HGG Advances (Apr 2021)
Genetic discovery and risk characterization in type 2 diabetes across diverse populations
- Linda M. Polfus,
- Burcu F. Darst,
- Heather Highland,
- Xin Sheng,
- Maggie C.Y. Ng,
- Jennifer E. Below,
- Lauren Petty,
- Stephanie Bien,
- Xueling Sim,
- Wei Wang,
- Pierre Fontanillas,
- Yesha Patel,
- Michael Preuss,
- Claudia Schurmann,
- Zhaohui Du,
- Yingchang Lu,
- Suhn K. Rhie,
- Joseph M. Mercader,
- Teresa Tusie-Luna,
- Clicerio González-Villalpando,
- Lorena Orozco,
- Cassandra N. Spracklen,
- Brian E. Cade,
- Richard A. Jensen,
- Meng Sun,
- Yoonjung Yoonie Joo,
- Ping An,
- Lisa R. Yanek,
- Lawrence F. Bielak,
- Salman Tajuddin,
- Aude Nicolas,
- Guanjie Chen,
- Laura Raffield,
- Xiuqing Guo,
- Wei-Min Chen,
- Girish N. Nadkarni,
- Mariaelisa Graff,
- Ran Tao,
- James S. Pankow,
- Martha Daviglus,
- Qibin Qi,
- Eric A. Boerwinkle,
- Simin Liu,
- Lawrence S. Phillips,
- Ulrike Peters,
- Chris Carlson,
- Lynne R. Wikens,
- Loic Le Marchand,
- Kari E. North,
- Steven Buyske,
- Charles Kooperberg,
- Ruth J.F. Loos,
- Daniel O. Stram,
- Christopher A. Haiman
Affiliations
- Linda M. Polfus
- Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA; Corresponding author
- Burcu F. Darst
- Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA
- Heather Highland
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Xin Sheng
- Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA
- Maggie C.Y. Ng
- Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
- Jennifer E. Below
- The Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
- Lauren Petty
- The Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
- Stephanie Bien
- Adaptive Biotechnologies Corporation, Seattle, WA, USA
- Xueling Sim
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
- Wei Wang
- 23andMe, Sunnyvale, CA, USA
- Pierre Fontanillas
- 23andMe, Sunnyvale, CA, USA
- Yesha Patel
- Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA
- Michael Preuss
- Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY, USA
- Claudia Schurmann
- Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY, USA
- Zhaohui Du
- Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA
- Yingchang Lu
- Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
- Suhn K. Rhie
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA
- Joseph M. Mercader
- Program in Metabolism, Broad Institute, Cambridge, MA, USA
- Teresa Tusie-Luna
- Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico
- Clicerio González-Villalpando
- Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Pública, Mexico City, Mexico
- Lorena Orozco
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
- Cassandra N. Spracklen
- Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA, USA
- Brian E. Cade
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA, USA
- Richard A. Jensen
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
- Meng Sun
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, USA
- Yoonjung Yoonie Joo
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Ping An
- Division of Statistical Genomics, School of Medicine, Washington University, St. Louis, MO, USA
- Lisa R. Yanek
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Lawrence F. Bielak
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
- Salman Tajuddin
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
- Aude Nicolas
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
- Guanjie Chen
- Center for Research on Genomics and Global Health, National Human Genome Institute, National Institutes of Health, Bethesda, MD, USA
- Laura Raffield
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Xiuqing Guo
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Wei-Min Chen
- Department of Public Health Sciences and Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA
- Girish N. Nadkarni
- Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY, USA
- Mariaelisa Graff
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Ran Tao
- Department of Biostatistics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
- James S. Pankow
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
- Martha Daviglus
- Institute for Minority Health Research, University of Illinois Chicago, Chicago, IL, USA
- Qibin Qi
- Center for Population Cohorts, Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Eric A. Boerwinkle
- Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA
- Simin Liu
- School of Public Health, Brown University, Providence, RI, USA
- Lawrence S. Phillips
- Atlanta VA Medical Center, Decatur, GA, USA; Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Ulrike Peters
- Division of Public Health Sciences, University of Washington, Department of Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Chris Carlson
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Lynne R. Wikens
- University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
- Loic Le Marchand
- University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
- Kari E. North
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Steven Buyske
- Department of Statistics, Rutgers University, Piscataway, NJ, USA
- Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Ruth J.F. Loos
- Icahn School of Medicine at Mount Sinai, The Mindich Child Health and Development Institute, The Charles Bronfman Institute for Personalized Medicine, New York, NY, USA
- Daniel O. Stram
- Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA
- Christopher A. Haiman
- Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA; Corresponding author
- Journal volume & issue
-
Vol. 2,
no. 2
p. 100029
Abstract
Summary: Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the TGFB1 gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p = 2.06 × 10−8), which replicated in independent studies of African ancestry (p = 6.26 × 10−23). We identified a multiethnic risk variant in the BACE2 gene (rs13052926, RAF = 14.1%, OR = 1.08, p = 5.75 × 10−9), which also replicated in independent studies (p = 3.45 × 10−4). We also observed a significant difference in the performance of a multiethnic genetic risk score (GRS) across population groups (pheterogeneity = 3.85 × 10−20). Comparing individuals in the top GRS risk category (40%–60%), the OR was highest in Asians (OR = 3.08) and European (OR = 2.94) ancestry populations, followed by Hispanic (OR = 2.39), Native Hawaiian (OR = 2.02), and African ancestry (OR = 1.57) populations. These findings underscore the importance of genetic discovery and risk characterization in diverse populations and the urgent need to further increase representation of non-European ancestry individuals in genetics research to improve genetic-based risk prediction across populations.
