, Pesce, Giancarlo, Steegers-Theunissen, Regine P.M., Lim, Ives Y., REIMANN, Brigitte, Caiazzo, Robert, Hian Tan, Kok, Chan, Jerry K.Y., Ronkainen, Justiina, Ziegler, Anette-G., NAWROT, Tim, Froguel, Philippe, Gluckman, Peter D., Raverdy, Violeta, Starling, Anne P., Howe, Caitlin G., Lahti, Jari, Mustaniemi, Sanna, Hivert, Marie-France, Seng Chong, Yap, Jaddoe, Vincent W.V., Perron, Patrice, Pattou, François, Annesi-Maesano, Isabella, Juvinao-Quintero, Diana L., Gaillard, Romy, Vääräsmäki, Marja, Plusquin, Michelle, Andrew, Toby, Kajantie, Eero, and Tzala, Evangelia
Subjects: Endocrinology, Diabetes and Metabolism, MESH: Epigenome, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Epigenesis, Genetic, Endocrinology & Metabolism, Epigenome, MESH: DNA Methylation, MESH: Pregnancy, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, SDG 3 - Good Health and Well-being, HYPERGLYCEMIA, Pregnancy, Internal Medicine, Humans, MESH: Fetal Blood, MESH: Epigenesis, Genetic, Advanced and Specialized Nursing, MESH: Diabetes, Gestational, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Science & Technology, MESH: Humans, MESH: Infant, Newborn, Infant, Newborn, DNA Methylation, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Fetal Blood, Diabetes, Gestational, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Diabetes Mellitus, Type 2, Female, Life Sciences & Biomedicine, MESH: Female, MESH: Diabetes Mellitus, Type 2
Abstract: OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring; a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effect meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmax= 3,503), insulin (Nmax= 2,062), and the area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (OGTT, Nmax= 1,505). We performed look-up analyses for identified CpG dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β= -0.013 [SE=2.1x10-3], PFDR= 5.1x10-3) and cg02988288 (β= -0.013 [SE=2.3x10-3], PFDR =0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSION Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent look-up analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.
Published: 2022

19. Rare Variant Analysis of Obesity-Associated Genes in Young Adults With Severe Obesity From a Consanguineous Population of Pakistan

Author: Sadia Saeed, Qasim M. Janjua, Attiya Haseeb, Roohia Khanam, Emmanuelle Durand, Emmanuel Vaillant, Lijiao Ning, Alaa Badreddine, Lionel Berberian, Mathilde Boissel, Souhila Amanzougarene, Mickaël Canouil, Mehdi Derhourhi, Amélie Bonnefond, Muhammad Arslan, and Philippe Froguel
Subjects: Pediatric Obesity, Endocrinology, Diabetes and Metabolism, Obesity, Morbid, Consanguinity, Mice, Young Adult, Internal Medicine, Animals, Humans, Receptor, Melanocortin, Type 4, Receptors, Leptin, Pakistan, Child, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract: Recent advances in genetic analysis have significantly helped in progressively attenuating the heritability gap of obesity and have brought into focus monogenic variants that disrupt the melanocortin signalling. In a previous study, next generation sequencing has revealed a monogenic aetiology in ~50% of the children with severe obesity from a consanguineous population in Pakistan. Here we assess rare variants in obesity causing genes in young adults with severe obesity from the same region. Genomic DNA from randomly selected 128 young adult obese subjects (BMI=37.2 ± 0.3; age=18.4 ± 0.3 years) was screened by conventional or augmented whole exome analysis for point mutations and copy number variants (CNVs). Leptin, insulin and cortisol levels were measured by ELISA. We identified thirteen subjects carrying 13 different pathogenic or likely pathogenic variants in LEPR, PCSK1, MC4R, NTRK2, POMC, SH2B1 and SIM1. We also identified for the first time in the human, two homozygous stop-gain mutations in ASNSD1 and IFI16 genes. Inactivation of these genes in mouse models has been shown to result in obesity. Additionally, we describe 9 homozygous mutations (7 missense, 1 stop-gain and 1 stop-loss) and 4 copy-loss CNVs in genes or genomic regions previously linked to obesity-associated traits by genome-wide association studies (GWAS). Unexpectedly, in contrast to obese children, pathogenic mutations in LEP and LEPR were either absent or rare, in this cohort of young adults. High morbidity and mortality risks and social disadvantage of children with LEP or LEPR deficiency may in part explain this difference between the two cohorts.
Published: 2022

20. Epigenetic changes associated with hyperglycaemia exposure in the longitudinal D.E.S.I.R. cohort

Author: Amna Khamis, Lijiao Ning, Beverley Balkau, Amélie Bonnefond, Mickaël Canouil, Ronan Roussel, Philippe Froguel, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Imperial College London, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Fibrose Inflammation Remodelage [Hôpitaux Universitaires Paris Nord Val de Seine] (DHU FIRE ), Hôpitaux Universitaires Paris Nord Val de Seine, ANR-10-EQPX-07-01, ANR-10-LABX-46, European Commission, EC, Agence Nationale de la Recherche, ANR: ANR-18-IBHU-0001, European Regional Development Fund, ERDF, Conseil Régional Hauts-de-France, This study was funded by LabEx EGID ( European Genomic Institute for Diabetes ) under Grant ANR-10-LABX-46, EquipEx LIGAN PM under Grant ANR-10-EQPX-07-01, and PreciDIAB (National Center for Precision Diabetic Medicine), which is jointly supported by the French National Agency for Research ( ANR-18-IBHU-0001 ), by the European Union (FEDER), by the Hauts-de-France Regional Council and by the European Metropolis of Lille (MEL)., ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), École pratique des hautes études (EPHE), and HAL UVSQ, Équipe
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Glycated Hemoglobin, Hyperglycaemia exposure, Endocrinology, Diabetes and Metabolism, General Medicine, DNA Methylation, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Methylation, Epigenesis, Genetic, Endocrinology, Diabetes Mellitus, Type 2, Hyperglycemia, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal Medicine, Longitudinal, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, CpG Islands, Epigenetics, Genome-Wide Association Study
Abstract: AimUnderstanding DNA methylation dynamics associated with progressive hyperglycaemia exposure could provide early diagnostic biomarkers and an avenue for delaying type 2 diabetes (T2D) disease. We aimed to identify DNA methylation changes during a 6-year period associated with early hyperglycaemia exposure using the longitudinal D.E.S.I.R. cohort.MethodsWe selected individuals with progressive hyperglycaemia exposure based on T2D diagnostic criteria: 27 with long-term exposure, 34 with short-term exposure and 34 normoglycaemic controls. DNA from blood at inclusion and at the 6-years visit was subjected to methylation analysis using 850K methylation-EPIC arrays. A linear mixed model was used to perform an epigenome-wide association study (EWAS) and identify methylated changes associated with hyperglycaemia exposure during 6-year time-period.ResultsWe did not identify differentially methylated sites that reached FDR-significance in our cohort. Based on EWAS, we focused our analysis on methylation sites that had a constant effect during the 6-years across the hyperglycaemia groups compared to controls and found the most statistically significant site was the reported cg19693031 probe (TXNIP). We also performed an EWAS with HbA1c, using the inclusion and the 6-years methylation data and did not identify any FDR-significant CpGs.ConclusionsOur study reveals that DNA methylation changes are not robustly associated with hyperglycaemia exposure or HbA1c during a short-term period, however, our top loci indicate potential interest and should be replicated in larger cohorts.
Published: 2022

21. Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Author: Natalia Pervjakova, Gunn-Helen Moen, Maria-Carolina Borges, Teresa Ferreira, James P Cook, Catherine Allard, Robin N Beaumont, Mickaël Canouil, Gad Hatem, Anni Heiskala, Anni Joensuu, Ville Karhunen, Soo Heon Kwak, Frederick T J Lin, Jun Liu, Sheryl Rifas-Shiman, Claudia H Tam, Wing Hung Tam, Gudmar Thorleifsson, Toby Andrew, Juha Auvinen, Bishwajit Bhowmik, Amélie Bonnefond, Fabien Delahaye, Ayse Demirkan, Philippe Froguel, Kadri Haller-Kikkatalo, Hildur Hardardottir, Sandra Hummel, Akhtar Hussain, Eero Kajantie, Elina Keikkala, Amna Khamis, Jari Lahti, Tove Lekva, Sanna Mustaniemi, Christine Sommer, Aili Tagoma, Evangelia Tzala, Raivo Uibo, Marja Vääräsmäki, Pia M Villa, Kåre I Birkeland, Luigi Bouchard, Cornelia M Duijn, Sarah Finer, Leif Groop, Esa Hämäläinen, Geoffrey M Hayes, Graham A Hitman, Hak C Jang, Marjo-Riitta Järvelin, Anne Karen Jenum, Hannele Laivuori, Ronald C Ma, Olle Melander, Emily Oken, Kyong Soo Park, Patrice Perron, Rashmi B Prasad, Elisabeth Qvigstad, Sylvain Sebert, Kari Stefansson, Valgerdur Steinthorsdottir, Tiinamaija Tuomi, Marie-France Hivert, Paul W Franks, Mark I McCarthy, Cecilia M Lindgren, Rachel M Freathy, Deborah A Lawlor, Andrew P Morris, Reedik Mägi, Quantitative Genetics, University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism, HUS Children and Adolescents, Department of Psychology and Logopedics, Clinicum, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Hyvinkää Hospital Area, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Department of Medical and Clinical Genetics, Tiinamaija Tuomi Research Group, Department of Medicine, Endokrinologian yksikkö, Tampere University, Clinical Medicine, Department of Gynaecology and Obstetrics, and Epidemiology
Subjects: cdkn2b gene, diabetes mellitus type 2, protein p16, endocrine system diseases, LD SCORE REGRESSION, LOCI, Medisinske Fag: 700::Klinisk medisinske fag: 750::Gynekologi og obstetrikk: 756 [VDP], Medisinske Fag: 700::Klinisk medisinske fag: 750::Endokrinologi: 774 [VDP], VARIANTS, 3121 Internal medicine, Polymorphism, Single Nucleotide, ANNOTATION, tcf7l2 gene, SDG 3 - Good Health and Well-being, HYPERGLYCEMIA, Genetics, Humans, Genetic Predisposition to Disease, genetics, INFLUENCING GLYCEMIC TRAITS, glucose, Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], genome, Molecular Biology, Genetics (clinical), RISK, genome-wide association study, 1184 Genetics, developmental biology, physiology, Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk molekylærbiologi: 711 [VDP], WOMEN, nutritional and metabolic diseases, General Medicine, BIRTH-WEIGHT, female genital diseases and pregnancy complications, Diabetes, Gestational, Glucose, PREGNANCY, Diabetes Mellitus, Type 2, genes p16, diabetes mellitus, 1182 Biochemistry, cell and molecular biology, Female, pregnancy, body mass index procedure, gestational diabetes, Genome-Wide Association Study
Abstract: Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P
Published: 2022
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22. Trans-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Author: Toby Andrew, Philippe Froguel, Maria Carolina Borges, Hildur Hardardottir, Frederick T.J. Lin, Marja Vaarasmaki, Ville Karhunen, Sanna Mustaniemi, Christine Sommer, Esa Hämäläinen, Sarah Finer, Graham A. Hitman, Bishwajit Bhowmik, Teresa Ferreira, Gudmar Thorleifsson, Fabien Delahaye, Hannele Laivuori, Leif Groop, Tiinamaija Tuomi, Emily Oken, Hak Chul Jang, Tove Lekva, Olle Melander, Anni Heiskala, Rashmi B. Prasad, Raivo Uibo, Geoffrey Hayes, Cornelia M. van Duijn, Juha Auvinen, Andrew P. Morris, Luigi Bouchard, Elina Keikkala, Marie-France Hivert, Elisabeth Qvigstad, Jari Lahti, Kåre I. Birkeland, James P. Cook, Jun Liu, Marjo-Riitta Järvelin, Catherine Allard, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Evangelia Tzala, Aili Tagoma, Paul W. Franks, Gad Hatem, Anne Karen Jenum, Sylvain Sebert, Mark I. McCarthy, Debbie A Lawlor, Kari Stefansson, Ayse Demirkan, Gunn-Helen Moen, Pia M. Villa, Rachel M. Freathy, Akhtar Hussain, Kyong Soo Park, Soo Heon Kwak, Sandra Hummel, Eero Kajantie, Amélie Bonnefond, Reedik Mägi, Robin N Beaumont, Mickaël Canouil, Natalia Pervjakova, Anni Joensuu, Amna Khamis, Sheryl L. Rifas-Shiman, Patrice Perron, and Kadri Haller-Kikkatalo
Subjects: 2. Zero hunger, 0303 health sciences, Pregnancy, endocrine system diseases, business.industry, Diabetes in pregnancy, nutritional and metabolic diseases, 030209 endocrinology & metabolism, Genome-wide association study, Type 2 diabetes, medicine.disease, Bioinformatics, 3. Good health, Gestational diabetes, 03 medical and health sciences, 0302 clinical medicine, Increased risk, Etiology, medicine, business, 030304 developmental biology, Genetic association
Abstract: Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5,485 women with GDM and 347,856 without GDM. Through trans-ancestry meta-analysis, we identified five loci with genome-wide significant association (p−8) with GDM, mapping to/near MTNR1B (p=4.3×10−54), TCF7L2 (p=4.0×10−16), CDKAL1 (p=1.6×10−14), CDKN2A-CDKN2B (p=4.1×10−9) and HKDC1 (p=2.9×10−8). Multiple lines of evidence pointed to genetic contributions to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.
Published: 2021

23. Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome

Author: Sandra Hummel, Sylvain Sebert, Elina Keikkala, Toby Andrew, Stéphane Lobbens, Marjo-Riitta Järvelin, Evangelia Tzala, Mickaël Canouil, Fabien Delahaye, Philippe Froguel, Marja Vääräsmäki, Sanna Mustaniemi, Amna Khamis, Eero Kajantie, and Amélie Bonnefond
Subjects: endocrine system diseases, Offspring, Endocrinology, Diabetes and Metabolism, Physiology, Type 2 diabetes, Epigenome, Insulin resistance, Pregnancy, Internal Medicine, medicine, Humans, Prospective Studies, Epigenetics, Epidemiology/Health Services Research, Advanced and Specialized Nursing, business.industry, GTPase-Activating Proteins, nutritional and metabolic diseases, DNA Methylation, medicine.disease, DNA-Binding Proteins, Gestational diabetes, Diabetes, Gestational, Diabetes Mellitus, Type 2, DNA methylation, Female, business, Transcription Factors
Abstract: OBJECTIVE Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure. RESEARCH DESIGN AND METHODS We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring. RESULTS We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10−2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. CONCLUSIONS Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.
Published: 2021

24. SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations

Author: Ophélie Pereira, Jean Personnaz, Céline Saint-Laurent, Toshiyuki Araki, Maithé Tauber, Jean-Pierre Salles, Philippe Valet, Adélaïde Gélineau, Mickaël Canouil, Romain Paccoud, Armelle Yart, Jacques Weill, Jean-Philippe Pradere, Mylène Tajan, Cédric Dray, Enzo Piccolo, Sophie Le Gonidec, Inès Baba, Thomas Edouard, Emmanuel L. Gautier, Haoussa Askia, Philippe Froguel, Benjamin G. Neel, Nicolas Beton, Simon Deleruyelle, Johanna Auriau, Sophie Branka, Alizée Dortignac, Maxime Branchereau, Isabelle Castan, Christophe Heymes, Rémy Burcelin, Julie Charpentier, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), ANR-17-CE14-0016,HOLISTic,Rôle de la protéine HMGB1 au cours du stress metabolique(2017), ANR-17-CE14-0009,CAPTOR,Contrôler la fonction des progéniteurs du tissu adipeux pour améliorer les désordres métaboliques de l'obésité(2017), and ANR-17-CE14-0023,TARGETKC,Homéostasie et rôles des cellules de Kupffer dans la stéatohépatite(2017)
Subjects: MESH: Inflammation, medicine.medical_specialty, endocrine system diseases, education, Inflammation, Type 2 diabetes, MESH: Mice, Knockout, Diabetes Mellitus, Experimental, Proinflammatory cytokine, Mice, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, MESH: Diabetes Mellitus, Experimental, medicine, Animals, Humans, Glucose homeostasis, MESH: Animals, Macrophage homeostasis, MESH: Mice, 030304 developmental biology, Mice, Knockout, 0303 health sciences, MESH: Humans, business.industry, Macrophages, Monocyte, nutritional and metabolic diseases, MESH: Macrophages, General Medicine, medicine.disease, 3. Good health, MESH: Insulin Resistance, medicine.anatomical_structure, Endocrinology, Adipose Tissue, Diabetes Mellitus, Type 2, Lipotoxicity, Insulin Resistance, medicine.symptom, business, MESH: Adipose Tissue, 030217 neurology & neurosurgery, MESH: Diabetes Mellitus, Type 2
Abstract: Insulin resistance is a key event in type 2 diabetes onset and a major comorbidity of obesity. It results from a combination of fat excess-triggered defects, including lipotoxicity and metaflammation, but the causal mechanisms remain difficult to identify. Here, we report that hyperactivation of the tyrosine phosphatase SHP2 found in Noonan syndrome (NS) led to an unsuspected insulin resistance profile uncoupled from altered lipid management (for example, obesity or ectopic lipid deposits) in both patients and mice. Functional exploration of an NS mouse model revealed this insulin resistance phenotype correlated with constitutive inflammation of tissues involved in the regulation of glucose metabolism. Bone marrow transplantation and macrophage depletion improved glucose homeostasis and decreased metaflammation in the mice, highlighting a key role of macrophages. In-depth analysis of bone marrow-derived macrophages in vitro and liver macrophages showed that hyperactive SHP2 promoted a proinflammatory phenotype, modified resident macrophage homeostasis, and triggered monocyte infiltration. Consistent with a role of SHP2 in promoting inflammation-driven insulin resistance, pharmaceutical SHP2 inhibition in obese diabetic mice improved insulin sensitivity even better than conventional antidiabetic molecules by specifically reducing metaflammation and alleviating macrophage activation. Together, these results reveal that SHP2 hyperactivation leads to inflammation-triggered metabolic impairments and highlight the therapeutical potential of SHP2 inhibition to ameliorate insulin resistance.
Published: 2021

25. Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study

Author: Sheikh M, Kai Simons, Florence Mehl, Dina Mansour Aly, Marko Barovic, Peter Rossing, Frédéric Burdet, Timothy J. Pullen, Min Kim, Filip Ottosson, Iulian Dragan, t Hart Lm, Imre Pavo, Asger Wretlind, Michele Solimena, Joline W.J. Beulens, Petra J. M. Elders, Gudmundsdottir, Céline Fernandez, M.J. Gerl, Giuseppe N. Giordano, Muniangi-Muhitu H, Mikael Åkerlund, Efanov A, Louise A. Donnelly, Lopez-Noriega L, Diana Marek, Kevin L. Duffin, Hugo Fitipaldi, Christian Klose, Guy A. Rutter, Olle Melander, Emma Ahlqvist, Lori L. Jennings, Akalestou E, Michael K. Hansen, Adnan Ali, Gerard A Bouland, Tommi Suvitaival, Bernard Thorens, Gudnason, Georgiadou E, Niknejad A, Leif Groop, E R Pearson, Mickaël Canouil, Paul W. Franks, Mark Ibberson, Leclerc I, Lyssenko, Roderick C. Slieker, Dmitry Kuznetsov, van der Heijden Aa, Cristina Legido Quigley, Philippe Froguel, and Andreas Festa
Subjects: Homocitrulline, 0303 health sciences, geography, geography.geographical_feature_category, business.industry, Insulin, medicine.medical_treatment, Type 2 diabetes, Disease, medicine.disease, Islet, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Apoptosis, 030220 oncology & carcinogenesis, Diabetes mellitus, Immunology, COTL1, medicine, business, 030304 developmental biology
Abstract: We have deployed a multi-omics approach in large cohorts of patients with existing type 2 diabetes to identify biomarkers for disease progression across three molecular classes, metabolites, lipids and proteins. A Cox regression analysis for association with time to insulin requirement in 2,973 patients in the DCS, ANDIS and GoDARTS cohorts identified homocitrulline, isoleucine and 2-aminoadipic acid, as well as the bile acids glycocholic and taurocholic acids, as predictive of more rapid deterioration. Increased levels of eight triacylglycerol species, and lowered levels of the sphingomyelin SM 42:2;2 were also predictive of disease progression. Of ∼1,300 proteins examined in two cohorts, levels of GDF-15/MIC1, IL-18RA, CRELD1, NogoR, FAS, and ENPP7 were associated with faster progression, whilst SMAC/DIABLO, COTL1, SPOCK1 and HEMK2 predicted lower progression rates. Strikingly, identified proteins and lipids were also associated with diabetes incidence and prevalence in external replication cohorts. Implicating roles in disease compensation, NogoR/RTN4R improved glucose tolerance in high fat-fed mice and tended to improved insulin signalling in liver cells whilst IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. Conversely, high NogoR levels led to islet cell apoptosis. This comprehensive, multi-disciplinary approach thus identifies novel biomarkers with potential prognostic utility, provides evidence for new disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
Published: 2021

26. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author: Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center
Subjects: Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract: © The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant
Published: 2019

27. The trans-ancestral genomic architecture of glycemic traits

Author: Albertine J. Oldehinkel, Wieland Kiess, Xueling Sim, Norihiro Kato, Philippe Froguel, Astrid van Hylckama Vlieg, Josée Dupuis, Nanette R. Lee, Symen Ligthart, Harry Campbell, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Massimo Mangino, Tian Xie, Niek Verweij, James B. Meigs, Chaolong Wang, Michael Y. Tsai, Erik Ingelsson, Colin N. A. Palmer, Erik B. van den Akker, Fumihiko Matsuda, Rainer Rauramaa, Yi-Cheng Chang, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Sven Bergmann, Ya X. Wang, Ching-Ti Liu, Annette Schürmann, Michael Boehnke, David J. Porteous, Kazuya Setoh, Qibin Qi, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Claire J. Steves, Jun Liu, Leslie A. Lange, Noël P. Burtt, Diana Kuh, Cassandra N. Spracklen, Ken K. Ong, Charumathi Sabanayagam, Jost B. Jonas, Ele Ferrannini, Lawrence J. Beilin, Qing Duan, Blair H. Smith, Isobel D. Stewart, Alexander P. Reiner, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Mark I. McCarthy, Anna L. Gloyn, D.I. Boomsma, Dennis Raven, Nicholas J. Timpson, Rona J. Strawbridge, George Dedoussis, Susan Redline, Jaeyoung Hong, Harald Grallert, Jagadish Vangipurapu, Rico Rueedi, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Johannes Waage, Jin Fang Chai, Yii-Der Ida Chen, Graciela E. Delgado, Thibaud S. Boutin, Yang Hai, Yoriko Heianza, Wei Zhao, Andres Metspalu, Tien Yin Wong, Mila Desi Anasanti, Inger Njølstad, Hans Bisgaard, Valeriya Lyssenko, Denis Rybin, Wanqing Wen, Torben Hansen, James F. Wilson, Sameline Grimsgaard, Annette Peters, Michele K. Evans, Damia Noce, Sarah C. Nelson, May E. Montasser, Nan Wang, Geltrude Mingrone, Gudny Eiriksdottir, Nicholas J. Wareham, Fouad Kandeel, Linda S. Adair, Kelvin Lam, Jaana Lindström, Eco J. C. de Geus, Debbie A Lawlor, Sara M. Willems, Xu Lin, Harold Snieder, Matt J. Neville, Naveed Sattar, Chelsea K. Raulerson, Paul M. Ridker, Jer-Yuarn Wu, Weihua Zhang, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Elena Tremoli, Toru Nabika, Jing Hua Zhao, Vilmundur Gudnason, Tao Huang, Robert C. Kaplan, Sohee Han, Mohammad Hadi Zafarmand, Aaron Leong, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Ivana Kolcic, Franco Giulianini, Tao Wang, Lu Qi, Stephan J. L. Bakker, Laura J Corbin, Zoltán Kutalik, Bruna Gigante, Willa A. Hsueh, Peter J. van der Most, Tin Louie, Yujie Wang, Stella Trompet, Fernando Rivideneira, Yasumasa Ohyagi, Lynne E. Wagenknecht, Jerry L. Nadler, Michael Stumvoll, Mark O. Goodarzi, Sahoko Ichihara, Jeffrey R. O'Connell, Tomohiro Katsuya, Giorgio Pistis, Alice Stanton, Sirkka Keinänen-Kiukaanniemi, Momoko Horikoshi, Honglan Li, Tanja G. M. Vrijkotte, Caroline Hayward, Karen L. Mohlke, Carola Marzi, Girish N. Nadkarni, Laura J. Rasmussen-Torvik, Alain G. Bertoni, Andrew R. Wood, Annique Claringbould, Mi Yeong Hwang, Hugh Watkins, Heikki A. Koistinen, Mattias Frånberg, Jani Heikkinen, Elizabeth Selvin, Donald W. Bowden, Abbas Dehghan, Christian Fuchsberger, Audrey Y. Chu, Kent D. Taylor, Katherine A. Kentistou, Johanna Kuusisto, Jingyi Tan, Huaixing Li, Eric Boerwinkle, Catharina A. Hartman, Archie Campbell, Kari E. North, Oluf Pedersen, Sölve Elmståhl, Emil V. R. Appel, Chang-Hsun Hsieh, Dennis O. Mook-Kanamori, Rob M. van Dam, Pontiano Kaleebu, Corri Black, Jennifer A. Brody, Bengt Sennblad, Shaofeng Huo, M. Larissa Avilés-Santa, Ruth J. F. Loos, Patricia B. Munroe, Chien-Hsiun Chen, Liang Sun, Zorayr Arzumanyan, Rebecca Rohde, Yasuharu Tabara, Albert V. Smith, Betina H. Thuesen, Niels Grarup, Jorgen Engmann, Tatijana Zemunik, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Ching-Yu Cheng, Serena Sanna, Damiano Baldassarre, Tarunveer S. Ahluwalia, Mark J. Caulfield, Anne Ndungu, Carl D. Langefeld, Lisa R. Yanek, Luigi Ferrucci, Ananda R. Wickremasinghe, Raymond Noordam, Trevor A. Mori, Tom Wilsgaard, Mika Kivimäki, Rita R. Kalyani, Alan B. Zonderman, Veronique Vitart, Patricia A. Peyser, Shuiqing Lai, Richa Saxena, Li-Ching Chang, Karin Leander, Wei Huang, Peter Vollenweider, Tanya M. Teslovich, Ying Wu, Shufa Du, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Stephen C. J. Parker, Tamar Sofer, Winfried März, Sharon L.R. Kardia, Peter K. Joshi, Neil R. Robertson, Anny H. Xiang, Fumihiko Takeuchi, N. Amin, Jouke-Jan Hottenga, Carol A. Wang, Stefan Gustafsson, Jung Ho Gong, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Gonneke Willemsen, Michael A. Province, Aliki-Eleni Farmaki, Segun Fatumo, Antje Körner, Pim van der Harst, Marie Loh, Kei Hang Katie Chan, Gonçalo R. Abecasis, Nicholette D. Palmer, Simin Liu, Ishminder K. Kooner, Javier Gayán, Arne Astrup, Laura J. Scott, Erwin P. Bottinger, Andrew Wong, Inga Prokopenko, Ping An, Markku Laakso, Matthias Blüher, Susan R. Heckbert, Thomas A. Buchanan, Tatsuaki Matsubara, Andrew P. Morris, Brian H. Chen, Kristi Läll, Teresa Tusie, Timo A. Lakka, Jie Yao, Michael Preuss, Teemu Kuulasmaa, Carlos Lorenzo, Stephen S. Rich, Marie Lauzon, Laura M. Raffield, Pankow S. James, Takahisa Kawaguchi, Kathleen A. Ryan, Wei Zheng, Igor Rudan, Thomas Sparsø, Hugoline G. de Haan, Sandosh Padmanabhan, Richard M. Watanabe, Alicia Huerta-Chagoya, Anette P. Gjesing, Andrew A. Hicks, Richard N. Bergman, Mitsuhiro Yokota, Heather M. Stringham, Bruce M. Psaty, Jian'an Luan, Anuj Goel, Eleanor Wheeler, Masahiro Nakatochi, Young-Jin Kim, Xiao-Ou Shu, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Mari Nelis, Adolfo Correa, Jaspal S. Kooner, Michiya Igase, Anubha Mahajan, Peter E. H. Schwarz, Craig E. Pennell, Claudia Schurmann, Xiaoran Chai, Ji Chen, Lori L. Bonnycastle, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Ilja M. Nolte, Gaëlle Marenne, Timothy M. Frayling, Bong-Jo Kim, Kerrin S. Small, Cecilia M. Lindgren, Bernhard O. Böhm, Shih-Yi Lin, Katharina E. Schraut, Cornelia M. van Duijn, Sanghoon Moon, Mark Walker, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Ko Willems van Dijk, Ozren Polasek, W. Craig Johnson, Dermot F. Reilly, Inês Barroso, Anke Tönjes, Manjinder S. Sandhu, Wen B. Wei, Jose C. Florez, Lorraine Southam, Leif Groop, Lawrence F. Bielak, Peter Kovacs, Jianjun Liu, Jouko Saramies, Helen R. Warren, Man Li, Daniel I. Chasman, Eleftheria Zeggini, Xiaoshuai Zhang, Loic Yengo, Shi Jinxiu, Jirong Long, Xiuqing Guo, Meena Kumari, Leslie J. Raffel, Jill M. Norris, Henrik Vestergaard, Jing He, Peter P. Pramstaller, Diana van Heemst, Kevin Sandow, Marjo-Ritta Jarvelin, Carlos A. Aguilar-Salinas, Peitao Wu, Hortensia Moreno-Macías, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Bernardo L. Horta, Heming Wang, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Rozenn N. Lemaitre, Paul R. H. J. Timmers, Timo Saaristo, Jaakko Tuomilehto, Reedik Mägi, Debashree Ray, J. Wouter Jukema, Claudia Langenberg, Marcus E. Kleber, Francis S. Collins, Klaus Bønnelykke, Lenore J. Launer, Arushi Varshney, Anders Hamsten, European Commission, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanger Institute, Wellcome Trust, Marenne, Gaëlle [0000-0002-4363-7170], Varshney, Arushi [0000-0001-9177-9707], Corbin, Laura J [0000-0002-4032-9500], Parker, Stephen CJ [0000-0001-8122-0117], Langenberg, Claudia [0000-0002-5017-7344], Wheeler, Eleanor [0000-0002-8616-6444], Morris, Andrew P [0000-0002-6805-6014], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Lifelines Cohort Study, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), de Haan, H.G., van den Akker, E., van der Most, P.J., de Geus, EJC, van Dam, R.M., van Heemst, D., van Hylckama Vlieg, A., van Willems van Dijk, K., de Silva, H.J., van der Harst, P., van Duijn, C., Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Helsinki University Hospital Area, University of Helsinki, Clinicum, Department of Public Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Physiology, AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, APH - Mental Health, Nutrition and Health, APH - Methodology, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Public and occupational health, Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Cardiovascular Centre (CVC)
Subjects: Blood Glucose, Disease risk, Multifactorial Inheritance, Glycated Hemoglobin A, [SDV]Life Sciences [q-bio], Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), LOCI, Genome-wide association study, Type 2 diabetes, VARIANTS, GLUCOSE, Epigenesis, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Mechanisms, WIDE ASSOCIATION, genetics, Gene-expression, HEMOGLOBIN, ComputingMilieux_MISCELLANEOUS, 11 Medical and Health Sciences, GENE-EXPRESSION, Genetics, Genetics & Heredity, 0303 health sciences, INSULIN-RESISTANCE, Genome, Loci, 1184 Genetics, developmental biology, physiology, Variants, ALSPAC, Physical Chromosome Mapping, Life Sciences & Biomedicine, Human, Quantitative Trait Loci, Wide association study, Biology, Quantitative trait locus, Article, White People, diseases, MECHANISMS, Quantitative Trait, 03 medical and health sciences, Insulin resistance, Quantitative Trait, Heritable, SDG 3 - Good Health and Well-being, Genetic, Lifelines Cohort Study, Diabetes mellitus, medicine, Humans, Hemoglobin, Heritable, METAANALYSIS, Alleles, 030304 developmental biology, Genetic association, Glycemic, Glycated Hemoglobin, Science & Technology, Genome, Human, Whites, Gene Expression Profiling, DISEASE RISK, Settore MED/13 - ENDOCRINOLOGIA, Insulin-resistance, 06 Biological Sciences, medicine.disease, Glucose, chemistry, Blood Glucose/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Glycated Hemoglobin A/metabolism, Multifactorial Inheritance/genetics, Quantitative Trait Loci/genetics, Glycated hemoglobin, 030217 neurology & neurosurgery, Meta analysis, Epigenesis, Developmental Biology
Abstract: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.
Published: 2021

28. Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion

Author: Inês Cebola, Michele Solimena, Mickaël Canouil, Paul Gadue, Guy A. Rutter, Sameena Nawaz, Piero Marchetti, Leonardo Alemeida-Souza, Amna Khamis, Anke M. Schulte, Harvey T. McMahon, Gaelle Carrat, Benoit Hastoy, Shuying Jiang, Ming Hu, Fabian L. Cardenas-Diaz, Philippe Froguel, Mark Ibberson, MRC Programme Grant, Wellcome Trust, and Helsinki Institute of Life Science HiLIFE
Subjects: 0301 basic medicine, insulin secretion, Regulator, 0601 Biochemistry and Cell Biology, Chromosome conformation capture, 0302 clinical medicine, Insulin-Secreting Cells, GWAS, T2D, TRANSCRIPTION, Fchsd2, Gwas, Stard10, T2d, Chromatin Structure, Enhancer Cluster, Gene Regulation, Genetic Variant, Insulin Secretion, Type 2 Diabetes, Regulation of gene expression, chromatin structure, 0303 health sciences, FCHSD2, Chromatin, Cell biology, ISLETS, DEFINES, type 2 diabetes, enhancer cluster, gene regulation, genetic variant, STARD10, EXPRESSION, PATHOPHYSIOLOGY, PROVIDES INSIGHTS, Locus (genetics), Biology, General Biochemistry, Genetics and Molecular Biology, Article, GENETIC ARCHITECTURE, ENHANCER, 03 medical and health sciences, Humans, GENOME-WIDE ASSOCIATION, Allele, Enhancer, Gene, 030304 developmental biology, Correction, Membrane Proteins, CTCF, Phosphoproteins, 030104 developmental biology, 1116 Medical Physiology, 1182 Biochemistry, cell and molecular biology, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: Summary Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-βH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function., Graphical Abstract, Highlights • Type 2 risk variants at STARD10 reside in CTCF-flanked enhancer clusters • Loss of the risk variant-bearing region inhibits regulated insulin secretion • 3D chromatin interaction maps reveal FCHSD2 as target of the enhancer cluster • Deletion of STARD10 or FCHSD2 from EndoC-βH1 β cells inhibits insulin secretion, In this article, Hu et al. show the importance, for gene regulation, of a genomic region harboring GWAS variants that affect type 2 diabetes risk at the STARD10 locus. They also identify FCHSD2 as a likely mediator of the effects of these variants on insulin secretion.
Published: 2021

29. Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants

Author: Xavier Deupi, Bianca Plouffe, Mathilde Boissel, Beverley Balkau, Badr Sokrat, Eunna Huh, Ronan Roussel, Ralf Jockers, Christian Le Gouill, Amélie Bonnefond, Alan Hégron, Michel Bouvier, Wenwen Gao, Olivier Lichtarge, Philippe Froguel, Mickaël Canouil, Guillaume Charpentier, Université Paris Cité, Equipe HAL, Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée - - LIGAN PM2010 - ANR-10-EQPX-0007 - EQPX - VALID, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Les récepteurs couplés aux protéines G mitochondriaux en neuroprotection - - mitoGPCR2019 - ANR-19-CE16-0025 - AAPG2019 - VALID, BLANC - Les récepteurs de la mélatonine dans le développement du diabète de type 2 chez l'homme - - MLT2D2011 - ANR-11-BSV1-0012 - BLANC - VALID, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Département de Biochimie et Médecine Moléculaire [UdeM-Montréal], Université de Montréal (UdeM), Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Baylor College of Medicine (BCM), Baylor University, Paul Scherrer Institute (PSI), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lille, Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Imperial College London, ANR-10-EQPX-0007,LIGAN PM,Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée(2010), ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-19-CE16-0025,mitoGPCR,Les récepteurs couplés aux protéines G mitochondriaux en neuroprotection(2019), ANR-11-BSV1-0012,MLT2D,Les récepteurs de la mélatonine dans le développement du diabète de type 2 chez l'homme(2011), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Centre d'études et de recherches pour l'intensification du traitement du diabète (CERITD), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
Subjects: Pharmacology, Nonsynonymous substitution, 0303 health sciences, GPCR variants, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Effector, Functional selectivity, Context (language use), Computational biology, Biology, 03 medical and health sciences, Mechanisms of activation, 0302 clinical medicine, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Pharmacology (medical), Signal transduction, Receptor, 030217 neurology & neurosurgery, Function (biology), 030304 developmental biology, G protein-coupled receptor, Melatonin
Abstract: International audience; Melatonin is a hormone mainly produced by the pineal gland and MT1 is one of the two G protein-coupled receptors (GPCRs) mediating its action. Despite an increasing number of available GPCR crystal structures, the molecular mechanism of activation of a large number of receptors, including MT1, remains poorly understood. The purpose of this study is to elucidate the structural elements involved in the process of MT1’s activation using naturally occurring variants affecting its function. Thirty-six nonsynonymous variants, including 34 rare ones, were identified in MTNR1A (encoding MT1) from a cohort of 8687 individuals and their signaling profiles were characterized using Bioluminescence Resonance Energy Transfer-based sensors probing 11 different signaling pathways. Computational analysis of the experimental data allowed us to group the variants in clusters according to their signaling profiles and to analyze the position of each variant in the context of the three-dimensional structure of MT1 to link functional selectivity to structure. MT1 variant signaling profiles revealed three clusters characterized by (1) wild-type-like variants, (2) variants with selective defect of βarrestin-2 recruitment, and (3) severely defective variants on all pathways. Our structural analysis allows us to identify important regions for βarrestin-2 recruitment as well as for Gα12 and Gα15 activation. In addition to identifying MT1 domains differentially controlling the activation of the various signaling effectors, this study illustrates how natural variants can be used as tools to study the molecular mechanisms of receptor activation.
Published: 2021

30. Elevated circulating follistatin associates with an increased risk of type 2 diabetes

Author: Andreas L. Birkenfeld, Mickaël Canouil, Yan Borné, Emma Ahlqvist, Marju Orho-Melander, Olle Melander, Dina Mansour Aly, Ewan R. Pearson, Erik Renström, Maykel López Rodríguez, Angela C. Shore, Cheng Luan, Rui Gao, Andreas Peter, Robert Wagner, Leif Groop, Yang De Marinis, Mun-Gwan Hong, Hans-Ulrich Häring, Jan Nilsson, Norbert Stefan, Markku Laakso, Paul W. Franks, Morris F. White, Peter M. Nilsson, Jianping Weng, Kevin L. Duffin, Ajit Regmi, Jonathan M. Wilson, William C. Roell, Gunnar Engström, Jochen M. Schwenk, Allan Vaag, Minna U. Kaikkonen, Jürgen Machann, Andrea Natali, Claes B. Wollheim, Rongya Tao, Chuanyan Wu, Andreas Fritsche, Harald Staiger, Faisel Khan, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, and Clinicum
Subjects: Follistatin, endocrine system diseases, General Physics and Astronomy, Adipose tissue, Type 2 diabetes, Genome-wide association studies, MYOSTATIN, GLUCOSE, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, P446L VARIANT, Insulin, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, biology, Glucokinase regulatory protein, Fatty liver, Middle Aged, 3. Good health, BINDING-PROTEIN, Adipose Tissue, embryonic structures, TRIGLYCERIDE, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, endocrine system, Science, 030209 endocrinology & metabolism, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Humans, Secretion, 030304 developmental biology, Adaptor Proteins, Signal Transducing, business.industry, Fatty acid, nutritional and metabolic diseases, General Chemistry, medicine.disease, GENE, MICE, Endocrinology, ACTIVIN-A, chemistry, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, biology.protein, Hepatocytes, Insulin Resistance, business, Genome-Wide Association Study, GLUCOKINASE
Abstract: The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p, Follistatin promotes in type 2 diabetes (T2D) pathogenesis in model animals and is elevated in patients with T2D. Here the authors report that plasma follistatin associates with increased risk of incident T2D in two longitudinal cohorts, and show that follistatin regulates insulin-induced suppression lipolysis in cultured human adipocytes.
Published: 2021
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31. Variable Clustering in High-Dimensional Linear Regression: The R Package clere.

