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Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study.

TitleGenetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study.
Publication TypeJournal Article
Year of Publication2019
AuthorsLin BM, Nadkarni GN, Tao R, Graff M, Fornage M, Buyske S, Matise TC, Highland HM, Wilkens LR, Carlson CS, S Park L, V Setiawan W, Ambite JLuis, Heiss G, Boerwinkle E, Lin D-Y, Morris AP, Loos RJF, Kooperberg C, North KE, Wassel CL
Secondary AuthorsFranceschini N
JournalFront Genet
Volume10
Pagination494
Date Published2019
ISSN1664-8021
Abstract

Background: Chronic 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.

Methods: We 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.

Results: The GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby (rs10906850, = 3.7 × 10) that replicated in the United Kingdom Biobank white British ( = 0.008). Several variants at the locus were associated with ESKD including the G1 rs73885319 ( = 1.2 × 10). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported locus ( = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at -values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry.

Conclusion: Our genetic study identified a novel association at for CKD and showed for the first time strong associations of the 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.

DOI10.3389/fgene.2019.00494
Alternate JournalFront Genet
PubMed ID31178898
PubMed Central IDPMC6544117
Grant ListU01 HG007417 / HG / NHGRI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
N01HC65234 / HL / NHLBI NIH HHS / United States
T32 HL129982 / HL / NHLBI NIH HHS / United States
N01HC65233 / HL / NHLBI NIH HHS / United States
P01 CA033619 / CA / NCI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
U01 CA098758 / CA / NCI NIH HHS / United States
R01 MD012765 / MD / NIMHD NIH HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HHSN268201100004C / WH / WHI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
U01 HG007419 / HG / NHGRI NIH HHS / United States
U01 HG004790 / HG / NHGRI NIH HHS / United States
HHSN268201100004I / HL / NHLBI NIH HHS / United States
U01 HG004802 / HG / NHGRI NIH HHS / United States
U01 HG007416 / HG / NHGRI NIH HHS / United States
R01 HG009974 / HG / NHGRI NIH HHS / United States
R56 DK104806 / DK / NIDDK NIH HHS / United States
HHSN268201100046C / HL / NHLBI NIH HHS / United States
R01 DK117445 / DK / NIDDK NIH HHS / United States
N01HC65236 / HL / NHLBI NIH HHS / United States
L30 HG009840 / HG / NHGRI NIH HHS / United States
HHSN268201100003C / WH / WHI NIH HHS / United States
U01 HG007376 / HG / NHGRI NIH HHS / United States
N01HC65235 / HL / NHLBI NIH HHS / United States
N01HC65237 / HL / NHLBI NIH HHS / United States
U01 HG004803 / HG / NHGRI NIH HHS / United States
HHSN271201100004C / AG / NIA NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
U01 CA136792 / CA / NCI NIH HHS / United States
P30 CA071789 / CA / NCI NIH HHS / United States
U01 HG007397 / HG / NHGRI NIH HHS / United States
R37 CA054281 / CA / NCI NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States