EBioMedicine (Jan 2021)
Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium
- Bridget M Lin,
- Kelsey E Grinde,
- Jennifer A Brody,
- Charles E Breeze,
- Laura M Raffield,
- Josyf C Mychaleckyj,
- Timothy A Thornton,
- James A Perry,
- Leslie J Baier,
- Lisa de las Fuentes,
- Xiuqing Guo,
- Benjamin D Heavner,
- Robert L Hanson,
- Yi-Jen Hung,
- Huijun Qian,
- Chao A Hsiung,
- Shih-Jen Hwang,
- Margaret R Irvin,
- Deepti Jain,
- Tanika N Kelly,
- Sayuko Kobes,
- Leslie Lange,
- James P Lash,
- Yun Li,
- Xiaoming Liu,
- Xuenan Mi,
- Solomon K Musani,
- George J Papanicolaou,
- Afshin Parsa,
- Alex P Reiner,
- Shabnam Salimi,
- Wayne H-H Sheu,
- Alan R Shuldiner,
- Kent D Taylor,
- Albert V Smith,
- Jennifer A Smith,
- Adrienne Tin,
- Dhananjay Vaidya,
- Robert B Wallace,
- Kenichi Yamamoto,
- Saori Sakaue,
- Koichi Matsuda,
- Yoichiro Kamatani,
- Yukihide Momozawa,
- Lisa R Yanek,
- Betsi A Young,
- Wei Zhao,
- Yukinori Okada,
- Gonzalo Abecasis,
- Bruce M Psaty,
- Donna K Arnett,
- Eric Boerwinkle,
- Jianwen Cai,
- Ida Yii-Der Chen,
- Adolfo Correa,
- L Adrienne Cupples,
- Jiang He,
- Sharon LR Kardia,
- Charles Kooperberg,
- Rasika A Mathias,
- Braxton D Mitchell,
- Deborah A Nickerson,
- Steve T Turner,
- Vasan S Ramachandran,
- Jerome I Rotter,
- Daniel Levy,
- Holly J Kramer,
- Anna Köttgen,
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,
- TOPMed Kidney Working Group,
- Stephen S Rich,
- Dan-Yu Lin,
- Sharon R Browning,
- Nora Franceschini
Affiliations
- Bridget M Lin
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States
- Kelsey E Grinde
- Department of Mathematics, Statistics, and Computer Science, Macalester College, St. Paul, MN, United States
- Jennifer A Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States
- Charles E Breeze
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MD, United States; UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom; Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
- Laura M Raffield
- Department of Genetics, University of North Carolina, Chapel Hill, NC, United States
- Josyf C Mychaleckyj
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States
- Timothy A Thornton
- Department of Biostatistics, University of Washington, Seattle, WA, United States
- James A Perry
- Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
- Leslie J Baier
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, United States
- Lisa de las Fuentes
- Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States
- Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA United States
- Benjamin D Heavner
- Department of Biostatistics, University of Washington, Seattle, WA, United States
- Robert L Hanson
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, United States
- Yi-Jen Hung
- Endocrinology and Metabolism, Tri-Service General Hospital Songshan branch, Taipei, Taiwan
- Huijun Qian
- Department of Statistics and Operations Research, University of North Carolina, Chapel Hill, NC, United States
- Chao A Hsiung
- Endocrinology and Metabolism, National Taiwan University Hospital, Taipei, Taiwan
- Shih-Jen Hwang
- National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, United States; National Heart, Lung and Blood Institute, Population Sciences Branch, Division of Intramural Research, Bethesda, MD, United States
- Margaret R Irvin
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States
- Deepti Jain
- Department of Biostatistics, University of Washington, Seattle, WA, United States
- Tanika N Kelly
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States
- Sayuko Kobes
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, United States
- Leslie Lange
- Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, United States
- James P Lash
- Department of Medicine, University of Illinois, Chicago, IL, United States
- Yun Li
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States; Department of Genetics, University of North Carolina, Chapel Hill, NC, United States
- Xiaoming Liu
- USF Genomics & College of Public Health, University of South Florida, Tampa, FL, United States
- Xuenan Mi
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States
- Solomon K Musani
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States
- George J Papanicolaou
- Epidemiology Branch, National Heart, Lung, and Blood Institute, Bethesda, MA, United States
- Afshin Parsa
- Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MA, United States
- Alex P Reiner
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
- Shabnam Salimi
- Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, United States
- Wayne H-H Sheu
- Endocrinology & Metabolism, Taichung Veterans General Hospital, Taichung, Taiwan
- Alan R Shuldiner
- Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
- Kent D Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA United States
- Albert V Smith
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States
- Jennifer A Smith
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States
- Adrienne Tin
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
- Dhananjay Vaidya
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Robert B Wallace
- University of Iowa College of Public Health, Iowa City, IA, United States
- Kenichi Yamamoto
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan; Department of Pediatrics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
- Saori Sakaue
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan; Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan
- Koichi Matsuda
- Department of Computational Biology and Medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan
- Yoichiro Kamatani
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo 108-8639, Japan
- Yukihide Momozawa
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
- Lisa R Yanek
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Betsi A Young
- Kidney Research Institute and Division of Nephrology, University of Washington, Seattle, WA, United States
- Wei Zhao
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States
- Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita 565-0871, Japan; Laboratory of Statistical Immunology, World Premier International Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita 565-0871, Japan
- Gonzalo Abecasis
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, An Arbor, MI, United States; Regeneron Pharmaceuticals, Tarrytown, NY, United States
- Bruce M Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States; Departments of Epidemiology and Health Services, University of Washington, Seattle, WA, United States
- Donna K Arnett
- College of Public Health, Dean's Office, University of Kentucky, Lexington, KY, United States
- Eric Boerwinkle
- 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, United States; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
- Jianwen Cai
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States
- Ida Yii-Der Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA United States
- Adolfo Correa
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States
- L Adrienne Cupples
- National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, United States; Department of Biostatistics, Boston University, Boston, MA, United States
- Jiang He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States
- Sharon LR Kardia
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States
- Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
- Rasika A Mathias
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Braxton D Mitchell
- Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, United States; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, United States
- Deborah A Nickerson
- Department of Genome Sciences, University of Washington, Seattle, WA, United States
- Steve T Turner
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States
- Vasan S Ramachandran
- Division of Preventive Medicine and Epidemiology and Cardiology, Boston University School of Medicine, Boston, MA, United States
- Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA United States
- Daniel Levy
- National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, United States; National Heart, Lung and Blood Institute, Population Sciences Branch, Division of Intramural Research, Bethesda, MD, United States
- Holly J Kramer
- Department of Public Health Sciences and Medicine, Loyola University Chicago, Maywood, IL, United States; Division of Nephrology and Hypertension, Loyola University Chicago, Maywood, IL, United States
- Anna Köttgen
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Members listed at the end of the article.
- TOPMed Kidney Working Group
- Members listed at the end of the article.
- Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States
- Dan-Yu Lin
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States
- Sharon R Browning
- Department of Biostatistics, University of Washington, Seattle, WA, United States
- Nora Franceschini
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States; Corresponding author. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516.
- Journal volume & issue
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Vol. 63
p. 103157
Abstract
Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10−11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10−9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10−9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10−9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10−9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
