medRxiv preprint doi: https://doi.org/10.1101/2020.11.13.20221812; this version posted November 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Rare Non-coding Variation Identified by Large Scale Whole Genome Sequencing Reveals Unexplained Heritability of Type 2 Diabetes AUTHORS & AFFILIATIONS Jennifer Wessel1,2,3+*, Timothy D Majarian4+, Heather M Highland5, Sridharan Raghavan6,7, Mindy D Szeto8, Natalie R Hasbani9, Paul S de Vries9, Jennifer A Brody10,11, Chloé Sarnowski12, Daniel DiCorpo12, Xianyong Yin13, Bertha Hidalgo14, Xiuqing Guo15, James Perry16,17, Jeffrey R O'Connell16,17, Samantha Lent12, May E Montasser16, Brian E Cade18,19,20, Deepti Jain21, Heming Wang18,19,20, Peitao Wu12, Silvia Bonàs-Guarch22,23, Ricardo D'Oliveira Albanus24, Aaron Leong25,26,27, Irene Miguel-Escalada22,23, Arushi Varshney24, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Anthropometry, DIAMANTE, Gregory L Kinney17,28, Lisa R Yanek29, Leslie Lange30, Marcio Almeida31, Juan M Peralta31, Stella Aslibekyan32, Abigail S Baldridge33, Alain G Bertoni34, Lawrence F Bielak35, Donald W Bowden36, Chung-Shiuan Chen37, Yii-Der Ida Chen15, Seung Hoan Choi20, Won Jung Choi38, Dawood Darbar39, James S Floyd40,41, Barry I Freedman42, Mark O Goodarzi43, Ryan Irvin14, Rita R Kalyani29, Tanika Kelly37, Seonwook Lee38, Ching-Ti Liu12, Douglas Loesch44,45,17, JoAnn E Manson26,46, Rami Nassir47, Nicholette D Palmer36, James S Pankow48, Laura J Rasmussen-Torvik33, Alexander P Reiner49, Elizabeth Selvin50, Aladdin H Shadyab51, Jennifer A Smith35,52, Daniel E Weeks53,54, Lu-Chen Weng20,55, Huichun Xu16,17, Jie Yao15, Zachary Yoneda56, Wei Zhao35, Jorge Ferrer22,23,57, Anubha Mahajan58†, Mark I McCarthy58,59†, Stephen Parker24,60, Alvaro Alonso61, Donna K Arnett62, John Blangero31, Eric Boerwinkle9, Michael H Cho63, Adolfo Correa64, L. Adrienne Cupples12,65, Joanne E Curran31, Ravindranath Duggirala31, Patrick T Ellinor20,55, Jiang He37, Susan R Heckbert40,49, Sharon LR Kardia35, Ryan W Kim38, NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.11.13.20221812; this version posted November 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Charles Kooperberg66, Simin Liu67, Steven A Lubitz20,55, Rasika A Mathias29, Stephen McGarvey68, Braxton D Mitchell16,17,69, Alanna C Morrison9, Patricia A Peyser35, Bruce M Psaty10,49,11,70, Susan Redline18,19,71, Dan Roden72, M. Benjamin Shoemaker73, Nicholas L Smith49,74,75, Kent D Taylor15, Ramachandran S Vasan65,76,77, Karine A Viaud-Martinez78, Jose C Florez4,20,25,26, James G Wilson79, Robert Sladek80,81, Josée Dupuis12, Stephen S Rich82, Jerome I Rotter15, James B Meigs20,26,27, Alisa K Manning4,26,83* †Present address: Genentech, 1 DNA Way, South San Francisco, CA 94080 1Department of Epidemiology, Fairbanks School of Public Health, Indiana University, IN, 46202, USA, 2Department of Medicine, School of Medicine, Indiana University, IN, 46202, USA, 3Diabetes Translational Research Center, Indiana University, IN, 46202, USA, 4Metabolism Program, The Broad Institute of MIT and Harvard, Cambridge, MA, 02124, USA, 5Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA, 6Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA, 7Department of Veterans Affairs Eastern Colorado Health Care System, Section of Hospital Medicine, Aurora, CO, 80045, USA, 8School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA, 9Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA, 10Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98101, USA, 11Department of Medicine, University of Washington, Seattle, WA, 98101, USA, 12Department 2 medRxiv preprint doi: https://doi.org/10.1101/2020.11.13.20221812; this version posted November 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA, 13Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA, 14Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, AL, 35294, USA, 15The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA, 16Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, 21201, USA, 17Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA, 18Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, 02115, USA, 19Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA, 20Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, 02124, USA, 21Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA, 22Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, 08003, ESP, 23Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM), ESP, 24Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA, 25Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA, 02114, USA, 26Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA, 27Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA, 28Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA, 29GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA, 30Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, 3 medRxiv preprint doi: https://doi.org/10.1101/2020.11.13.20221812; this version posted November 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. CO, 80045, USA, 31Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville and Edinburg, TX, 78539, USA, 3223andMe, Sunnyvale, CA, 94086, USA, 33Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA, 34Department of Epidemiology & Prevention, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA, 35Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA, 36Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA, 37Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, 70112, USA, 38Psomagen, Inc., Rockville, MD, 20850, USA, 39Division of Cardiology, University of Illinois at Chicago, Chicago, IL, 60612, USA, 40Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98195, USA, 41Department of Medicine, University of Washington, Seattle, WA, 98195, USA, 42Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA, 43Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA, 44Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA, 45Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA, 46Brigham and Women's Hospital, Boston, MA, 02115, USA, 47Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, 24381, Saudi Arabia, 48Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, 55454, USA, 49Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA, 50Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21287, 4 medRxiv preprint doi: https://doi.org/10.1101/2020.11.13.20221812; this version posted November 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. USA, 51Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, 92093, USA, 52Survey Research Center, Institute for Social Research, University