Author: Loïc Yengo, Julien Jacques, Christophe Biernacki, and Mickaël Canouil
Published: 2016
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32. Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study

Author: Agata Wesolowska-Andersen, Caroline A. Brorsson, Roberto Bizzotto, Andrea Mari, Andrea Tura, Robert Koivula, Anubha Mahajan, Ana Vinuela, Juan Fernandez Tajes, Sapna Sharma, Mark Haid, Cornelia Prehn, Anna Artati, Mun-Gwan Hong, Petra B. Musholt, Azra Kurbasic, Federico De Masi, Kostas Tsirigos, Helle Krogh Pedersen, Valborg Gudmundsdottir, Cecilia Engel Thomas, Karina Banasik, Chrisopher Jennison, Angus Jones, Gwen Kennedy, Jimmy Bell, Louise Thomas, Gary Frost, Henrik Thomsen, Kristine Allin, Tue Haldor Hansen, Henrik Vestergaard, Torben Hansen, Femke Rutters, Petra Elders, Leen t’Hart, Amelie Bonnefond, Mickaël Canouil, Soren Brage, Tarja Kokkola, Alison Heggie, Donna McEvoy, Andrew Hattersley, Timothy McDonald, Harriet Teare, Martin Ridderstrale, Mark Walker, Ian Forgie, Giuseppe N. Giordano, Philippe Froguel, Imre Pavo, Hartmut Ruetten, Oluf Pedersen, Emmanouil Dermitzakis, Paul W. Franks, Jochen M. Schwenk, Jerzy Adamski, Ewan Pearson, Mark I. McCarthy, Søren Brunak, Epidemiology and Data Science, ACS - Diabetes & metabolism, APH - Aging & Later Life, APH - Health Behaviors & Chronic Diseases, General practice, Brage, Soren [0000-0002-1265-7355], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, precision medicine, soft-clustering, glycaemic deterioration, archetypes, Genomics, patient stratification, multi-omics, Middle Aged, Article, General Biochemistry, Genetics and Molecular Biology, disease progression, Phenotype, Diabetes Mellitus, Type 2, SDG 3 - Good Health and Well-being, Risk Factors, Humans, Female, Genetic Predisposition to Disease, type 2 diabetes, patient clustering, Follow-Up Studies
Abstract: Summary The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments., Graphical abstract, Highlights • Soft clustering based on 32 phenotypes identified 4 quantitative archetypes • These reflect different patterns of dysfunction across T2D etiological processes • The four archetypes are different in disease progression, GRSs, and omics signals • Some patients are dominated by one archetype, but many have etiological combinations, Wesolowska-Andersen et al. represent the clinical heterogeneity of newly diagnosed T2D as four quantitative archetype profiles reflecting patterns of dysfunction in disease etiological processes, rather than clustering individuals into categorical subgroups as attempted by others. The archetype profiles differ in genetic risk scores, disease progression, and circulating omics biomarkers.
Published: 2022

33. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author: Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris
Subjects: 0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.
Published: 2020

34. The Trans-Ancestral Genomic Architecture of Glycaemic Traits

Author: Hugoline G. de Haan, Andrew A. Hicks, Achilleas Pitsilides, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Anders Hamsten, Dennis O. Mook-Kanamori, Zorayr Arzumanyan, Betina H. Thuesen, Karin Leander, Fernando Rivideneira, Lynne E. Wagenknecht, Andrew R. Wood, Annique Claringbould, Ele Ferranni, Sölve Elmståhl, Eleanor Wheeler, Sharon L.R. Kardia, Richa Saxena, Tatijana Zemunik, Cassandra N. Spracklen, Ken K. Ong, Xiao-Ou Shu, Johannes Waage, Blair H. Smith, Rozenn N. Lemaitre, Torben Hansen, Peter K. Joshi, Lisa R. Yanek, Neil R. Robertson, Sven Bergmann, Mila Desi Anasanti, Inger Njølstad, Ananda R. Wickremasinghe, Xu Lin, Harold Snieder, Wanqing Wen, Veronique Vitart, Paul R. H. J. Timmers, Timo Saaristo, James F. Wilson, Tian Xie, Tao Huang, Rainer Rauramaa, Kei Hang, Rebecca Rohde, Li-Ching Chang, Jing Hua Zhao, Kazuya Setoh, Yasuharu Tabara, Michael Stumvoll, Mark O. Goodarzi, Igor Rudan, James B. Meigs, Jaakko Tuomilehto, Richard M. Watanabe, Ruth J. F. Loos, Reedik Mägi, Jouke-Jan Hottenga, Ozren Polasek, Michael Y. Tsai, Donald W. Bowden, Diana Kuh, Erik B. van den Akker, Yii-Der Ida Chen, Daniel I. Chasman, Weihua Zhang, Nicholette D. Palmer, Marcus E. Kleber, Anny H. Xiang, Chang-Hsun Hsieh, Alan B. Zonderman, Stefan Gustafsson, Timo A. Lakka, Brian H. Chen, Dermot F. Reilly, Francis S. Collins, Oluf Pedersen, Corri Black, Yang Hai, Zoltán Kutalik, Yoriko Heianza, Willa A. Hsueh, Vilmundur Gudnason, Robert C. Kaplan, Jun Liu, Michael A. Province, Aliki-Eleni Farmaki, Stephen S. Rich, Jian'an Luan, Erik Ingelsson, Marie Loh, Michael Preuss, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Colin N. A. Palmer, Fumihiko Matsuda, Takahisa Kawaguchi, Sohee Han, Ching-Ti Liu, Young-Jin Kim, L. Southam, Sara M. Willems, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Stephan J. L. Bakker, Momoko Horikoshi, Tarunveer S. Ahluwalia, Annette Schürmann, Graciela E. Delgado, Thibaud S. Boutin, Thomas Sparsø, Sandosh Padmanabhan, Fouad Kandeel, Eco J. C. de Geus, Anubha Mahajan, Claudia Schurmann, Klaus Bønnelykke, Leslie A. Lange, Qing Duan, Rona J. Strawbridge, Dennis Raven, Gonçalo R. Abecasis, Mitsuhiro Yokota, Jani Heikkinen, Elizabeth Selvin, Audrey Y. Chu, Anke Tönjes, Marta E. Alarcón-Riquelme, Hans Bisgaard, P. Eline Slagboom, Eric Boerwinkle, Massimo Mangino, Catharina A. Hartman, Geltrude Mingrone, Lenore J. Launer, Michael Boehnke, Emil V. R. Appel, Niels Grarup, Arushi Varshney, Archie Campbell, Kari E. North, W. Craig Johnson, Inês Barroso, Ya X. Wang, Carola Marzi, Anuj Goel, Eleftheria Zeggini, Lu Qi, Yasumasa Ohyagi, Tien Yin Wong, Tanja G. M. Vrijkotte, Gudny Eiriksdottir, Harald Grallert, Ishminder K. Kooner, Trevor A. Mori, Jagadish Vangipurapu, Laura J Corbin, Tomohiro Katsuya, Wen B. Wei, Segun Fatumo, Debashree Ray, Annette Peters, Lori L. Bonnycastle, Ilja M. Nolte, M. Arfan Ikram, Manjinder S. Sandhu, Marit E. Jørgensen, Christian Herder, Damia Noce, Sarah C. Nelson, Chien-Hsiun Chen, Heather M. Stringham, Yong-Bing Xiang, Bruce M. Psaty, Alain G. Bertoni, Gaëlle Marenne, Timothy M. Frayling, Jose C. Florez, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Damiano Baldassarre, J. Wouter Jukema, Wei Huang, Yi-Cheng Chang, Albertine J. Oldehinkel, Xiaoshuai Zhang, Yujie Wang, Shaofeng Huo, Xueling Sim, Norihiro Kato, Bernhard O. Böhm, Lorraine Southam, Mari Nelis, Gonneke Willemsen, Laura J. Rasmussen-Torvik, Philippe Froguel, Charumathi Sabanayagam, Leif Groop, Loic Yengo, Shi Jinxiu, Adolfo Correa, Serena Sanna, Arne Astrup, Teemu Kuulasmaa, Symen Ligthart, Shih-Yi Lin, David J. Porteous, Harry Campbell, Peter Vollenweider, Mark J. Caulfield, Kristi Läll, Anne Ndungu, Carl D. Langefeld, Tanya M. Teslovich, Heikki A. Koistinen, Ying Wu, Mattias Frånberg, D.I. Boomsma, Lawrence F. Bielak, Diana van Heemst, Peter Kovacs, Markku Laakso, Leslie J. Raffel, Katharina E. Schraut, Noël P. Burtt, Michiya Igase, Craig E. Pennell, Claudia Langenberg, Huaixing Li, Teresa Tusie, Laura M. Raffield, Jorgen Engmann, Stephen C. J. Parker, Michele K. Evans, Chaolong Wang, Rico Rueedi, Jianjun Liu, Pankow S. James, Hortensia Moreno-Macías, Fumihiko Takeuchi, Cornelia M. van Duijn, Sanghoon Moon, Susan R. Heckbert, Thomas A. Buchanan, Ko Willems van Dijk, Toru Nabika, May E. Montasser, Caroline Hayward, Jie Yao, Aaron Leong, Antje Körner, Jouko Saramies, Jost B. Jonas, Pim van der Harst, Naveed Sattar, Helen R. Warren, Alice Stanton, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Mi Yeong Hwang, Jin Fang Chai, Alicia Huerta-Chagoya, Anette P. Gjesing, Ching-Yu Cheng, Debbie A Lawlor, Simin Liu, Man Li, Ivana Kolcic, Erwin P. Bottinger, Andrew Wong, Stella Trompet, Heming Wang, Jirong Long, Xiuqing Guo, Jeffrey R. O'Connell, Meena Kumari, Sirkka Keinänen-Kiukaanniemi, Rita R. Kalyani, Bengt Sennblad, Mohammad Hadi Zafarmand, Kent D. Taylor, Katherine A. Kentistou, Carol A. Wang, Shuiqing Lai, Patricia B. Munroe, Patricia A. Peyser, Lawrence J. Beilin, Niek Verweij, Inga Prokopenko, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Ping An, Matthias Blüher, Isobel D. Stewart, Alexander P. Reiner, Anna L. Gloyn, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, Wei Zhao, Andres Metspalu, Wieland Kiess, Kathleen A. Ryan, Astrid van Hylckama Vlieg, Jaana Lindström, Wei Zheng, E. Shyong Tai, Josée Dupuis, Nanette R. Lee, Laura J. Scott, Nicholas J. Timpson, George Dedoussis, Mark I. McCarthy, Tatsuaki Matsubara, Carlos Lorenzo, Denis Rybin, Luigi Ferruci, Chelsea K. Raulerson, Mika Kivimäki, Paul M. Ridker, Jer-Yuarn Wu, Shufa Du, Jaeyoung Hong, Linda S. Adair, Tin Louie, Valeriya Lyssenko, Susan Redline, Kelvin Lam, Qibin Qi, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Peter J. van der Most, Sahoko Ichihara, Nicholas J. Wareham, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Rob M. van Dam, Claire J. Steves, Liang Sun, Albert V. Smith, Raymond Noordam, Tom Wilsgaard, Winfried März, Jung Ho Gong, Matt J. Neville, Jerry L. Nadler, Giorgio Pistis, Karen L. Mohlke, Bruna Gigante, Jennifer A. Brody, Andrew P. Morris, Marie Lauzon, Peter E. H. Schwarz, Bernardo L. Horta, Xiaoran Chai, Ji Chen, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Javier Gayán, Elena Tremoli, Girish N. Nadkarni, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Jingyi Tan, Sameline Grimsgaard, Bong-Jo Kim, Kerrin S. Small, Jill M. Norris, Cecilia M. Lindgren, Richard N. Bergman, Mark Walker, Henrik Vestergaard, Larissa Aviles-Santa, Jing He, Masahiro Nakatochi, Peter P. Pramstaller, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Kevin Sandow, Jaspal S. Kooner, Carlos A. Aguilar-Salinas, Peitao Wu, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Nan Wang, Franco Giulianini, Tao Wang, Honglan Li, Abbas Dehghan, Christian Fuchsberger, and Pontiano Kaleebu
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Type 2 diabetes, medicine.disease, Fasting insulin, Fasting glucose, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Diabetes mellitus, medicine, Genomic architecture, business, Glycated haemoglobin, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.
Published: 2020

35. 1901-P: Individual and Longitudinal Effects of Gastric Bypass Surgery on the Circulating Proteome

Author: Ragna S. Häussler, Violeta Raverdy, Mickaël Canouil, Ana Viñuela, Cecilia Engel Thomas, Mun-Gwan Hong, Matilda Dale, Philippe Froguel, Gianluca Mazzoni, Søren Brunak, and Jochen M. Schwenk
Subjects: medicine.medical_specialty, Gastric bypass surgery, business.industry, Endocrinology, Diabetes and Metabolism, medicine.disease_cause, medicine.disease, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, media_common.cataloged_instance, European commission, European union, business, Glycemic, media_common
Abstract: Roux-en-Y gastric bypass surgery (RYGB) has been effective for inducing weight-loss and remission of diabetes in obese persons. Nonetheless, the response to RYGB and resulting improvements in glycemic control are heterogeneous and not well understood. To gain molecular insights into how individuals respond to RYGB, we monitored the longitudinal effects of RYGB surgery via circulating proteins. We quantified 368 proteins using multiplexed and sensitive immunoassays (Olink) in sera collected from 146 obese persons with T2D (BMI > 35 kg/m2) prior to, and at one and three months after surgery. We observed an overall longitudinal change in circulating levels for ∼50% of the proteins (FDR < 0.01). This included a post-RYGB increase in levels of GH, IGFBP-2, NT-proBNP, REGA1 and MMP-3, as well as a decrease in levels of SSC4D, SERPINA12, GIF, FBP1, CES1. To deconvolute the inter-individual heterogeneity of the circulating proteomes and protein-related longitudinal dynamics, we clustered the total of ∼44,000 protein profiles into 10 response patterns. Just 8% (28/368) of the proteins’ levels changed in a common manner across the majority of individuals, as these were grouped into 3 or fewer clusters. Among these were proteins related to adipogenesis (LEP, DLK1, GH), white adipocyte differentiation (LEP, FABP4), as well as innate immunity (CHIT1, PTX3, CSTB). However, out of these 28 proteins, only levels of VSIG2 were significantly associated (FDR < 0.01) with diabetes remission at 12 months (HbA1c < 6.5%, no diabetes medication). Overall, our results suggest a wide-reaching, individual-specific, but predominantly short-term impact of RYGB surgery on the circulating proteome. Current investigations examine how genetic variance and mRNA expression in adipose and liver tissue influence the donors’ circulating proteomes in order to explain the observed heterogeneity and its impact on a person’s molecular homeostasis. Disclosure C.E. Thomas: None. R.S. Häussler: None. M. Hong: None. V. Raverdy: None. M. Dale: None. M. Canouil: None. G. Mazzoni: None. A. Viñuela: None. P. Froguel: None. S. Brunak: Board Member; Self; Intomics A/S, Proscion A/S. Research Support; Self; Novo Nordisk Foundation. Stock/Shareholder; Self; Lundbeck, Novo Nordisk A/S. J.M. Schwenk: None. Funding Innovative Medicines Initiative Joint Undertaking (115317); European Union’s Seventh Framework Programme (FP7/2007-2013); Conseil Regional Nord-Pas-de-Calais; European Commission (FEDER 12003944); European Genomic Institute for Diabetes (ANR-10-LABX-46); Foundation Coeur et Arteres (R15112EE); Fonds hospitalier d’aide a l’emergence et a la structuration des activities et des equipes de recherche 2015 (CHRU Lille, France)
Published: 2020

36. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Author: Yongmei Liu, Tuomas O. Kilpeläinen, Kenneth Rice, Ching-Ti Liu, Jin-Fang Chai, Donna K. Arnett, Dhananjay Vaidya, Nicholette D. Palmer, Lili Milani, Yuri Milaneschi, Leo-Pekka Lyytikäinen, Colleen M. Sitlani, Richard S. Cooper, Gudny Eiriksdottir, Daniel Levy, Jerome I. Rotter, Lihua Wang, Sven Bergmann, Yih Chung Tham, Thomas Meitinger, Lynne E. Wagenknecht, Virginia Fisher, Babatunde L. Salako, Vilmundur Gudnason, Bamidele O. Tayo, Caizheng Yu, Barry I. Freedman, Muhammad Riaz, Kaare Christensen, Ulrich Broeckel, W. James Gauderman, Massimiliano Cocca, Eric Boerwinkle, Meian He, Rob M. van Dam, M. Arfan Ikram, Lisa de las Fuentes, Jiang He, Aldi T. Kraja, Nancy L. Pedersen, Albert V. Smith, Woon-Puay Koh, Bernardo L. Horta, He Gao, Traci M. Bartz, Mike A. Nalls, Federica Laguzzi, Raymond Noordam, Paul M. Ridker, Tien Yin Wong, Patricia B. Munroe, Paul S. de Vries, Adolfo Correa, Maris Alver, Dan E. Arking, Colin A. McKenzie, John M. Starr, Chi Charles Gu, Dongfeng Gu, Stefan Weiss, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Jill M. Norris, Patrik K. E. Magnusson, Tamar Sofer, Ioanna Ntalla, Xiuqing Guo, Paul Elliott, Lawrence F. Bielak, Konstantin Strauch, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Ilja M. Nolte, Steven C. Hunt, Mario Sims, Giorgia Girotto, Chuan Gao, Pamela J. Schreiner, Philippe Froguel, Archie Campbell, Xiao-Ou Shu, Claude Bouchard, Kurt Lohman, David R. Weir, José Eduardo Krieger, Yii-Der Ida Chen, Rainer Rauramaa, Walter Palmas, Cornelia M. van Duijn, James M. Shikany, Michael M. Province, Jennifer A. Smith, Wei Zheng, Xiaofeng Zhu, Jianjun Liu, Ozren Polasek, Alexandre C. Pereira, Diane M. Becker, Kari E. North, Salman M. Tajuddin, Deng Xuan, Leslie J. Raffel, Jie Yao, Astrid Petersmann, Ervin F. Fox, Mark J. Caulfield, Daniel I. Chasman, Jasmin Divers, Claudia P. Cabrera, Rico Rueedi, M. Yldau van der Ende, Carl D. Langefeld, Mika Kähönen, Terrence Forrester, Tangchun Wu, Harold Snieder, Caroline Hayward, Tamara B. Harris, Fang-Chi Hsu, Helen R. Warren, Brenda W.J.H. Penninx, Chiea Chuen Khor, Ruifang Li-Gao, Changwei Li, Sami Heikkinen, Jeffrey R. O'Connell, Christian Gieger, Michele K. Evans, Ching-Yu Cheng, Jingjing Liang, Stephen B. Kritchevsky, Gregory L. Burke, Donald W. Bowden, Alexander Teumer, Marcus Dörr, Alanna C. Morrison, Jian-Min Yuan, Annette Peters, Dennis O. Mook-Kanamori, Pedro Marques-Vidal, Pirjo Komulainen, Lisa R. Yanek, Melanie Waldenberger, Alisa K. Manning, Charles N. Rotimi, Chew-Kiat Heng, Tõnu Esko, Franco Giulianini, Miao Li Chee, Treva Rice, David J. Porteous, Yechiel Friedlander, Bing Yu, Myriam Fornage, Karin Leander, Dina Vojinovic, Sharon L.R. Kardia, Xiaoyin Li, Najaf Amin, Karen Schwander, Thomas T. Perls, Oscar Leonel Rueda-Ochoa, Erin B. Ware, Ya Xing Wang, Sandosh Padmanabhan, H. Janaka de Silva, André G. Uitterlinden, Rajkumar Dorajoo, Bruna Gigante, Jennifer A. Brody, Paolo Gasparini, Maryam Kavousi, Wanqing Wen, Stephen Sidney, Alan B. Zonderman, Michael R. Brown, Tuomo Rankinen, Timo A. Lakka, Yun Ju Sung, Alaitz Poveda, Bruce M. Psaty, Terho Lehtimäki, Tanika N. Kelly, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, John M. C. Connell, Mickaël Canouil, Niek Verweij, Thomas W. Winkler, Ian J. Deary, Marco Brumat, Yize Li, Fumihiko Takeuchi, Wei Zhao, Andres Metspalu, Marguerite R. Irvin, David C. Liewald, Pim van der Harst, Hugues Aschard, Candace M. Kammerer, Melissa A. Richard, Adesola Ogunniyi, Wen Bin Wei, Morris A. Swertz, Fernando Pires Hartwig, Dabeeru C. Rao, Reedik Mägi, Solomon K. Musani, Mathilde Boissel, Jonathan Marten, Nilesh J. Samani, Amy R. Bentley, Sarah E. Harris, Charumathi Sabanayagam, Mary F. Feitosa, Jost B. Jonas, Andrea R. V. R. Horimoto, Paul W. Franks, E. Shyong Tai, Medical Research Council (MRC), de las Fuentes, L., Sung, Y. J., Noordam, R., Winkler, T., Feitosa, M. F., Schwander, K., Bentley, A. R., Brown, M. R., Guo, X., Manning, A., Chasman, D. I., Aschard, H., Bartz, T. M., Bielak, L. F., Campbell, A., Cheng, C. -Y., Dorajoo, R., Hartwig, F. P., Horimoto, A. R. V. R., Li, C., Li-Gao, R., Liu, Y., Marten, J., Musani, S. K., Ntalla, I., Rankinen, T., Richard, M., Sim, X., Smith, A. V., Tajuddin, S. M., Tayo, B. O., Vojinovic, D., Warren, H. R., Xuan, D., Alver, M., Boissel, M., Chai, J. -F., Chen, X., Christensen, K., Divers, J., Evangelou, E., Gao, C., Girotto, G., Harris, S. E., He, M., Hsu, F. -C., Kuhnel, B., Laguzzi, F., Li, X., Lyytikainen, L. -P., Nolte, I. M., Poveda, A., Rauramaa, R., Riaz, M., Rueedi, R., Shu, X. -O., Snieder, H., Sofer, T., Takeuchi, F., Verweij, N., Ware, E. B., Weiss, S., Yanek, L. R., Amin, N., Arking, D. E., Arnett, D. K., Bergmann, S., Boerwinkle, E., Brody, J. A., Broeckel, U., Brumat, M., Burke, G., Cabrera, C. P., Canouil, M., Chee, M. L., Chen, Y. -D. I., Cocca, M., Connell, J., de Silva, H. J., de Vries, P. S., Eiriksdottir, G., Faul, J. D., Fisher, V., Forrester, T., Fox, E. F., Friedlander, Y., Gao, H., Gigante, B., Giulianini, F., Gu, C. C., Gu, D., Harris, T. B., He, J., Heikkinen, S., Heng, C. -K., Hunt, S., Ikram, M. A., Irvin, M. R., Kahonen, M., Kavousi, M., Khor, C. C., Kilpelainen, T. O., Koh, W. -P., Komulainen, P., Kraja, A. T., Krieger, J. E., Langefeld, C. D., Li, Y., Liang, J., Liewald, D. C. M., Liu, C. -T., Liu, J., Lohman, K. K., Magi, R., Mckenzie, C. A., Meitinger, T., Metspalu, A., Milaneschi, Y., Milani, L., Mook-Kanamori, D. O., Nalls, M. A., Nelson, C. P., Norris, J. M., O'Connell, J., Ogunniyi, A., Padmanabhan, S., Palmer, N. D., Pedersen, N. L., Perls, T., Peters, A., Petersmann, A., Peyser, P. A., Polasek, O., Porteous, D. J., Raffel, L. J., Rice, T. K., Rotter, J. I., Rudan, I., Rueda-Ochoa, O. -L., Sabanayagam, C., Salako, B. L., Schreiner, P. J., Shikany, J. M., Sidney, S. S., Sims, M., Sitlani, C. M., Smith, J. A., Starr, J. M., Strauch, K., Swertz, M. A., Teumer, A., Tham, Y. C., Uitterlinden, A. G., Vaidya, D., van der Ende, M. Y., Waldenberger, M., Wang, L., Wang, Y. -X., Wei, W. -B., Weir, D. R., Wen, W., Yao, J., Yu, B., Yu, C., Yuan, J. -M., Zhao, W., Zonderman, A. B., Becker, D. M., Bowden, D. W., Deary, I. J., Dorr, M., Esko, T., Freedman, B. I., Froguel, P., Gasparini, P., Gieger, C., Jonas, J. B., Kammerer, C. M., Kato, N., Lakka, T. A., Leander, K., Lehtimaki, T., Magnusson, P. K. E., Marques-Vidal, P., Penninx, B. W. J. H., Samani, N. J., van der Harst, P., Wagenknecht, L. E., Wu, T., Zheng, W., Zhu, X., Bouchard, C., Cooper, R. S., Correa, A., Evans, M. K., Gudnason, V., Hayward, C., Horta, B. L., Kelly, T. N., Kritchevsky, S. B., Levy, D., Palmas, W. R., Pereira, A. C., Province, M. M., Psaty, B. M., Ridker, P. M., Rotimi, C. N., Tai, E. S., van Dam, R. M., van Duijn, C. M., Wong, T. Y., Rice, K., Gauderman, W. J., Morrison, A. C., North, K. E., Kardia, S. L. R., Caulfield, M. J., Elliott, P., Munroe, P. B., Franks, P. W., Rao, D. C., Fornage, M., Washington University in Saint Louis (WUSTL), Leiden University Medical Center (LUMC), University of Regensburg, Washington University School of Medicine in St. Louis, National Institutes of Health [Bethesda] (NIH), Harbor UCLA Medical Center [Torrance, Ca.], Massachusetts General Hospital [Boston], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Lifelines Cohort Study, Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Cardiovascular Centre (CVC)
Subjects: 0301 basic medicine, CORONARY-HEART-DISEASE, SOCIOECONOMIC-STATUS, RISK-FACTORS, CARDIOVASCULAR-DISEASE, ESSENTIAL-HYPERTENSION, C825T POLYMORPHISM, SOCIAL-CLASS, ASSOCIATION, EXPRESSION, VARIANTS, Blood Pressure, Genome, 0302 clinical medicine, 11 Medical and Health Sciences, Genetics, Psychiatry, [STAT.AP]Statistics [stat]/Applications [stat.AP], 17 Psychology and Cognitive Sciences, Psychiatry and Mental health, Meta-analysis, Hypertension, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, GNB3, Biochemistry & Molecular Biology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Lifelines Cohort Study, SDG 3 - Good Health and Well-being, Humans, Risk factor, Molecular Biology, Gene, Science & Technology, Neurosciences, Epistasis, Genetic, 06 Biological Sciences, Genetic architecture, Educational attainment, 030104 developmental biology, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurosciences & Neurology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Blood Pressure/genetics, Genome-Wide Association Study, Hypertension/genetics, 030217 neurology & neurosurgery
Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Published: 2020

37. Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion

Author: Anke M. Schulte, Shuying Jiang, Sameena Nawaz, Michele Solimena, Amna Khamis, Inês Cebola, Mickaël Canouil, Guy A. Rutter, Paul Gadue, Ming Hu, Philippe Froguel, Mark Ibberson, Piero Marchetti, Fabian L. Cardenas-Diaz, Leonardo Alemeida-Souza, Harvey T. McMahon, Gaelle Carrat, and Benoit Hastoy
Subjects: 0303 health sciences, Regulator, Locus (genetics), Biology, Chromatin, Cell biology, Chromosome conformation capture, 03 medical and health sciences, 0302 clinical medicine, CRISPR, Enhancer, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, STARD10
Abstract: SUMMARYGenome-wide association studies have identified thousands of genetic variants associated with type 2 diabetes (T2D) risk. Using chromatin conformation capture we show that an enhancer cluster in the STARD10 T2D locus forms a defined 3D chromatin domain. A 4.1 Kb region within this region, carrying five disease-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of an associated enhancer, in human pancreatic beta cells impaired glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2, but not ARAP1, was reduced in cells harboring CRISPR deletions, and expression of STARD10 and FCHSD2 was associated with the possession of variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2 impaired regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function.
Published: 2020

