Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program

Daniel DiCorpo; Sheila M Gaynor; Emily M Russell; Kenneth E Westerman; Laura M Raffield; Timothy D Majarian; Peitao Wu; Chloé Sarnowski; Heather M Highland; Anne Jackson; Natalie R Hasbani; Paul S de Vries; Jennifer A Brody; Bertha Hidalgo; Xiuqing Guo; James A Perry; Jeffrey R O'Connell; Samantha Lent; May E Montasser; Brian E Cade; Deepti Jain; Heming Wang; Ricardo D'Oliveira Albanus; Arushi Varshney; Lisa R Yanek; Leslie Lange; Nicholette D Palmer; Marcio Almeida; Juan M Peralta; Stella Aslibekyan; Abigail S Baldridge; Alain G Bertoni; Lawrence F Bielak; Chung-Shiuan Chen; Yii-Der Ida Chen; Won Jung Choi; Mark O Goodarzi; James S Floyd; Marguerite R Irvin; Rita R Kalyani; Tanika N Kelly; Seonwook Lee; Ching-Ti Liu; Douglas Loesch; JoAnn E Manson; Ryan L Minster; Take Naseri; James S Pankow; Laura J Rasmussen-Torvik; Alexander P Reiner; Muagututi'a Sefuiva Reupena; Elizabeth Selvin; Jennifer A Smith; Daniel E Weeks; Huichun Xu; Jie Yao; Wei Zhao; Stephen Parker; Alvaro Alonso; Donna K Arnett; John Blangero; Eric Boerwinkle; Adolfo Correa; L Adrienne Cupples; Joanne E Curran; Ravindranath Duggirala; Jiang He; Susan R Heckbert; Sharon L R Kardia; Ryan W Kim; Charles Kooperberg; Simin Liu; Rasika A Mathias; Stephen T McGarvey; Braxton D Mitchell; Alanna C Morrison; Patricia A Peyser; Bruce M Psaty; Susan Redline; Alan R Shuldiner; Kent D Taylor; Ramachandran S Vasan; Karine A Viaud-Martinez; Jose C Florez; James G Wilson; Robert Sladek; Stephen S Rich; Jerome I Rotter; Xihong Lin; Josée Dupuis; James B Meigs; Jennifer Wessel; Alisa K Manning

doi:10.1038/s42003-022-03702-4

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program

Commun Biol. 2022 Jul 28;5(1):756. doi: 10.1038/s42003-022-03702-4.

Authors

Daniel DiCorpo^#¹, Sheila M Gaynor^#², Emily M Russell³, Kenneth E Westerman^{4

5

6}, Laura M Raffield⁷, Timothy D Majarian⁵, Peitao Wu¹, Chloé Sarnowski¹, Heather M Highland⁸, Anne Jackson⁹, Natalie R Hasbani¹⁰, Paul S de Vries¹¹, Jennifer A Brody^{12

13}, Bertha Hidalgo¹⁴, Xiuqing Guo¹⁵, James A Perry^{16

17}, Jeffrey R O'Connell^{16

17}, Samantha Lent¹, May E Montasser¹⁶, Brian E Cade^{18

19

20}, Deepti Jain²¹, Heming Wang^{18

19

20}, Ricardo D'Oliveira Albanus²², Arushi Varshney²², Lisa R Yanek²³, Leslie Lange²⁴, Nicholette D Palmer²⁵, Marcio Almeida²⁶, Juan M Peralta²⁶, Stella Aslibekyan²⁷, Abigail S Baldridge²⁸, Alain G Bertoni²⁹, Lawrence F Bielak³⁰, Chung-Shiuan Chen³¹, Yii-Der Ida Chen¹⁵, Won Jung Choi³², Mark O Goodarzi³³, James S Floyd^{34

35}, Marguerite R Irvin¹⁴, Rita R Kalyani²³, Tanika N Kelly³¹, Seonwook Lee³², Ching-Ti Liu¹, Douglas Loesch^{17

36

37}, JoAnn E Manson^{6

38}, Ryan L Minster³, Take Naseri³⁹, James S Pankow⁴⁰, Laura J Rasmussen-Torvik²⁸, Alexander P Reiner⁴¹, Muagututi'a Sefuiva Reupena⁴², Elizabeth Selvin⁴³, Jennifer A Smith^{30

44}, Daniel E Weeks^{3

45}, Huichun Xu^{16

17}, Jie Yao¹⁵, Wei Zhao³⁰, Stephen Parker^{22

46}, Alvaro Alonso⁴⁷, Donna K Arnett⁴⁸, John Blangero²⁶, Eric Boerwinkle¹⁰, Adolfo Correa⁴⁹, L Adrienne Cupples^{1

50}, Joanne E Curran²⁶, Ravindranath Duggirala²⁶, Jiang He³¹, Susan R Heckbert^{34

