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Get Free AccessMetabolic dysregulation in multiple tissues influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits we investigated associations of exome-array variants in up to 144,060 nondiabetic individuals of multiple ancestries. Single-variant analyses identified 21 novel coding variant associations (18 loci), whilst gene-based tests revealed novel signals at TF (HbA1c) and G6PC [(Fasting Glucose (FG), Fasting Insulin (FI)]. Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and islets for FG, implicated adipose tissue in FI and gut in 2hGlu, and a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that the liver-enriched G6PC and the islet-specific G6PC2 were driven by multiple rare variants, with G6PC2 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.
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, A.M. 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/10.2139/ssrn.3469835.
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Type
Article
Year
2019
Authors
100
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.2139/ssrn.3469835
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