38. NACHO: an R package for quality control of NanoString nCounter data

Author: Amélie Bonnefond, Philippe Froguel, Gerard A Bouland, Roderick C. Slieker, Mickaël Canouil, Leen M 't Hart, Epidemiology and Data Science, APH - Aging & Later Life, and APH - Health Behaviors & Chronic Diseases
Subjects: Statistics and Probability, Normalization (statistics), Quality Control, 0303 health sciences, business.industry, Computer science, 030302 biochemistry & molecular biology, computer.software_genre, Biochemistry, Computer Science Applications, 03 medical and health sciences, Computational Mathematics, R package, Software, Computational Theory and Mathematics, Data mining, business, Molecular Biology, computer, 030304 developmental biology
Abstract: Summary The NanoStringTM nCounter® is a platform for the targeted quantification of expression data in biofluids and tissues. While software by the manufacturer is available in addition to third parties packages, they do not provide a complete quality control (QC) pipeline. Here, we present NACHO (‘NAnostring quality Control dasHbOard’), a comprehensive QC R-package. The package consists of three subsequent steps: summarize, visualize and normalize. The summarize function collects all the relevant data and stores it in a tidy format, the visualize function initiates a dashboard with plots of the relevant QC outcomes. It contains QC metrics that are measured by default by the manufacturer, but also calculates other insightful measures, including the scaling factors that are needed in the normalization step. In this normalization step, different normalization methods can be chosen to optimally preprocess data. Together, NACHO is a comprehensive method that optimizes insight and preprocessing of nCounter® data. Availability and implementation NACHO is available as an R-package on CRAN and the development version on GitHub https://github.com/mcanouil/NACHO. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2020

39. Persistent or Transient Human β-Cell Dysfunction Induced by Metabolic Stress Associates with Specific Signatures and Shared Gene Expression of Type 2 Diabetes

Author: Ivon Bakaj, Maikel Luis Colli, Alessandro Pocai, Vincenzo De Tata, Lorella Marselli, Anke Shulte, Decio L. Eizirik, Michele Solimena, Pratibha Singh, Peter Andrew Hecht, Miguel Lopes, Daniela Nasteska, Maurizio Ronci, Jean-Valry Turatsinze, Paolo De Simone, Miriam Cnop, Philippe Frogues, Daniela Campani, Brian Rady, Mara Suleiman, Marco Bugliani, Bernard Thorens, Mickaël Canouil, Amna Khamis, Carmela De Luca, Ugo Boggi, Laura Giusti, Anthony Piron, Piero Marchetti, Mark Ibberson, Lisa Norquay, and Guy A. Rutter
Subjects: endocrine system, geography, geography.geographical_feature_category, endocrine system diseases, Insulin, medicine.medical_treatment, Cell, Type 2 diabetes, Biology, medicine.disease, Islet, Pathogenesis, Transcriptome, medicine.anatomical_structure, Gene expression, Expression quantitative trait loci, Cancer research, medicine
Abstract: Pancreatic β-cell failure is key to type 2 diabetes (T2D) onset and progression. We assessed whether human β-cell dysfunction induced by metabolic stress is reversible, evaluated the molecular pathways underlying persistent or transient damage, and explored the relationships with T2D islet traits. Twenty-six human islet preparations were exposed to several lipo- and/or glucotoxicity conditions, some of which impaired insulin release depending on stressor type, concentration and combination. Interestingly, reversal of dysfunction occurred after wash out for some, but not for all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA-sequencing and eQTL analysis identified specific pathways underlying β-cell failure and recovery. Notably, comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β-cell lipoglucotoxicity showed shared gene expression signatures. The identification of mechanisms associated with human β-cell dysfunction and recovery, and their overlap with T2D islet traits provide novel insights into T2D pathogenesis and should foster the development of improved β-cell targeted therapeutic strategies.
Published: 2020

40. Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension

Author: Cécile Aubert, Maithé Tauber, Ronan Roussel, Bénédicte Toussaint, François Pattou, Philippe Froguel, Jean-Michel Borys, Amjad Ghulam, Hélène Loiselle, Mathilde Boissel, Emmanuelle Durand, Sylvia Franc, Julie Kerr-Conte, Julie Maillet, Morgane Baron, Marlène Huyvaert, Amélie Bonnefond, Raphaël Boutry, J. Philippe, Jérémy Thomas, Guillaume Charpentier, Claire Lévy-Marchal, Michel Marre, Mehdi Derhourhi, Aurélie Dechaume, Emmanuel Vaillant, B. Balkau, Stefan Gaget, Raphael Scharfmann, Jacques Weill, Mickaël Canouil, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'études et de recherches pour l'intensification du traitement du diabète (CERITD), Centre Hospitalier Sud Francilien, Association Fleurbaix Laventie Ville Santé (FLVS), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Hopital Robert Debre, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'endocrinologie pédiatrique [CHU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondation ILDYS (ILDYS), Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP. Université Paris Saclay, Clinique Ambroise Paré [Centres Médico-Chirurgicaux Ambroise Pré, Pierre Cherest, Hartmann], Imperial College London, This work was supported by grants from the French-speaking Society of Diabetes (Société Française du Diabète) to A.B., from the European Foundation for the Study of Diabetes/Lilly (to A.B.), from the French National Research Agency (ANR-10-LABX-46 (European Genomics Institute for Diabetes) and ANR-10-EQPX-07-01 (LIGAN-PM) to P.F.), from the European Research Council (ERC GEPIDIAB-294785 to P.F. and ERC Reg-Seq-715575 to A.B.), from FEDER (to P.F.) and from the ‘Région Nord Pas-de-Calais’ (to P.F.). A.B. was supported by Inserm., ANR-10-EQPX-0007,LIGAN PM,Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée(2010), European Project: 294785,EC:FP7:ERC,ERC-2011-ADG_20110310,GEPIDIAB(2012), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire de Biochimie et Hormonologie [CHRU LIlle] (Centre de Biologie Pathologie), Service de Diabétologie [Orsay, Corbeil-Essonnes], Université Paris-Sud - Paris 11 (UP11)-Hôpital Sud Francilien Corbeil Essonne, Centre d'Etudes et de Recherches pour l'Intensification du Traitement du Diabète (CERITD), Association 'Fleurbaix Laventie Ville Santé' (FLVS), Association Fleurbaix Laventie Ville Santé, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ildys Foundation [Roscoff, France], Départment de Diabétologie, Endocrinologie et Nutrition [AP-HP Hôpital Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-DHU FIRE Centre de compétence des maladies pulmonaires rares, École pratique des hautes études (EPHE), UFR de Médecine - Sorbonne Paris Cité (Université Paris Diderot - Paris 7 - UPD7), Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), CMC Ambroise Paré [Neuilly-sur-Seine, France], Department of Metabolism [London, UK] (Section of Genomics of Common Disease), Bonnefond, Amelie, Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée - - LIGAN PM2010 - ANR-10-EQPX-0007 - EQPX - VALID, and Genetics and epigenetics of Type 2 Diabetes physiology - GEPIDIAB - - EC:FP7:ERC2012-11-01 - 2017-10-31 - 294785 - VALID
Subjects: 0301 basic medicine, Male, MESH: Hypertension / complications, MESH: Hypertension / pathology, [SDV.GEN] Life Sciences [q-bio]/Genetics, 0302 clinical medicine, Loss of Function Mutation, Risk Factors, MESH: Obesity / complications, Receptor, Child, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Obesity / metabolism, MESH: Loss of Function Mutation / genetics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Receptor, Melanocortin, Type 4 / genetics, General Medicine, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Metabolic effects, Hypertension, Receptor, Melanocortin, Type 4, Female, Melanocortin, MESH: Hyperglycemia / pathology, Adult, medicine.medical_specialty, Adolescent, MESH: Energy Metabolism / genetics, Obesity risk, Hyperphagia, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Islets of Langerhans, Young Adult, MESH: Genetic Predisposition to Disease, Internal medicine, medicine, Humans, MESH: Adaptor Proteins, Signal Transducing / genetics, Genetic Predisposition to Disease, Obesity, Loss function, Adaptor Proteins, Signal Transducing, MESH: Hyperphagia / pathology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, Pancreatic islets, Energy control, medicine.disease, 030104 developmental biology, Blood pressure, Endocrinology, Hyperglycemia, MESH: Obesity / pathology, business, Energy Metabolism, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Hyperphagia / complications
Abstract: International audience; The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.
Published: 2019

41. Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion

Author: Ana Ortalli, Marlène Huyvaert, AmÃ©lie Bonnefond, Lorella Marselli, Piero Marchetti, Marie Verbanck, Fatou K. Ndiaye, Julie Kerr-Conte, RaphaÃ«l Scharfmann, Emmanuelle Durand, Philippe Froguel, Amar Abderrahmani, Mickaël Canouil, Olivier Sand, Vikash Chandra, FranÃ§ois Pattou, RaphaÃ«l Boutry, ValÃ©rie Pawlowski, Odile Poulain-Godefroy, C. Lecoeur, Iandry Rabearivelo, and Clara Salazar-Cardozo
Subjects: 0301 basic medicine, endocrine system diseases, medicine.medical_treatment, EndoC-βH1, Gene regulatory network, Mice, Obese, EndoC-beta H1, Genome-wide association study, Cell Cycle Proteins, Type 2 diabetes, VARIANTS, Bioinformatics, Expression analysis, PATHWAY, MELLITUS, Mice, Insulin-Secreting Cells, OF-FUNCTION MUTATIONS, Insulin, Gene Regulatory Networks, Genetics, Insulin secretion, 3. Good health, DNA-Binding Proteins, Original Article, Female, ACCURATE, Life Sciences & Biomedicine, lcsh:Internal medicine, Racemases and Epimerases, LINE, Biology, EndoC-Î²H1, RNAi screening, Molecular Biology, Cell Biology, Cell Line, Endocrinology & Metabolism, 03 medical and health sciences, medicine, Animals, Humans, Secretion, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, lcsh:RC31-1245, Gene, Transcription factor, Genetic association, Adaptor Proteins, Signal Transducing, Science & Technology, nutritional and metabolic diseases, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Diabetes Mellitus, Type 2, PANCREATIC BETA-CELLS, GLUCOSE-HOMEOSTASIS, Transcription Factors
Abstract: Objectives Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells. Methods The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-βH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-βH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function. Results We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-βH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-βH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression of Prc1, Srr, Zfand6, and Zfand3 was found in mouse pancreatic islets with altered beta-cell function. Conclusions This study showed the ability of post-GWAS functional studies to identify new genes and pathways involved in human pancreatic beta-cell function and in T2D pathophysiology., Highlights • Expression of genes located nearby T2D associated signals is enriched in β cells. • Knockdown of 7 T2D genes with known role in β cell changes insulin secretion. • Knockdown of 4 T2D genes with unknown role in β cell impairs insulin secretion. • RNA-seq in cells with knockdown of these 4 genes detected T2D-related networks.
Published: 2017

42. Epigenetic regulation of hepatic DPP4

Author: Stéphane Lobbens, A Kammel, Annette Schürmann, S Saussenthaler, F. Pattou, C Baumeier, Mickaël Canouil, P Froguel, and Robert W. Schwenk
Subjects: Endocrinology, Diabetes and Metabolism, Epigenetics, Biology, Cell biology
Published: 2017

43. Hepatic DPP4 DNA Methylation Associates With Fatty Liver

Author: Violeta Raverdy, Charlotte Ling, Sophie Saussenthaler, Markus Jähnert, Philippe Froguel, A Kammel, Stéphane Lobbens, Annette Schürmann, Robert Caiazzo, Deike Hesse, François Pattou, Robert W. Schwenk, Jussi Pihlajamäki, Christian Baumeier, Mickaël Canouil, Emma Nilsson, and Luisa Schlüter
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Dipeptidyl Peptidase 4, Endocrinology, Diabetes and Metabolism, Blotting, Western, Adipose tissue, 030209 endocrinology & metabolism, Biology, Cell Line, Pathogenesis, Mice, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Internal medicine, Internal Medicine, medicine, Animals, Cells, Cultured, Triglycerides, Dipeptidyl peptidase-4, Regulation of gene expression, Fatty liver, Methylation, DNA Methylation, medicine.disease, Immunohistochemistry, Fatty Liver, Mice, Inbred C57BL, Glucose, 030104 developmental biology, Endocrinology, Gene Expression Regulation, Liver, CpG site, DNA methylation, Hepatocytes, CpG Islands
Abstract: Hepatic DPP4 expression is elevated in subjects with ectopic fat accumulation in the liver. However, whether increased dipeptidyl peptidase 4 (DPP4) is involved in the pathogenesis or is rather a consequence of metabolic disease is not known. We therefore studied the transcriptional regulation of hepatic Dpp4 in young mice prone to diet-induced obesity. Already at 6 weeks of age, expression of hepatic Dpp4 was increased in mice with high weight gain, independent of liver fat content. In the same animals, methylation of four intronic CpG sites was decreased, amplifying glucose-induced transcription of hepatic Dpp4. In older mice, hepatic triglyceride content was increased only in animals with elevated Dpp4 expression. Expression and release of DPP4 were markedly higher in the liver compared with adipose depots. Analysis of human liver biopsy specimens revealed a correlation of DPP4 expression and DNA methylation to stages of hepatosteatosis and nonalcoholic steatohepatitis. In summary, our results indicate a crucial role of the liver in participation to systemic DPP4 levels. Furthermore, the data show that glucose-induced expression of Dpp4 in the liver is facilitated by demethylation of the Dpp4 gene early in life. This might contribute to early deteriorations in hepatic function, which in turn result in metabolic disease such as hepatosteatosis later in life.
Published: 2016

44. Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals

Author: Niek Verweij, Iva Miljkovic, Peter Vollenweider, Denis Rybin, Aaron Isaacs, Arthur W. Musk, Eero Kajantie, Sara M. Willems, Ronan Roussel, Martina Müller-Nurasyid, Inês Barroso, Beverley Balkau, Stephan J. L. Bakker, Tamara B. Harris, Ching-Ti Liu, Jennie Hui, Letizia Marullo, Joseph Hung, John Beilby, Annette Peters, Cornelia M. van Duijn, Zoltán Kutalik, Kelly S. Benke, Mickaël Canouil, Johan G. Eriksson, Nicole Vogelzangs, James B. Meigs, Loic Yengo, Philippe Froguel, Rico Rueedi, Wolfgang Rathmann, Jennifer L. Bragg-Gresham, Daniel DiCorpo, Maryam Kavousi, Harald Grallert, Chiara Scapoli, Laura J. Rasmussen-Torvik, Jose C. Florez, Pim van der Harst, Nabila Bouatia-Naji, Jordi Merino, Carola Marzi, Tanguy Corre, Alan James, Lyle J. Palmer, Ghislain Rocheleau, Inga Prokopenko, Josée Dupuis, Jari Lahti, Sven Bergmann, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Department of Psychology and Logopedics, Developmental Psychology Research Group, Helsinki Collegium for Advanced Studies, HUS Children and Adolescents, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Epidemiology, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1 - Thrombosis and haemostasis, Epidemiologie, RS: CARIM - R3 - Vascular biology, RS: Carim - B01 Blood proteins & engineering, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, and RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health
Subjects: 0301 basic medicine, Blood Glucose, Male, PREDICTION, LOCI, lcsh:Medicine, Physiology, Genome-wide association study, Type 2 diabetes, VARIANTS, 0302 clinical medicine, Weight loss, LS2_1, Medicine, Longitudinal Studies, lcsh:Science, POPULATION, RISK, education.field_of_study, Multidisciplinary, Medical genetics, Middle Aged, 3. Good health, Phenotype, LIFE-STYLE INTERVENTION, Female, medicine.symptom, Non diabetic, Medical genetics, Type 2 diabetes, Genotype, 515 Psychology, Population, WEIGHT-LOSS, Polymorphism, Single Nucleotide, White People, Article, NO, GENETIC ARCHITECTURE, Fasting glucose, 03 medical and health sciences, TYPE-2, SDG 3 - Good Health and Well-being, Genetic variation, Humans, education, business.industry, lcsh:R, Genetic Variation, medicine.disease, PREVENTION, Genetic architecture, 030104 developmental biology, Diabetes Mellitus, Type 2, lcsh:Q, 3111 Biomedicine, sense organs, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P −8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P
Published: 2019

45. A trans-ancestral meta-analysis of Genome-wide Association Studies reveals loci associated with childhood obesity

Author: Jaakko T. Leinonen, Nicholas J. Timpson, Mohammad Hadi Zafarmand, Mette Hollensted, Anne E. Justice, Robert L. Hanson, Struan F.A. Grant, Frank D. Gilliland, Jesús Peralta-Romero, Diana L. Cousminer, Carol A. Wang, Jens-Christian Holm, Lindsay Fernández-Rhodes, Elina Hyppönen, Marc Vaudel, Marjo-Riitta Järvelin, Amélie Bonnefond, Esteban J. Parra, Robert I. Berkowitz, Koon K. Teo, Adnan Custovic, Christian Theil Have, Mariona Bustamante, Kari E. North, Stefan Johansson, Mustafa Atalay, Christine Frithioff-Bøjsøe, Estela Blanco, Adan Valladares-Salgado, Sylvain Sebert, Suzanne Vogelezang, Yujie Wang, Mark I. McCarthy, Timo A. Lakka, Christine Power, Raimo Joro, Oluf Pedersen, Heather M. Highland, Yik Ying Teo, Zhanghua Chen, Pål R. Njølstad, Momoko Horikoshi, William J. Gauderman, Øyvind Helgeland, Klaus Bønnelykke, Anke Hinney, Natalia Vilor-Tejedor, V. Saroja Voruganti, Niels Grarup, Sayuko Kobes, Shana E. McCormack, Christopher D. Brown, Alessandra Chesi, Nancy F. Butte, Triinu Peters, Miguel Cruz, Johan G. Eriksson, Torben Hansen, Babette S. Zemel, Terho Lehtimäki, Niina Pitkänen, Akram Alyass, Vincent W. V. Jaddoe, Elisabeth Thiering, Jonathan P. Bradfield, Eileen Tai-Hui Boh, Janine F. Felix, Olli T. Raitakari, Philippe Froguel, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Martine Vrijheid, Ville Karhunen, Mika Kähönen, Marie Standl, Angela Simpson, Seang-Mei Saw, David Meyre, Anthony G. Comuzzie, Mickaël Canouil, Tarunveer S. Ahluwalia, John A. Curtin, Barbera D. C. van Schaik, Johannes Hebebrand, Elisabeth Widen, Tanja G. M. Vrijkotte, Leslie J. Baier, Sheila Gahagan, Joachim Heinrich, Claire Monnereau, Jesús Vioque, Hans Bisgaard, Hakon Hakonarson, Estelle Lowry, Craig E. Pennell, Shelley A. Cole, Thorkild I. A. Sørensen, André G. Uitterlinden, Virpi Lindi, Genomics of Sex Differences, Institute for Molecular Medicine Finland, University of Helsinki, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Bradfield, Jonathan P., Vogelezang, Suzanne, Felix, Janine F., Chesi, Alessandra, Hyppönen, Elina, Jaddoe, Vincent W.V., Early Growth Genetics Consortium, Epidemiology and Data Science, Public and occupational health, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, APH - Global Health, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, ARD - Amsterdam Reproduction and Development, APH - Methodology, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, obesity, Pediatric Obesity, Medizin, IDENTIFIES 3, Genome-wide association study, VARIANTS, ethnic group, single nucleotide polymorphism, genetics, bayesian analysis, genes, Association Studies Article, Child, Genetics (clinical), 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, child, 0303 health sciences, adult, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Chromosome Mapping, General Medicine, 3. Good health, Female, body mass index procedure, childhood obesity, Life Sciences & Biomedicine, asian, Biochemistry & Molecular Biology, SUSCEPTIBILITY LOCI, DATABASE, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Wilms Tumor, Childhood obesity, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, medicine, MANAGEMENT, Humans, Genetic Predisposition to Disease, genome, Molecular Biology, 030304 developmental biology, genome-wide association study, Science & Technology, Early Growth Genetics Consortium, Case-control study, Bayes Theorem, 06 Biological Sciences, medicine.disease, Obesity, MC3R GENE, Genetic Loci, Case-Control Studies, 1182 Biochemistry, cell and molecular biology, Body mass index, Genome-Wide Association Study
Abstract: Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2–18 years old) and 15 599 controls (consistently
Published: 2019

46. A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Author: Bamidele O. Tayo, RJ Waken, Mario Sims, Diane M. Becker, Tõnu Esko, Yingchang Lu, Pamela J. Schreiner, Antonietta Robino, Anne U. Jackson, H. Janaka de Silva, Peter J. van der Most, Archie Campbell, Ozren Polasek, Salman M. Tajuddin, Jing Hua Zhao, Barbara V. Howard, Saima Afaq, Vilmundur Gudnason, Lynda M. Rose, Francis S. Collins, Massimiliano Cocca, Ruth J. F. Loos, Yii-Der Ida Chen, W. James Gauderman, Jaspal S. Kooner, Lawrence F. Bielak, Ulrich Broeckel, Anuradhani Kasturiratne, Melissa A. Richard, Tomohiro Katsuya, Nicola D. Kerrison, Tin Aung, Lisa de las Fuentes, Lynne E. Wagenknecht, Oscar H. Franco, Yongmei Liu, Eric Boerwinkle, Nana Matoba, Saskia P. Hagenaars, Rob M. van Dam, Tibor V. Varga, Nilesh J. Samani, Tangchun Wu, Thomas H. Mosley, Caroline Hayward, Joseph H. Lee, Frida Renström, Tamara B. Harris, Alena Stančáková, Adesola Ogunniyi, Wen Bin Wei, Lenore J. Launer, Marcus Dörr, Xiuqing Guo, Jennifer A. Smith, Terho Lehtimäki, Dan E. Arking, Fang-Chi Hsu, Karin Leander, Martin Farrall, Konstantin Strauch, Albert V. Smith, Richard S. Cooper, Chiea Chuen Khor, Changwei Li, James E. Hixson, Sami Heikkinen, David R. Weir, Pirjo Komulainen, Renée de Mutsert, Raymond Noordam, Ubaydah Nasri, Paul M. Ridker, C. Charles Gu, Tamuno Alfred, Jerome I. Rotter, Nora Franceschini, Nita G. Forouhi, Lihua Wang, Alanna C. Morrison, Jian-Min Yuan, Ching-Yu Cheng, Peter S. Braund, Paul Elliott, Gregory P. Wilson, Jianjun Liu, Xiaofeng Zhu, Markku Laakso, Christian Gieger, Yukihide Momozawa, Rainer Rettig, Carsten Oliver Schmidt, Amy R. Bentley, Wei Zhao, Ioanna Ntalla, Kenneth Rice, Yoichiro Kamatani, Andres Metspalu, Helen R. Warren, Yechiel Friedlander, Susan Redline, Kurt Lohman, Cornelia M. van Duijn, Aravinda Chakravarti, Traci M. Bartz, Sarah E. Harris, Yih Chung Tham, He Gao, Mike A. Nalls, Mathilde Boissel, Donna K. Arnett, Harold Snieder, James S. Pankow, Babatunde L. Salako, Laura J. Bierut, Tin Louie, Albertine J. Oldehinkel, Xueling Sim, Thomas Meitinger, Maris Alver, Claudia Langenberg, Stephen B. Kritchevsky, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Alexandre C. Pereira, Michael R. Brown, Karen Schwander, Charles Kooperberg, Blair H. Smith, Annette Peters, Fernando Pires Hartwig, Yanhua Zhou, Jie Yao, Alisa K. Manning, Keng-Hung Lin, Dennis O. Mook-Kanamori, Ervin R. Fox, Tuomo Rankinen, Timo A. Lakka, Charles N. Rotimi, Nicholette D. Palmer, Jiang He, Nicholas J. Wareham, Jingmin Liu, Yun Ju Sung, Cathy C. Laurie, Donald W. Bowden, Yong-Bing Xiang, Lisa R. Yanek, B. Kuhnel, Nancy L. Pedersen, Yajuan Wang, Ananda R. Wickremasinghe, Jonathan Marten, Yi-Jen Hung, Dabeeru C. Rao, Bernardo L. Horta, Joel D. Kaufman, Barry I. Freedman, Chuan Gao, Olli T. Raitakari, Reedik Mägi, Solomon K. Musani, Albert Hofman, Wanqing Wen, Heming Wang, Xiao-Ou Shu, Y Liu, Mark J. Caulfield, Meian He, Daniel I. Chasman, Carl D. Langefeld, Charumathi Sabanayagam, Bruce M. Psaty, Jasmin Divers, R. Graham Barr, Chew-Kiat Heng, Stella Aslibekyan, John M. Starr, Stefan Weiss, Anuj Goel, Tuomas O. Kilpeläinen, Terrence Forrester, Mary F. Feitosa, Jost B. Jonas, Kae-Woei Liang, Colleen M. Sitlani, Daniel Levy, Marie Loh, Qing Duan, Aldi T. Kraja, Tien Yin Wong, Myriam Fornage, Andrea R. V. R. Horimoto, Michele K. Evans, David J. Porteous, Dina Vojinovic, Hua Tang, Michael A. Province, Ching-Ti Liu, Rainer Rauramaa, William R. Scott, Cora E. Lewis, Charles B. Eaton, Sharon L.R. Kardia, Michael Boehnke, James Scott, Colin A McKenzie, Jin-Fang Chai, Woon-Puay Koh, Yucheng Jia, Claude Bouchard, Peter S. Sever, Koichi Matsuda, Najaf Amin, Ulf de Faire, Walter Palmas, André G. Uitterlinden, Thomas T. Perls, Erin B. Ware, Wayne Huey-Herng Sheu, Michiaki Kubo, Ya Xing Wang, Hugh Watkins, Steven C. Hunt, Weihua Zhang, Johanna Kuusisto, Lili Milani, Rajkumar Dorajoo, Georg Ehret, L. Adrienne Cupples, Franco Giulianini, Zoltán Kutalik, Jose E Krieger, Kevin Sandow, Bruna Gigante, Alexander P. Reiner, Preeti Gupta, Heikki A. Koistinen, Treva Rice, Patricia B. Munroe, Wen-Jane Lee, Jennifer A. Brody, Paolo Gasparini, Paul W. Franks, Yik Ying Teo, Leo-Pekka Lyytikäinen, Thomas W. Winkler, Patricia A. Peyser, Ian J. Deary, Jessica D. Faul, Sing Hui Lim, Fumihiko Takeuchi, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, E. Shyong Tai, Candace M Kammerer, Mary K. Wojczynski, Pim van der Harst, Marzyeh Amini, Jennifer G. Robinson, Erwin P. Bottinger, Alan B. Zonderman, Benjamin Lehne, M. Waldenberger, Jeffrey R. O'Connell, Hugues Aschard, Ilaria Gandin, Kent D. Taylor, Igor Rudan, Christopher P. Nelson, John M. C. Connell, Jian'an Luan, Mickaël Canouil, Robert A. Scott, Yize Li, Marguerite R. Irvin, Sung, Yun Ju, de Las Fuentes, Lisa, Winkler, Thomas W, Chasman, Daniel I, Bentley, Amy R, Kraja, Aldi T, Ntalla, Ioanna, Warren, Helen R, Guo, Xiuqing, Schwander, Karen, Manning, Alisa K, Brown, Michael R, Aschard, Hugue, Feitosa, Mary F, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K, Kilpeläinen, Tuomas O, Richard, Melissa A, Aslibekyan, Stella, Bartz, Traci M, Dorajoo, Rajkumar, Li, Changwei, Liu, Yongmei, Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M, Tayo, Bamidele O, Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kammerer, Candace M, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Mckenzie, Colin A, Nelson, Christopher P, Noordam, Raymond, Scott, Robert A, Sheu, Wayne H H, Stančáková, Alena, Takeuchi, Fumihiko, van der Most, Peter J, Varga, Tibor V, Waken, Robert J, Wang, Heming, Wang, Yajuan, Ware, Erin B, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan E, Aung, Tin, Barr, R Graham, Bielak, Lawrence F, Boerwinkle, Eric, Bottinger, Erwin P, Braund, Peter S, Brody, Jennifer A, Broeckel, Ulrich, Cade, Brian, Campbell, Archie, Canouil, Mickaël, Chakravarti, Aravinda, Cocca, Massimiliano, Collins, Francis S, Connell, John M, de Mutsert, Renée, de Silva, H Janaka, Dörr, Marcu, Duan, Qing, Eaton, Charles B, Ehret, Georg, Evangelou, Evangelo, Faul, Jessica D, Forouhi, Nita G, Franco, Oscar H, Friedlander, Yechiel, Gao, He, Gigante, Bruna, Gu, C Charle, Gupta, Preeti, Hagenaars, Saskia P, Harris, Tamara B, He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hofman, Albert, Howard, Barbara V, Hunt, Steven C, Irvin, Marguerite R, Jia, Yucheng, Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D, Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A, Kooperberg, Charles B, Krieger, Jose E, Kubo, Michiaki, Kutalik, Zoltan, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Joseph H, Lehne, Benjamin, Levy, Daniel, Lewis, Cora E, Li, Yize, Lim, Sing Hui, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Yeheng, Loh, Marie, Lohman, Kurt K, Louie, Tin, Mägi, Reedik, Matsuda, Koichi, Meitinger, Thoma, Metspalu, Andre, Milani, Lili, Momozawa, Yukihide, Mosley, Thomas H, Nalls, Mike A, Nasri, Ubaydah, O'Connell, Jeff R, Ogunniyi, Adesola, Palmas, Walter R, Palmer, Nicholette D, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Porteous, David, Raitakari, Olli T, Renström, Frida, Rice, Treva K, Ridker, Paul M, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L, Sandow, Kevin, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Sims, Mario, Sitlani, Colleen M, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tang, Hua, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Wilson, Gregory, Wojczynski, Mary K, Xiang, Yong-Bing, Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Chen, Yii-Der Ida, Weir, David R, de Faire, Ulf, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Forrester, Terrence, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost Bruno, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Lehtimäki, Terho, Liang, Kae-Woei, Magnusson, Patrik K E, Oldehinkel, Albertine J, Pereira, Alexandre C, Perls, Thoma, Rauramaa, Rainer, Redline, Susan, Rettig, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wareham, Nicholas J, Watkins, Hugh, Wickremasinghe, Ananda R, Wu, Tangchun, Kamatani, Yoichiro, Laurie, Cathy C, Bouchard, Claude, Cooper, Richard S, Evans, Michele K, Gudnason, Vilmundur, Hixson, Jame, Kardia, Sharon L R, Kritchevsky, Stephen B, Psaty, Bruce M, van Dam, Rob M, Arnett, Donna K, Mook-Kanamori, Dennis O, Fornage, Myriam, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Loos, Ruth J F, Reiner, Alex P, Rotimi, Charles N, Bierut, Laura J, Zhu, Xiaofeng, Cupples, L Adrienne, Province, Michael A, Rotter, Jerome I, Franks, Paul W, Rice, Kenneth, Elliott, Paul, Caulfield, Mark J, Gauderman, W Jame, Munroe, Patricia B, Rao, Dabeeru C, Morrison, Alanna C, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), U.S. National Heart, Lung, and Blood Institute (NHLBI) (K25HL121091 to Y.J.S.), National Institutes of Health (R01HL118305), We thank anonymous reviewers for critical reading and providing constructive and insightful comments, which substantially improved the article. This project, like several other projects, was carried out as part of the CHARGE Gene–Lifestyle Interactions Working Group., Conflict of Interest statement. The authors declare no competing financial interests except for the following: B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson, O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health), L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,‘Markers for Addiction’ covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction, P.S. has received research awards from Pfizer Inc, J.B.J. is a consultant for Mundipharma Co. (Cambridge, UK), Patent holder with Biocompatibles UK Ltd (Franham, Surrey, UK) (title: treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor, Patent number: 20120263794) and Patent application with University of Heidelberg (Heidelberg, Germany) (title: agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia, Europäische Patentanmeldung 15000771.4), P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative project, M.A.N.'s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, M.A.N. also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others, and M.J. C. is chief scientist for Genomics England, a UK government company., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), University Management, Department of Medicine, University of Helsinki, HUS Abdominal Center, Endokrinologian yksikkö, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)
Subjects: Male, Receptors, Vasopressin, multi-ancestry, Genome-wide association study, Blood Pressure, HYDROCARBON RECEPTOR AHR, 030204 cardiovascular system & hematology, Antiporters, gene-smoking interaction, 0302 clinical medicine, Polymorphism (computer science), genome-wide study, Ethnicity, OXIDATIVE STRESS, Association Studies Article, 11 Medical and Health Sciences, Genetics (clinical), Genetics & Heredity, Genetics, ddc:616, Aged, 80 and over, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], DEPENDENT HYPERTENSION, CARDIOVASCULAR RISK, Smoking, 1184 Genetics, developmental biology, physiology, General Medicine, ASSOCIATION, Middle Aged, Caspase 9, 3. Good health, Pulse pressure, ENVIRONMENT INTERACTION, Sulfate Transporters, T-CADHERIN, Hypertension, Female, Life Sciences & Biomedicine, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, Biochemistry & Molecular Biology, Mean arterial pressure, Adolescent, Diastole, Biology, elevated blood pressure, gene-smoking interactions, 03 medical and health sciences, Young Adult, Insulin resistance, Lifelines Cohort Study, medicine, Humans, Arterial Pressure, Molecular Biology, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, Polymorphism, Genetic, Tumor Suppressor Proteins, Racial Groups, Membrane Proteins, 06 Biological Sciences, SYSTOLIC BLOOD-PRESSURE, BODY-MASS INDEX, medicine.disease, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Heart failure, 1182 Biochemistry, cell and molecular biology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Gene-Environment Interaction, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genome-Wide Association Study
Abstract: Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P
Published: 2019

47. Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes

Author: Florian Ehehalt, Lorella Marselli, Philippe Froguel, Amélie Bonnefond, Bernard Thorens, Daniela Richter, Michele Solimena, Jürgen Weitz, Afshan Siddiq, Mario Falchi, Ioannis Xenarios, Marius Distler, Anke M. Schulte, Amna Khamis, Mark Ibberson, Mickaël Canouil, Piero Marchetti, Krister Bokvist, Hutokshi Crouch, Manon von Bulow, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M))
Subjects: 0301 basic medicine, lcsh:Internal medicine, [SDV]Life Sciences [q-bio], Quantitative Trait Loci, Kinesins, 030209 endocrinology & metabolism, Genome-wide association study, Single-nucleotide polymorphism, Computational biology, Biology, Quantitative trait locus, Genome, Polymorphism, Single Nucleotide, Type 2 Diabetes, Eqtls, Genetics, Islets, Laser Capture Microdissection, 03 medical and health sciences, Islets of Langerhans, 0302 clinical medicine, medicine, Humans, Cytochrome P450 Family 4, Peptide Synthases, lcsh:RC31-1245, Molecular Biology, Gene, Laser capture microdissection, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Pancreatic islets, eQTLs, Membrane Proteins, Type 2 diabetes, Cell Biology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics, Cytochrome P450 Family 4/genetics, Diabetes Mellitus, Type 2/genetics, Diabetes Mellitus, Type 2/pathology, Islets of Langerhans/metabolism, Kinesin/genetics, Membrane Proteins/genetics, Peptide Synthases/genetics, PPP, Phenotyped Pancreatectomized Patients, 030104 developmental biology, medicine.anatomical_structure, Diabetes Mellitus, Type 2, LCM, Laser Capture Microdissection, Expression quantitative trait loci, Original Article
Abstract: Objective Genome wide association studies (GWAS) for type 2 diabetes (T2D) have identified genetic loci that often localise in non-coding regions of the genome, suggesting gene regulation effects. We combined genetic and transcriptomic analysis from human islets obtained from brain-dead organ donors or surgical patients to detect expression quantitative trait loci (eQTLs) and shed light into the regulatory mechanisms of these genes. Methods Pancreatic islets were isolated either by laser capture microdissection (LCM) from surgical specimens of 103 metabolically phenotyped pancreatectomized patients (PPP) or by collagenase digestion of pancreas from 100 brain-dead organ donors (OD). Genotyping (> 8.7 million single nucleotide polymorphisms) and expression (> 47,000 transcripts and splice variants) analyses were combined to generate cis-eQTLs. Results After applying genome-wide false discovery rate significance thresholds, we identified 1,173 and 1,021 eQTLs in samples of OD and PPP, respectively. Among the strongest eQTLs shared between OD and PPP were CHURC1 (OD p-value=1.71 × 10-24; PPP p-value = 3.64 × 10–24) and PSPH (OD p-value = 3.92 × 10−26; PPP p-value = 3.64 × 10−24). We identified eQTLs in linkage-disequilibrium with GWAS loci T2D and associated traits, including TTLL6, MLX and KIF9 loci, which do not implicate the nearest gene. We found in the PPP datasets 11 eQTL genes, which were differentially expressed in T2D and two genes (CYP4V2 and TSEN2) associated with HbA1c but none in the OD samples. Conclusions eQTL analysis of LCM islets from PPP led us to identify novel genes which had not been previously linked to islet biology and T2D. The understanding gained from eQTL approaches, especially using surgical samples of living patients, provides a more accurate 3-dimensional representation than those from genetic studies alone., Highlights • We identified eQTLs from human islets: 1,173 eQTLs from organ donors and 1,021 from surgical samples. • eQTLs in LD with GWAS loci for T2D and associated traits did not always implicate the nearest gene. • We identified 11 eQTL genes differentially expressed in T2D compared to controls only in PPP surgical patients. • Two genes (CYP4V2 and TSEN2) associated with elevated HbA1C only in PPP.
Published: 2019

48. Chromatin 3D Interaction Analysis of the STARD10 Locus Unveils FCHSD2 as a New Regulator of Insulin Secretion

Author: Shuying Jiang, Michele Solimena, Anke M. Schulte, Paul Gadue, Piero Marchetti, Philippe Froguel, Harvey T. McMahon, Fabian L. Cardenas-Diaz, Ming Hu, Amna Khamis, Mark Ibberson, Inês Cebola, Leonardo Alemeida-Souza, Gaelle Carrat, Mickaël Canouil, and Guy A. Rutter
Subjects: Regulation of gene expression, Chromosome conformation capture, Locus (genetics), Secretion, Genome-wide association study, Biology, Enhancer, Gene, Chromatin, Cell biology
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with type 2 diabetes (T2D) risk. Using chromatin conformation capture we show that an enhancer cluster in the STARD10 T2D locus forms a defined 3D chromatin domain. A 4.1 Kb region within this region, carrying five disease-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identified FCHSD2 as an additional target of the enhancer cluster. Deletion of the variant region, or an associated enhancer (R2), from EndoC-βH1 cells using CRISPR-Cas9 reduced STARD10 and FCHSD2, but not neighboring ARAP1 expression, and impaired glucose-stimulated insulin secretion. Correspondingly, CRISPR-Cas9-mediated knockout of STARD10 or FCHSD2 impaired secretion. Finally, expression of STARD10 and FCHSD2 in human islets was associated with the possession of variant alleles. Thus, multiple genes at the STARD10 locus influence β cell function to alter disease risk.
Published: 2019

49. NACHO: a Nanostring nCounter data QC package

Author: Mickaël Canouil, Gerard A Bouland, Amélie Bonnefond, Philippe Froguel, Leen ’t Hart, Roderick Slieker
Published: 2019
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50. The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward

Author: Amna Khamis, Ana Ortalli, Marlène Huyvaert, Julie Kerr-Conte, Amélie Bonnefond, François Pattou, Beverley Balkau, Mickaël Canouil, Stéphane Lobbens, Cecile Lecoeur, Lorella Marselli, Marie Verbanck, Michel Marre, Ronan Roussel, Piero Marchetti, Fatou K. Ndiaye, and Philippe Froguel
Subjects: Adult, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, Medicine (miscellaneous), 030209 endocrinology & metabolism, Substantia nigra, Single-nucleotide polymorphism, Genome-wide association study, Hyperphagia, Biology, Polymorphism, Single Nucleotide, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Reward, medicine, Humans, Genetic Predisposition to Disease, Obesity, 030212 general & internal medicine, Allele, media_common, Genetic association, Cerebral Cortex, Genetics, Nutrition and Dietetics, Addiction, nutritional and metabolic diseases, Middle Aged, medicine.disease, Behavior, Addictive, Substantia Nigra, Insula, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified more than 250 loci associated with body mass index (BMI) and obesity. However, post-GWAS functional genomic investigations have been inadequate for understanding how these genetic loci physiologically impact disease development. We performed a PCR-free expression assay targeting genes located nearby the GWAS-identified SNPs associated with BMI/obesity in a large panel of human tissues. Furthermore, we analyzed several genetic risk scores (GRS) summing GWAS-identified alleles associated with increased BMI in 4236 individuals. We found that the expression of BMI/obesity susceptibility genes was strongly enriched in the brain, especially in the insula (p = 4.7 × 10–9) and substantia nigra (p = 6.8 × 10–7), which are two brain regions involved in addiction and reward. Inversely, we found that top obesity/BMI-associated loci, including FTO, showed the strongest gene expression enrichment in the two brain regions. Our data suggest for the first time that the susceptibility genes for common obesity may have an effect on eating addiction and reward behaviors through their high expression in substantia nigra and insula, i.e., a different pattern from monogenic obesity genes that act in the hypothalamus and cause hyperphagia. Further epidemiological studies with relevant food behavior phenotypes are necessary to confirm these findings.
Published: 2019

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