Dynamic changes in immune gene co-expression networks predict development of type 1 diabetes
Authors: Brænne Ingrid , Onengut-Gumuscu Suna , Chen Ruoxi , Manichaikul Ani W. , Rich Stephen S. , Chen Wei-Min , Farber Charles R. ,   the TEDDY Study Group,   Colorado Clinical Center, Rewers Marian , Barbour Aaron , Bautista Kimberly , Baxter Judith , Felipe-Morales Daniel , Driscoll Kimberly , Frohnert Brigitte I. , Stahl Marisa , Gesualdo Patricia , Hoffman Michelle , Karban Rachel , Liu Edwin , Norris Jill , Peacock Stesha , Shorrosh Hanan , Steck Andrea , Stern Megan , Villegas Erica , Waugh Kathleen ,   Finland Clinical Center, Toppari Jorma , Simell Olli G. , Adamsson Annika , Ahonen Suvi , Åkerlund Mari , Hakola Leena , Hekkala Anne , Holappa Henna , Hyöty Heikki , Ikonen Anni , Ilonen Jorma , Jäminki Sinikka , Jokipuu Sanna , Karlsson Leena , Kero Jukka , Kähönen Miia , Knip Mikael , Koivikko Minna-Liisa , Koskinen Merja , Koreasalo Mirva , Kurppa Kalle , Kytölä Jarita , Latva-aho Tiina , Lindfors Katri , Lönnrot Maria , Mäntymäki Elina , Mattila Markus , Miettinen Maija , Multasuo Katja , Mykkänen Teija , Niininen Tiina , Niinistö Sari , Nyblom Mia , Oikarinen Sami , Ollikainen Paula , Othmani Zhian , Pohjola Sirpa , Rajala Petra , Rautanen Jenna , Riikonen Anne , Riski Eija , Pekkola Miia , Romo Minna , Ruohonen Satu , Simell Satu , Sjöberg Maija , Stenius Aino , Tossavainen Päivi , Vähä-Mäkilä Mari , Vainionpää Sini , Varjonen Eeva , Veijola Riitta , Viinikangas Irene , Virtanen Suvi M. ,   Georgia/Florida Clinical Center, She Jin-Xiong , Schatz Desmond , Hopkins Diane , Steed Leigh , Bryant Jennifer , Silvis Katherine , Haller Michael , Gardiner Melissa , McIndoe Richard , Sharma Ashok , Anderson Stephen W. , Jacobsen Laura , Marks John , Towe P. D. ,   Germany Clinical Center, Ziegler Anette G. , Bonifacio Ezio , Gavrisan Anita , Gezginci Cigdem , Heublein Anja , Hoffmann Verena , Hummel Sandra , Keimer Andrea , Knopff Annette , Koch Charlotte , Koletzko Sibylle , Ramminger Claudia , Roth Roswith , Scholz Marlon , Stock Joanna , Warncke Katharina , Wendel Lorena , Winkler Christiane ,   Sweden Clinical Center, Lernmark Åke , Agardh Daniel , Aronsson Carin Andrén , Ask Maria , Bennet Rasmus , Cilio Corrado , Engqvist Helene , Ericson-Hallström Emelie , Fors Annika , Fransson Lina , Gard Thomas , Hansen Monika , Jisser Hanna , Johansen Fredrik , Jonsdottir Berglind , Jovic Silvija , Larsson Helena Elding , Lindström Marielle , Lundgren Markus , Maziarz Marlena , Månsson-Martinez Maria , Markan Maria , Melin Jessica , Mestan Zeliha , Nilsson Caroline , Ottosson Karin , Rahmati Kobra , Ramelius Anita , Salami Falastin , Sjöberg Anette , Sjöberg Birgitta , Svensson Malin , Törn Carina , Wallin Anne , Wimar Åsa , Åberg Sofie ,   Washington Clinical Center, Hagopian William A. , Killian Michael , Crouch Claire Cowen , Skidmore Jennifer , Hervey Rachel , Lyons Rachel , Meyer Arlene , Mulenga Denise , Romancik Matei , Schmitt Davey ,   Pennsylvania Satellite Center, Becker Dorothy , Franciscus Margaret , Smith MaryEllen Dalmagro-Elias , Daftary Ashi , Klein Mary Beth , Yates Chrystal ,   Data Coordinating Center, Krischer Jeffrey P. , Austin-Gonzalez Sarah , Avendano Maryouri , Baethke Sandra , Brown Rasheedah , Burkhardt Brant , Butterworth Martha , Clasen Joanna , Cuthbertson David , Dankyi Stephen , Eberhard Christopher , Fiske Steven , Garmeson Jennifer , Gowda Veena , Heyman Kathleen , Hsiao Belinda , Karges Christina , Laras Francisco Perez , Lee Hye-Seung , Li Qian , Liu Shu , Liu Xiang , Lynch Kristian , Maguire Colleen , Malloy Jamie , McCarthy Cristina , Merrell Aubrie , Parikh Hemang , Quigley Ryan , Remedios Cassandra , Shaffer Chris , Smith Laura , Smith Susan , Sulman Noah , Tamura Roy , Tewey Dena , Toth Michael , Uusitalo Ulla , Vehik Kendra , Vijayakandipan Ponni , Wood Keith , Yang Jimin ,   Past staff, Abbondondolo Michael , Ballard Lori , Hadley David , McLeod Wendy , Meulemans Steven ,   Autoantibody Reference Laboratories, Yu Liping , Miao Dongmei , Bingley Polly , Williams Alistair , Chandler Kyla , Ball Olivia , Kelland Ilana , Grace Sian ,   HLA Reference Laboratory, Chavoshi Masumeh , Radtke Jared , Zink Sarah , Erlich Previously Henry , Mack Steven J. , Fear Anna Lisa ,   Repository, Ke Sandra , Mulholland Niveen ,   RNA Laboratory and Gene Expression Laboratory, Liu Haitao , Nechtman John , Zhao Yansheng , Jiang Na , Tian Yanna , Dong Guangkuo ,   SNP Laboratory, Farber Emily , Pickin Rebecca Roche , Davis Jonathan , Davis Jordan , Gallo Dan , Bonnie Jessica , Campolieto Paul ,   Project scientist, Akolkar Beena ,   Other contributors, Bourcier Kasia , Briese Thomas , Johnson Suzanne Bennett , Triplett Eric 
Published: November 2021

Significant progress has been made in elucidating genetic risk factors influencing Type 1 diabetes (T1D); however, features other than genetic variants that initiate and/or accelerate islet autoimmunity that lead to the development of clinical T1D remain largely unknown. We hypothesized that genetic and environmental risk factors can both contribute to T1D through dynamic alterations of molecular interactions in physiologic networks. To test this hypothesis, we utilized longitudinal blood transcriptomic profiles in The Environmental Determinants of Diabetes in the Young (TEDDY) study to generate gene co-expression networks. In network modules that contain immune response genes associated with T1D, we observed highly dynamic differences in module connectivity in the 600 days (~ 2 years) preceding clinical diagnosis of T1D. Our results suggest that gene co-expression is highly plastic and that connectivity differences in T1D-associated immune system genes influence the timing and development of clinical disease.