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Get Free AccessSummary Metabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference. Highlights 23 novel coding variant associations (single-point and gene-based) for glycemic traits 51 effector transcripts highlighted different pathway/tissue signatures for each trait The exocrine pancreas and gut influence fasting and 2h glucose, respectively Multiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia
Natasha Hui Jin Ng, Sara M. Willems, Juan Fernandez, Rebecca S. Fine, Eleanor Wheeler, Jennifer Wessel, Hidetoshi Kitajima, Gaëlle Marenne, Jana K. Rundle, Xueling Sim, Hanieh Yeghootkar, Nicola L. Beer, Anne Raimondo, Andrei I. Tarasov, Soren K. Thomsen, Martijn van de Bunt, Shuai Wang, Sai Chen, Yuning Chen, Yii‐Der Ida Chen, Hugoline G. de Haan, Niels Grarup, Ruifang Li‐Gao, Tibor V. Varga, Jennifer L. Asimit, Shuang Feng, Rona J. Strawbridge, Erica L. Kleinbrink, Tarunveer S. Ahluwalia, Ping An, Emil V. R. Appel, Dan E. Arking, Juha Auvinen, Lawrence F. Bielak, Nathan A. Bihlmeyer, Jette Bork‐Jensen, Jennifer A. Brody, Archie Campbell, Audrey Y. Chu, Gail Davies, Ayşe Demirkan, James S. Floyd, Franco Giulianini, Xiuqing Guo, Stefan Gustafsson, Benoît Hastoy, Anne Jackson, Jóhanna Jakobsdóttir, Paul M Ridker, Richard A. Jensen, Stavroula Kanoni, Sirkka Keinänen‐Kiukaanniemi, Jin Li, Man Li, Kurt Lohman, Yingchang Lu, Jian’an Luan, Alisa K. Manning, Jonathan Marten, Carola Marzi, Karina Meidtner, Dennis O. Mook‐Kanamori, Taulant Muka, Giorgio Pistis, Bram P. Prins, Kenneth Rice, Neil Robertson, Serena Sanna, Yuan Shi, Albert V. Smith, Jennifer A. Smith, Lorraine Southam, Heather M. Stringham, Salman M. Tajuddin, Vinicius Tragante, Sander W. van der Laan, Helen R. Warren, Jie Yao, Andrianos M. Yiorkas, Weihua Zhang, Wei Zhao, Emma Ahlqvist, Mariaelisa Graff, Heather M. Highland, Anne E. Justice, Ken Sin Lo, Eirini Marouli, Carolina Medina‐Gómez, Saima Afaq, Wesam A. Alhejily, Najaf Amin, Folkert W. Asselbergs, Lori L. Bonnycastle, Michiel L. Bots, Ivan Brandslund, Chen Ji, Cramer Christensen, John Danesh, Renée de Mutsert, Abbas Dehghan (2019). Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation. , DOI: https://doi.org/10.1101/790618.
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Type
Preprint
Year
2019
Authors
100
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1101/790618
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