41}, Sharon L R Kardia³⁰, Ryan W Kim³², Charles Kooperberg⁵¹, Simin Liu⁵², Rasika A Mathias²³, Stephen T McGarvey⁵³, Braxton D Mitchell^{16

17

54}, Alanna C Morrison¹⁰, Patricia A Peyser³⁰, Bruce M Psaty^{12

13

41

55}, Susan Redline^{18

19

56}, Alan R Shuldiner⁵⁷, Kent D Taylor¹⁵, Ramachandran S Vasan^{50

58

59}, Karine A Viaud-Martinez⁶⁰, Jose C Florez^{5

6

20

61}, James G Wilson⁶², Robert Sladek^{63

64}, Stephen S Rich⁶⁵, Jerome I Rotter¹⁵, Xihong Lin², Josée Dupuis¹, James B Meigs^{6

20

66}, Jennifer Wessel^{67

68

69}, Alisa K Manning^{70

71

72}

Affiliations

¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
² Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
³ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
⁴ Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁵ Metabolism Program, The Broad Institute of MIT and Harvard, Cambridge, MA, 02124, USA.
⁶ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
⁷ Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁸ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
⁹ Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁰ Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
¹¹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
¹² Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98101, USA.
¹³ Department of Medicine, University of Washington, Seattle, WA, 98101, USA.
¹⁴ Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
¹⁵ The 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.
¹⁶ Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
¹⁷ Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
¹⁸ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, 02115, USA.
¹⁹ Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA.
²⁰ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, 02124, USA.
²¹ Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.
²² Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
²³ GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
²⁴ Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, 80045, USA.
²⁵ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
²⁶ Department 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.
²⁷ 23andMe, Sunnyvale, CA, 94086, USA.
²⁸ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
²⁹ Department of Epidemiology & Prevention, Wake Forest School of Medicine, Winston-, Salem, NC, 27157, USA.
³⁰ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
³¹ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, 70112, USA.
³² Psomagen, Inc, Rockville, MD, 20850, USA.
³³ Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
³⁴ Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98195, USA.
³⁵ Department of Medicine, University of Washington, Seattle, WA, 98195, USA.
³⁶ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
³⁷ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
³⁸ Brigham and Women's Hospital, Boston, MA, 02115, USA.
³⁹ Ministry of Health, Government of Samoa, Apia, Samoa.
⁴⁰ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, 55454, USA.
⁴¹ Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA.
⁴² Lutia i Puava 'ae Mapu i Fagalele, Apia, Samoa.
⁴³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21287, USA.
⁴⁴ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁴⁵ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
⁴⁶ Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
⁴⁷ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA.
⁴⁸ College of Public Health, University of Kentucky, Lexington, KY, 40506, USA.
⁴⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39211, USA.
⁵⁰ National Heart Lung and Blood Institute and Boston University's Framingham Heart Study, Framingham, MA, 01702, USA.
⁵¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
⁵² Center for Global Cardiometabolic Health (CGCH), Boston, MA, 02215, USA.
⁵³ International Health Institute and Department of Epidemiology, Brown University School of Public Health, Providence, RI, 02912, USA.
⁵⁴ Geriatrics Research and Education Clinical Center, Baltimore VA Medical Center, Baltimore, MD, 21201, USA.
⁵⁵ Department of Health Services, University of Washington, Seattle, WA, 98101, USA.
⁵⁶ Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA.
⁵⁷ Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, 21231, USA.
⁵⁸ Evans Department of Medicine, Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA, 02118, USA.
⁵⁹ Evans Department of Medicine, Whitaker Cardiovascular Institute and Cardiology Section, Boston University School of Medicine, Boston, MA, 02118, USA.
⁶⁰ Illumina Laboratory Services, Illumina, Inc, San Diego, CA, 92122, USA.
⁶¹ Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁶² Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA.
⁶³ Department of Human Genetics, McGill University, Montreal, Montreal, Quebec, H3A 0G1, Canada.
⁶⁴ Department of Medicine, McGill University, Montreal, Montreal, Quebec, H3A 0G1, Canada.
⁶⁵ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
⁶⁶ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁶⁷ Department of Epidemiology, Fairbanks School of Public Health, Indiana University, IN, 46202, USA. [email protected].
⁶⁸ Department of Medicine, School of Medicine, Indiana University, IN, 46202, USA. [email protected].
⁶⁹ Diabetes Translational Research Center, Indiana University, IN, 46202, USA. [email protected].
⁷⁰ Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, 02114, USA. [email protected].
⁷¹ Metabolism Program, The Broad Institute of MIT and Harvard, Cambridge, MA, 02124, USA. [email protected].
⁷² Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. [email protected].

^# Contributed equally.

Abstract

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2* / genetics
Fasting*
Glucose
Humans
Insulin / genetics
National Heart, Lung, and Blood Institute (U.S.)
Nerve Tissue Proteins / genetics
Polymorphism, Single Nucleotide
Precision Medicine
Receptors, Immunologic / genetics
United States

Substances

Insulin
Nerve Tissue Proteins
Receptors, Immunologic
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding