Kyle J Gaulton1. 1. Department of Pediatrics, University of California San Diego, San Diego, CA, 92093, USA. kgaulton@ucsd.edu.
Abstract
PURPOSE OF REVIEW: Deciphering the mechanisms of type 2 diabetes (T2DM) risk loci can greatly inform on disease pathology. This review discusses current knowledge of mechanisms through which genetic variants influence T2DM risk and considerations for future studies. RECENT FINDINGS: Over 100 T2DM risk loci to date have been identified. Candidate causal variants at risk loci map predominantly to non-coding sequence. Physiological, epigenomic and gene expression data suggest that variants at many known T2DM risk loci affect pancreatic islet regulation, although variants at other loci also affect protein function and regulatory processes in adipose, pre-adipose, liver, skeletal muscle and brain. The effects of T2DM variants on regulatory activity in these tissues appear largely, but not exclusively, due to altered transcription factor binding. Putative target genes of T2DM variants have been defined at an increasing number of loci and some, such as FTO, may entail several genes and multiple tissues. Gene networks in islets and adipocytes have been implicated in T2DM risk, although the molecular pathways of risk genes remain largely undefined. Efforts to fully define the mechanisms of T2DM risk loci are just beginning. Continued identification of risk mechanisms will benefit from combining genetic fine-mapping with detailed phenotypic association data, high-throughput epigenomics data from diabetes-relevant tissue, functional screening of candidate genes and genome editing of cellular and animal models.
PURPOSE OF REVIEW: Deciphering the mechanisms of type 2 diabetes (T2DM) risk loci can greatly inform on disease pathology. This review discusses current knowledge of mechanisms through which genetic variants influence T2DM risk and considerations for future studies. RECENT FINDINGS: Over 100 T2DM risk loci to date have been identified. Candidate causal variants at risk loci map predominantly to non-coding sequence. Physiological, epigenomic and gene expression data suggest that variants at many known T2DM risk loci affect pancreatic islet regulation, although variants at other loci also affect protein function and regulatory processes in adipose, pre-adipose, liver, skeletal muscle and brain. The effects of T2DM variants on regulatory activity in these tissues appear largely, but not exclusively, due to altered transcription factor binding. Putative target genes of T2DM variants have been defined at an increasing number of loci and some, such as FTO, may entail several genes and multiple tissues. Gene networks in islets and adipocytes have been implicated in T2DM risk, although the molecular pathways of risk genes remain largely undefined. Efforts to fully define the mechanisms of T2DM risk loci are just beginning. Continued identification of risk mechanisms will benefit from combining genetic fine-mapping with detailed phenotypic association data, high-throughput epigenomics data from diabetes-relevant tissue, functional screening of candidate genes and genome editing of cellular and animal models.
Entities:
Keywords:
Epigenomics; GWAS; Gene regulation; Human genetics; Physiology
Authors: Qianghua Xia; Alessandra Chesi; Elisabetta Manduchi; Brian T Johnston; Sumei Lu; Michelle E Leonard; Ursula W Parlin; Eric F Rappaport; Peng Huang; Andrew D Wells; Gerd A Blobel; Matthew E Johnson; Struan F A Grant Journal: Diabetologia Date: 2016-08-18 Impact factor: 10.122
Authors: Alexander Gusev; Arthur Ko; Huwenbo Shi; Gaurav Bhatia; Wonil Chung; Brenda W J H Penninx; Rick Jansen; Eco J C de Geus; Dorret I Boomsma; Fred A Wright; Patrick F Sullivan; Elina Nikkola; Marcus Alvarez; Mete Civelek; Aldons J Lusis; Terho Lehtimäki; Emma Raitoharju; Mika Kähönen; Ilkka Seppälä; Olli T Raitakari; Johanna Kuusisto; Markku Laakso; Alkes L Price; Päivi Pajukanta; Bogdan Pasaniuc Journal: Nat Genet Date: 2016-02-08 Impact factor: 38.330
Authors: Fabian Grubert; Judith B Zaugg; Maya Kasowski; Oana Ursu; Damek V Spacek; Alicia R Martin; Peyton Greenside; Rohith Srivas; Doug H Phanstiel; Aleksandra Pekowska; Nastaran Heidari; Ghia Euskirchen; Wolfgang Huber; Jonathan K Pritchard; Carlos D Bustamante; Lars M Steinmetz; Anshul Kundaje; Michael Snyder Journal: Cell Date: 2015-08-20 Impact factor: 41.582
Authors: Nicole Soranzo; Serena Sanna; Eleanor Wheeler; Christian Gieger; Dörte Radke; Josée Dupuis; Nabila Bouatia-Naji; Claudia Langenberg; Inga Prokopenko; Elliot Stolerman; Manjinder S Sandhu; Matthew M Heeney; Joseph M Devaney; Muredach P Reilly; Sally L Ricketts; Alexandre F R Stewart; Benjamin F Voight; Christina Willenborg; Benjamin Wright; David Altshuler; Dan Arking; Beverley Balkau; Daniel Barnes; Eric Boerwinkle; Bernhard Böhm; Amélie Bonnefond; Lori L Bonnycastle; Dorret I Boomsma; Stefan R Bornstein; Yvonne Böttcher; Suzannah Bumpstead; Mary Susan Burnett-Miller; Harry Campbell; Antonio Cao; John Chambers; Robert Clark; Francis S Collins; Josef Coresh; Eco J C de Geus; Mariano Dei; Panos Deloukas; Angela Döring; Josephine M Egan; Roberto Elosua; Luigi Ferrucci; Nita Forouhi; Caroline S Fox; Christopher Franklin; Maria Grazia Franzosi; Sophie Gallina; Anuj Goel; Jürgen Graessler; Harald Grallert; Andreas Greinacher; David Hadley; Alistair Hall; Anders Hamsten; Caroline Hayward; Simon Heath; Christian Herder; Georg Homuth; Jouke-Jan Hottenga; Rachel Hunter-Merrill; Thomas Illig; Anne U Jackson; Antti Jula; Marcus Kleber; Christopher W Knouff; Augustine Kong; Jaspal Kooner; Anna Köttgen; Peter Kovacs; Knut Krohn; Brigitte Kühnel; Johanna Kuusisto; Markku Laakso; Mark Lathrop; Cécile Lecoeur; Man Li; Mingyao Li; Ruth J F Loos; Jian'an Luan; Valeriya Lyssenko; Reedik Mägi; Patrik K E Magnusson; Anders Mälarstig; Massimo Mangino; María Teresa Martínez-Larrad; Winfried März; Wendy L McArdle; Ruth McPherson; Christa Meisinger; Thomas Meitinger; Olle Melander; Karen L Mohlke; Vincent E Mooser; Mario A Morken; Narisu Narisu; David M Nathan; Matthias Nauck; Chris O'Donnell; Konrad Oexle; Nazario Olla; James S Pankow; Felicity Payne; John F Peden; Nancy L Pedersen; Leena Peltonen; Markus Perola; Ozren Polasek; Eleonora Porcu; Daniel J Rader; Wolfgang Rathmann; Samuli Ripatti; Ghislain Rocheleau; Michael Roden; Igor Rudan; Veikko Salomaa; Richa Saxena; David Schlessinger; Heribert Schunkert; Peter Schwarz; Udo Seedorf; Elizabeth Selvin; Manuel Serrano-Ríos; Peter Shrader; Angela Silveira; David Siscovick; Kjioung Song; Timothy D Spector; Kari Stefansson; Valgerdur Steinthorsdottir; David P Strachan; Rona Strawbridge; Michael Stumvoll; Ida Surakka; Amy J Swift; Toshiko Tanaka; Alexander Teumer; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Anke Tönjes; Gianluca Usala; Veronique Vitart; Henry Völzke; Henri Wallaschofski; Dawn M Waterworth; Hugh Watkins; H-Erich Wichmann; Sarah H Wild; Gonneke Willemsen; Gordon H Williams; James F Wilson; Juliane Winkelmann; Alan F Wright; Carina Zabena; Jing Hua Zhao; Stephen E Epstein; Jeanette Erdmann; Hakon H Hakonarson; Sekar Kathiresan; Kay-Tee Khaw; Robert Roberts; Nilesh J Samani; Mark D Fleming; Robert Sladek; Gonçalo Abecasis; Michael Boehnke; Philippe Froguel; Leif Groop; Mark I McCarthy; W H Linda Kao; Jose C Florez; Manuela Uda; Nicholas J Wareham; Inês Barroso; James B Meigs Journal: Diabetes Date: 2010-09-21 Impact factor: 9.461
Authors: Adam Auton; Lisa D Brooks; Richard M Durbin; Erik P Garrison; Hyun Min Kang; Jan O Korbel; Jonathan L Marchini; Shane McCarthy; Gil A McVean; Gonçalo R Abecasis Journal: Nature Date: 2015-10-01 Impact factor: 49.962
