Gene-by-Sleep Duration Interaction for Glycemic Traits in More Than 480,000 Individuals
Heming Wang, Pavithra Nagarajan, Clint L. Miller, Amy R. Bentley, Raymond Noordam, Kenneth E. Westerman, Michael R. Brown, Aldi T. Kraja, Jeffrey R. O’Connell, Karen Schwander, Changwei Li, Mihir M. Sanghvi, Yipei Song, Traci M. Bartz, Vincent Braunack-Mayer, Ling Chen, Jiawen Du, Diana Dunca, Mary F. Feitosa, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E. Harris, Heather M. Highland, Zhijie Huang, Changhoon Kang, Timo A. Lakka, Christophe Lefevre, Jian’an Luan, Leo-Pekka Lyytikäinen, Celestin Missikpode, John L. Morrison, Nicholette D. Palmer, Anne Richmond, Mina Shahisavandi, Jingxian Tang, Peter J. van der Most, Stefan Weiss, Chenglong Yu, Wanying Zhu, Md Abu Yusuf Ansari, Pramod Anugu, Hugues Aschard, Kaavya Ashok, John R. Attia, Lydia A. Bazzano, Brian E. Cade, Archie Campbell, Latchezar M. Dimitrov, Anh Do, Tariq Faquih, Sandy L. FinesilverSmith, Susan P. Fisher-Hoch, Amanda M. Fretts, Sina A. Gharib, Mark O. Goodarzi, Mariaelisa Graff, Charles Gu, Paul Hanson, Jiang He, Sami Heikkinen, James Hixson, Sarah Hsu, Mika Kähönen, Minjung Kho, Hyunju Kim, Pirjo Komulainen, Lenore J. Launer, Rozenn N. Lemaitre, John J. McNeil, Joseph B. McCormick, Ilja M. Nolte, Laura M. Raffield, Olli T. Raitakari, Julia Ramírez, Renata L. Riha, Martin Risch, Lorenz Risch, Tom C. Russ, Chloé Sarnowski, Miranda T. Schram, Rodney J. Scott, Tamar Sofer, Quan Sun, Uwe Völker, Henry Völzke, Yujie Wang, Ko Willems van Dijk, Alexis C. Wood, Kristin L. Young, Ruiyuan Zhang, Xiaofeng Zhu, Jennifer E. Below, David Conen, Simon R. Cox, Ervin R. Fox, Nora Franceschini, Mohsen Ghanbari, Hans Jörgen Grabe, Vilmundur Gudnason, Caroline Hayward, Elizabeth G. Holliday, Cashell E. Jaquish, Paul Lacaze, Seunggeun Lee, Terho Lehtimäki, Ching-Ti Liu, Alanna C. Morrison, Kari E. North, Patricia A. Peyser, Michael A. Province, Bruce M. Psaty, Rainer Rauramaa, Frits R. Rosendaal, Jerome I. Rotter, Harold Snieder, Lynne E. Wagenknecht, Nicholas J. Wareham, Ayush Giri, Tanika N. Kelly, Patricia B. Munroe, James Gauderman, Thomas W. Winkler, Paul S. de Vries, Dabeeru C. Rao, Alisa K. Manning, Han Chen, Lisa de las Fuentes, Susan Redline, James B. Meigs,Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the current study, we conducted genome-wide gene-by-sleep duration meta-analyses, separately assessing interactions of short and long sleep, for fasting glucose, fasting insulin, and hemoglobin A1c in up to 489,309 individuals without diabetes from seven different population groups. In total, 16 loci were identified to interact with sleep duration—6 with short sleep and 10 with long sleep. Of these, four loci were identified through cross-population meta-analysis. Mapped genes exhibited pathway connections to pericyte apoptosis, N-methyl-d-aspartate receptor activity, the GLUT1 receptor, neurological health, and sleep architecture. Eleven loci (VRK2, PCDH7, TFAP2A, CAP2, PAPPA, ZCCHC2, MYH9, SGIP1, JAKMIP3, RRAS2, and MAPT) have not been reported in previous glycemic trait genome-wide association studies. Interaction loci identified divergent biological mechanisms for short and long sleep duration influencing glycemic control, suggesting specific pathways of intervention for precision medicine approaches to diabetes prevention and management.
Article Highlights
The biological mechanisms of how sleep duration impacts type 2 diabetes pathogenesis and glycemic control are unclear. This study reveals 16 loci (11 novel) that interact with either short or long sleep duration to influence hemoglobin A1c, fasting glucose, or fasting insulin. Short and long sleep duration loci were nonoverlapping. Regulation of copper and diacylglycerol levels appear as distinct cellular mechanisms implicated by long and short sleep duration loci, respectively. Identified gene targets present insight for potential type 2 diabetes therapeutic design approaches related to JIP1–c-Jun N-terminal kinase interaction disruption, pericyte health, N-methyl-d-aspartate receptor activity, anti-inflammatory and leptin-enhancing dietary supplements, and serpins.