bioRxiv preprint doi: https://doi.org/10.1101/790618; this version posted October 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation 1,2 3 4 5,6,7 Natasha H. J. Ng *, Sara M. Willems *, Juan Fernandez , Rebecca S. Fine , Eleanor Wheeler8,3, Jennifer Wessel9,10, Hidetoshi Kitajima4, Gaelle Marenne8, Jana K. Rundle1, Xueling Sim11,12, Hanieh Yeghootkar13, Nicola L. Beer1, Anne Raimondo1, Andrei I. Tarasov1, Soren K. Thomsen1,14, Martijn van de Bunt4,1, Shuai Wang15, Sai Chen12, Yuning Chen15, Yii-Der Ida Chen16, Hugoline G. de Haan17, Niels Grarup18, Ruifang Li-Gao17, Tibor V. Varga19, Jennifer L Asimit8,20, Shuang Feng21, Rona J. Strawbridge22,23, Erica L. Kleinbrink24, Tarunveer S. Ahluwalia25,26, Ping An27, Emil V. Appel18, Dan E Arking28, Juha Auvinen29,30, Lawrence F. Bielak31, Nathan A. Bihlmeyer28, Jette Bork-Jensen18, Jennifer A. Brody32,33, Archie Campbell34, Audrey Y Chu35, Gail Davies36,37, Ayse Demirkan38, James S. Floyd32,33, Franco Giulianini35, Xiuqing Guo16, Stefan Gustafsson39, Benoit Hastoy1, Anne U. Jackson12, Johanna Jakobsdottir40, Marjo-Riitta Jarvelin41,29,42, Richard A. Jensen32,33, Stavroula Kanoni43, Sirkka Keinanen- Kiukaanniemi44,45, Jin Li46, Man Li47,48, Kurt Lohman49, Yingchang Lu50,51, Jian'an Luan3, Alisa K. Manning52,53, Jonathan Marten54, Carola Marzi55,56, Karina Meidtner57,56, Dennis O. Mook- Kanamori17,58, Taulant Muka59,38, Giorgio Pistis60,61, Bram Prins8, Kenneth M. Rice32,62, Neil Robertson4, Serena Sanna60,63, Yuan Shi64, Albert Vernon Smith40,65, Jennifer A. Smith31,66, Lorraine Southam8,4,67, Heather M. Stringham12, Salman M. Tajuddin68, Vinicius Tragante69, Sander W. van der Laan70,71, Helen R. Warren43,72, Jie Yao16, Andrianos M. Yiorkas73,74, Weihua 75,76 31 77 78 78,79 Zhang , Wei Zhao , Emma Ahlqvist , Mariaelisa Graff , Heather M. Highland , Anne E. Justice78, Ken Sin Lo80, Eirini Marouli43, Carolina Medina-Gomez38,81, Saima Afaq41, Wesam A Alhejily43,82, Najaf Amin38, Folkert W. Asselbergs69,83,84 , Lori L. Bonnycastle85, Michiel L. Bots86, Ivan Brandslund87, Ji Chen8, Cramer Christensen88, John Danesh89, Renée de Mutsert17, Abbas Dehghan38,90,91, Tapani Ebeling92, Paul Elliott41,93,94, EPIC-InterAct Consortium, Aliki-Eleni Farmaki95,96, Jessica D. Faul66, Paul W. Franks19,97,6, Steve Franks98, Andreas Fritsche99,56, Anette P. Gjesing18, Mark O. Goodarzi100, Vilmundur Gudnason40,65, Göran Hallmans101, Tamara B. Harris40, Karl-Heinz Herzig102,103, Marie-France Hivert104,105, Jan-Håkan Jansson106, Min A Jhun31,107, Torben Jørgensen108,109,110, Marit E. Jørgensen26,111, Pekka Jousilahti112, Eero Kajantie113,112,114,115, Maria Karaleftheri116, Sharon L.R. Kardia31, Leena Kinnunen112, Heikki A. Koistinen112,117,118, Pirjo Komulainen119, Peter Kovacs120,121, Johanna Kuusisto122, Markku Laakso122, Leslie A. Lange123, Lenore J112. Launer40, Jung-Jin Lee124, Aaron Leong125, Jaana Lindström112, Jocelyn E. Manning Fox126,127, Satu Männistö112, Nisa M Maruthur128,129,48, Leena Moilanen130, Antonella Mulas60,131, Mike A. Nalls132,133, Matthew Neville1, James S. Pankow134, Alison Pattie37, Eva R.B. Petersen135, Hannu Puolijoki136, Asif Rasheed137, Paul Redmond37, Frida Renström19,101, Michael Roden138,139,56, Danish Saleheen124,137, Juha Saltevo140, Kai Savonen119,141, Sylvain Sebert44,42, Tea Skaaby108, Kerrin S Small142, Alena Stančáková122, Jakob Stokholm25, Konstantin Strauch143, E-Shyong Tai144,11,145, Kent D. Taylor16, Betina H. Thuesen108, Anke Tönjes121, Emmanouil Tsafantakis146, Tiinamaija Tuomi147,148,149, Jaakko Tuomilehto112,150,151,152, Understanding Society Scientific Group, Matti Uusitupa153, Marja Vääräsmäki154,155, Ilonca Vaartjes86, Magdalena Zoledziewska60, Goncalo Abecasis61, Beverley Balkau156, Hans Bisgaard25, Alexandra I. Blakemore74,73, Matthias Blüher120,121, Heiner Boeing157, Eric Boerwinkle158, Klaus Bønnelykke25, Erwin P. Bottinger50, bioRxiv preprint doi: https://doi.org/10.1101/790618; this version posted October 