Authors: Shane McCarthy; Sayantan Das; Warren Kretzschmar; Olivier Delaneau; Andrew R Wood; Alexander Teumer; Hyun Min Kang; Christian Fuchsberger; Petr Danecek; Kevin Sharp; Yang Luo; Carlo Sidore; Alan Kwong; Nicholas Timpson; Seppo Koskinen; Scott Vrieze; Laura J Scott; He Zhang; Anubha Mahajan; Jan Veldink; Ulrike Peters; Carlos Pato; Cornelia M van Duijn; Christopher E Gillies; Ilaria Gandin; Massimo Mezzavilla; Arthur Gilly; Massimiliano Cocca; Michela Traglia; Andrea Angius; Jeffrey C Barrett; Dorrett Boomsma; Kari Branham; Gerome Breen; Chad M Brummett; Fabio Busonero; Harry Campbell; Andrew Chan; Sai Chen; Emily Chew; Francis S Collins; Laura J Corbin; George Davey Smith; George Dedoussis; Marcus Dorr; Aliki-Eleni Farmaki; Luigi Ferrucci; Lukas Forer; Ross M Fraser; Stacey Gabriel; Shawn Levy; Leif Groop; Tabitha Harrison; Andrew Hattersley; Oddgeir L Holmen; Kristian Hveem; Matthias Kretzler; James C Lee; Matt McGue; Thomas Meitinger; David Melzer; Josine L Min; Karen L Mohlke; John B Vincent; Matthias Nauck; Deborah Nickerson; Aarno Palotie; Michele Pato; Nicola Pirastu; Melvin McInnis; J Brent Richards; Cinzia Sala; Veikko Salomaa; David Schlessinger; Sebastian Schoenherr; P Eline Slagboom; Kerrin Small; Timothy Spector; Dwight Stambolian; Marcus Tuke; Jaakko Tuomilehto; Leonard H Van den Berg; Wouter Van Rheenen; Uwe Volker; Cisca Wijmenga; Daniela Toniolo; Eleftheria Zeggini; Paolo Gasparini; Matthew G Sampson; James F Wilson; Timothy Frayling; Paul I W de Bakker; Morris A Swertz; Steven McCarroll; Charles Kooperberg; Annelot Dekker; David Altshuler; Cristen Willer; William Iacono; Samuli Ripatti; Nicole Soranzo; Klaudia Walter; Anand Swaroop; Francesco Cucca; Carl A Anderson; Richard M Myers; Michael Boehnke; Mark I McCarthy; Richard Durbin Journal: Nat Genet Date: 2016-08-22 Impact factor: 38.330
Authors: Anshul Kundaje; Wouter Meuleman; Jason Ernst; Misha Bilenky; Angela Yen; Alireza Heravi-Moussavi; Pouya Kheradpour; Zhizhuo Zhang; Jianrong Wang; Michael J Ziller; Viren Amin; John W Whitaker; Matthew D Schultz; Lucas D Ward; Abhishek Sarkar; Gerald Quon; Richard S Sandstrom; Matthew L Eaton; Yi-Chieh Wu; Andreas R Pfenning; Xinchen Wang; Melina Claussnitzer; Yaping Liu; Cristian Coarfa; R Alan Harris; Noam Shoresh; Charles B Epstein; Elizabeta Gjoneska; Danny Leung; Wei Xie; R David Hawkins; Ryan Lister; Chibo Hong; Philippe Gascard; Andrew J Mungall; Richard Moore; Eric Chuah; Angela Tam; Theresa K Canfield; R Scott Hansen; Rajinder Kaul; Peter J Sabo; Mukul S Bansal; Annaick Carles; Jesse R Dixon; Kai-How Farh; Soheil Feizi; Rosa Karlic; Ah-Ram Kim; Ashwinikumar Kulkarni; Daofeng Li; Rebecca Lowdon; GiNell Elliott; Tim R Mercer; Shane J Neph; Vitor Onuchic; Paz Polak; Nisha Rajagopal; Pradipta Ray; Richard C Sallari; Kyle T Siebenthall; Nicholas A Sinnott-Armstrong; Michael Stevens; Robert E Thurman; Jie Wu; Bo Zhang; Xin Zhou; Arthur E Beaudet; Laurie A Boyer; Philip L De Jager; Peggy J Farnham; Susan J Fisher; David Haussler; Steven J M Jones; Wei Li; Marco A Marra; Michael T McManus; Shamil Sunyaev; James A Thomson; Thea D Tlsty; Li-Huei Tsai; Wei Wang; Robert A Waterland; Michael Q Zhang; Lisa H Chadwick; Bradley E Bernstein; Joseph F Costello; Joseph R Ecker; Martin Hirst; Alexander Meissner; Aleksandar Milosavljevic; Bing Ren; John A Stamatoyannopoulos; Ting Wang; Manolis Kellis Journal: Nature Date: 2015-02-19 Impact factor: 69.504
Authors: Teodor T Postolache; Laura Del Bosque-Plata; Serge Jabbour; Michael Vergare; Rongling Wu; Claudia Gragnoli Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2019-02-06 Impact factor: 3.568
Authors: Holly B Ende; M James Lozada; David H Chestnut; Sarah S Osmundson; Rachel L Walden; Matthew S Shotwell; Jeanette R Bauchat Journal: Obstet Gynecol Date: 2021-02-01 Impact factor: 7.661
Authors: Yahui Kong; Rohit B Sharma; Socheata Ly; Rachel E Stamateris; William M Jesdale; Laura C Alonso Journal: Diabetes Date: 2018-02-06 Impact factor: 9.461