Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study
BackgroundChronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide asso...
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Frontiers Media S.A.
2019-05-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.00494/full |
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DOAJ |
language |
English |
format |
Article |
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DOAJ |
author |
Bridget M. Lin Girish N. Nadkarni Girish N. Nadkarni Ran Tao Ran Tao Mariaelisa Graff Myriam Fornage Steven Buyske Tara C. Matise Heather M. Highland Lynne R. Wilkens Christopher S. Carlson Christopher S. Carlson S. Lani Park V. Wendy Setiawan Jose Luis Ambite Gerardo Heiss Eric Boerwinkle Dan-Yu Lin Andrew P. Morris Andrew P. Morris Ruth J. F. Loos Ruth J. F. Loos Charles Kooperberg Kari E. North Christina L. Wassel Nora Franceschini |
spellingShingle |
Bridget M. Lin Girish N. Nadkarni Girish N. Nadkarni Ran Tao Ran Tao Mariaelisa Graff Myriam Fornage Steven Buyske Tara C. Matise Heather M. Highland Lynne R. Wilkens Christopher S. Carlson Christopher S. Carlson S. Lani Park V. Wendy Setiawan Jose Luis Ambite Gerardo Heiss Eric Boerwinkle Dan-Yu Lin Andrew P. Morris Andrew P. Morris Ruth J. F. Loos Ruth J. F. Loos Charles Kooperberg Kari E. North Christina L. Wassel Nora Franceschini Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study Frontiers in Genetics genetics chronic kidney disease stages genome-wide association studies APOL1 end stage kidney disease diverse populations |
author_facet |
Bridget M. Lin Girish N. Nadkarni Girish N. Nadkarni Ran Tao Ran Tao Mariaelisa Graff Myriam Fornage Steven Buyske Tara C. Matise Heather M. Highland Lynne R. Wilkens Christopher S. Carlson Christopher S. Carlson S. Lani Park V. Wendy Setiawan Jose Luis Ambite Gerardo Heiss Eric Boerwinkle Dan-Yu Lin Andrew P. Morris Andrew P. Morris Ruth J. F. Loos Ruth J. F. Loos Charles Kooperberg Kari E. North Christina L. Wassel Nora Franceschini |
author_sort |
Bridget M. Lin |
title |
Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study |
title_short |
Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study |
title_full |
Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study |
title_fullStr |
Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study |
title_full_unstemmed |
Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study |
title_sort |
genetics of chronic kidney disease stages across ancestries: the page study |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Genetics |
issn |
1664-8021 |
publishDate |
2019-05-01 |
description |
BackgroundChronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study.MethodsWe assembled multi-ethnic genome-wide imputed data on CKD non-overlapping cases [4,150 mild to moderate CKD, 1,105 end-stage kidney disease (ESKD)] and non-CKD controls for up to 41,041 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian, and American Indians). We implemented a generalized estimating equation approach for GWAS using ancestry combined data while adjusting for age, sex, principal components, study, and ethnicity.ResultsThe GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby NMT2 (rs10906850, p = 3.7 × 10-8) that replicated in the United Kingdom Biobank white British (p = 0.008). Several variants at the APOL1 locus were associated with ESKD including the APOL1 G1 rs73885319 (p = 1.2 × 10-9). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported APOL1 locus (p = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at p-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry.ConclusionOur genetic study identified a novel association at NMT2 for CKD and showed for the first time strong associations of the APOL1 variants with ESKD across multi-ethnic populations. Our findings suggest differences in genetic effects across CKD severity and provide information for study design of genetic studies of CKD in diverse populations. |
topic |
genetics chronic kidney disease stages genome-wide association studies APOL1 end stage kidney disease diverse populations |
url |
https://www.frontiersin.org/article/10.3389/fgene.2019.00494/full |
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doaj-7ba2ad342bb444b5b8f804c4305a95332020-11-25T00:59:39ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-05-011010.3389/fgene.2019.00494451940Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE StudyBridget M. Lin0Girish N. Nadkarni1Girish N. Nadkarni2Ran Tao3Ran Tao4Mariaelisa Graff5Myriam Fornage6Steven Buyske7Tara C. Matise8Heather M. Highland9Lynne R. Wilkens10Christopher S. Carlson11Christopher S. Carlson12S. Lani Park13V. Wendy Setiawan14Jose Luis Ambite15Gerardo Heiss16Eric Boerwinkle17Dan-Yu Lin18Andrew P. Morris19Andrew P. Morris20Ruth J. F. Loos21Ruth J. F. Loos22Charles Kooperberg23Kari E. North24Christina L. Wassel25Nora Franceschini26Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United StatesDivision of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United StatesDepartment of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United StatesVanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United StatesDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesThe University of Texas Health Science Center at Houston, Houston, TX, United StatesDepartment of Genetics, Rutgers University, Piscataway, NJ, United StatesDepartment of Genetics, Rutgers University, Piscataway, NJ, United StatesDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesEpidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States0Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States1Department of Epidemiology, University of Washington, Seattle, WA, United States2Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States2Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States3Information Sciences Institute, University of Southern California, Marina del Rey, CA, United StatesDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesThe University of Texas Health Science Center at Houston, Houston, TX, United StatesDepartment of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States4Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom5Wellcome Centre for Human Genetics, University of Oxford, Oxford, United KingdomCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States6Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States0Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United StatesDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States7Applied Sciences, Premier, Inc., Charlotte, NC, United StatesDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBackgroundChronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study.MethodsWe assembled multi-ethnic genome-wide imputed data on CKD non-overlapping cases [4,150 mild to moderate CKD, 1,105 end-stage kidney disease (ESKD)] and non-CKD controls for up to 41,041 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian, and American Indians). We implemented a generalized estimating equation approach for GWAS using ancestry combined data while adjusting for age, sex, principal components, study, and ethnicity.ResultsThe GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby NMT2 (rs10906850, p = 3.7 × 10-8) that replicated in the United Kingdom Biobank white British (p = 0.008). Several variants at the APOL1 locus were associated with ESKD including the APOL1 G1 rs73885319 (p = 1.2 × 10-9). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported APOL1 locus (p = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at p-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry.ConclusionOur genetic study identified a novel association at NMT2 for CKD and showed for the first time strong associations of the APOL1 variants with ESKD across multi-ethnic populations. Our findings suggest differences in genetic effects across CKD severity and provide information for study design of genetic studies of CKD in diverse populations.https://www.frontiersin.org/article/10.3389/fgene.2019.00494/fullgeneticschronic kidney disease stagesgenome-wide association studiesAPOL1end stage kidney diseasediverse populations |