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Mark J. Caulfield43,72, John C Chambers41,76,159, Daniel I Chasman35,160,161, Ching-Yu 64,162,163 1 85 48,129 60,131 Cheng , Anne Clark , Francis S. Collins , Josef Coresh , Francesco Cucca , Gert J. de Borst164, Ian J. Deary36,37, George Dedoussis95, Panos Deloukas43,165, Hester M. den Ruijter70, Josée Dupuis15,166, Michele K. Evans68, Ele Ferrannini167, Oscar H Franco38,59, Harald Grallert55,56, Leif Groop168,149, Torben Hansen18,169, Andrew T. Hattersley170, Caroline Hayward54, Joel N. Hirschhorn171,6,7, Arfan Ikram38, Erik Ingelsson46,39,172,173, Fredrik Karpe1,174, Kay-Tee Kaw175, Wieland Kiess176, Jaspal S Kooner177,76,159, Antje Körner176, Timo Lakka178,119,141, Claudia Langenberg3, Lars Lind179, Cecilia M Lindgren4,180, Allan Linneberg108,181, Leonard Lipovich24,182, Ching-Ti Liu15, Jun Liu38, Yongmei Liu183, Ruth J.F. Loos50,184, Patrick E. MacDonald126,127, Karen L. Mohlke185, Andrew D Morris186, Patricia B. Munroe43,72, Alison Murray187, Sandosh Padmanabhan188, Colin N A Palmer189, Gerard Pasterkamp70,71, Oluf Pedersen18, Patricia A. Peyser31, Ozren Polasek190, David Porteous34, Michael A. Province27, Bruce M Psaty32,33,191,192, Rainer Rauramaa119, Paul M Ridker35,160,193, Olov Rolandsson194, 1,174 17 186 112 Patrik Rorsman , Frits R. Rosendaal , Igor Rudan , Veikko Salomaa , Matthias B. Schulze57,56, Robert Sladek195,196, Blair H Smith189, Timothy D Spector142, John M. Starr197,36, Michael Stumvoll121, Cornelia M van Duijn38, Mark Walker198, Nick J. Wareham3, David R. Weir66, James G. Wilson199, Tien Yin Wong64,162,163, Eleftheria Zeggini8,67, Alan B. Zonderman68, Jerome I. Rotter16, Andrew P. Morris200,4, Michael Boehnke12, Jose Florez201,202, Mark I McCarthy4,1,174, James B Meigs125,202, Anubha Mahajan4, Robert A. Scott3, Anna L Gloyn1,4,174*+, Inês Barroso8,3*+ *Authors contributed equally +Corresponding authors: Anna L Gloyn - [email protected] Inês Barroso- [email protected] 1. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK, OX3 7LE. 2. Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore 3. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. 4. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK, OX3 7BN 5. Department of Genetics, Harvard Medical School, Boston, MA, 02115 6. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115 7. Broad Institute of MIT and Harvard, Cambridge, MA, 02142 8. Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK 9. Departments of Epidemiology & Medicine, Schools of Public Health & Medicine, Indiana University, Indiaiapolis, IN 46202 10. Diabetes Translational Research Center, Indiana University School of Medicine, Indianapolis, IN 46202 bioRxiv preprint doi: https://doi.org/10.1101/790618; this version posted October 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 11. Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore 117549, Singapore. 12. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA 13. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK 14. Present address: Vertex Pharmaceuticals Europe Ltd, Milton Park, Abingdon, OX14 4RW, UK 15. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 16. Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABiomed at Harbor-UCLA Medical Center, Torrance, CA, USA 17. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands 18. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark 19. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden 20. MRC Biostatistics Unit, Cambridge Biomedical Campus, Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge CB2 0SR, UK. 21. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA 22. UKRI Innovation Fellow at HDR UK,Mental Health and Wellbeing, Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Room 113, 1 Lilybank Gardens ,Glasgow, G12 8RZ 23. Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm,171 76, Sweden 24. Center for Molecular Medicine and Genetics, Wayne State University,