Genome-wide association study of kidney function decline in individuals of European descent.

Kidney Int
Authors
Keywords
Abstract

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

Year of Publication
2015
Journal
Kidney Int
Volume
87
Issue
5
Pages
1017-29
Date Published
2015 May
ISSN
1523-1755
URL
DOI
10.1038/ki.2014.361
PubMed ID
25493955
PubMed Central ID
PMC4425568
Links
Grant list
HHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
N01-HC-95162 / HC / NHLBI NIH HHS / United States
K12 RR023250 / RR / NCRR NIH HHS / United States
R01 MH081802 / MH / NIMH NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
R24 OD017870 / OD / NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
N01-HC-85079-01-HC-85086 / HC / NHLBI NIH HHS / United States
N01 AG062101 / AG / NIA NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
K12RR023250 / RR / NCRR NIH HHS / United States
HHSN268201100005C / PHS HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
R01 HL087660 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
N01-HC-95163 / HC / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
N01-HC-95168 / HC / NHLBI NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
UL1-RR-024156 / RR / NCRR NIH HHS / United States
HHSN268201100009C / PHS HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
P30 DK079637 / DK / NIDDK NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
UL1 RR024156 / RR / NCRR NIH HHS / United States
N01-HC-95159 / HC / NHLBI NIH HHS / United States
R01 AG18728 / AG / NIA NIH HHS / United States
1R01AG032098-01A1 / AG / NIA NIH HHS / United States
U01 GM074518-04 / GM / NIGMS NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01-HC-95165 / HC / NHLBI NIH HHS / United States
R01 DK075787 / DK / NIDDK NIH HHS / United States
N01HC95164 / HL / NHLBI NIH HHS / United States
N01-AG-1-2100 / AG / NIA NIH HHS / United States
M01 RR 16500 / RR / NCRR NIH HHS / United States
N01 AG062106 / AG / NIA NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01HC95162 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / PHS HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
N01HC95168 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
R01 AG032098 / AG / NIA NIH HHS / United States
U01 HL084756 / HL / NHLBI NIH HHS / United States
R01 MH059160 / MH / NIMH NIH HHS / United States
1 R01 DK075787-01A1 / DK / NIDDK NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
Intramural NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
HHSN268201100008C / PHS HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / PHS HHS / United States
M01RR00425 / RR / NCRR NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01-HC-95169 / HC / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
N01 AG062103 / AG / NIA NIH HHS / United States
N01-HC-95164 / HC / NHLBI NIH HHS / United States
N01HC95165 / HL / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
N01HC95161 / HL / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-95160 / HC / NHLBI NIH HHS / United States
U01 HL072515 / HL / NHLBI NIH HHS / United States
M01 RR016500 / RR / NCRR NIH HHS / United States
HHSN268201100007C / PHS HHS / United States
M01 RR000425 / RR / NCRR NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
N01HC95167 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01-HC-95161 / HC / NHLBI NIH HHS / United States
HHSN268200782096C / PHS HHS / United States
U01 HL072515-06 / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC95166 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / PHS HHS / United States
N01-HC-95166 / HC / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01 HL-87660 / HL / NHLBI NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
R01 DK090311 / DK / NIDDK NIH HHS / United States
R01 AG018728 / AG / NIA NIH HHS / United States
U01 GM074518 / GM / NIGMS NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
N01-HC-95167 / HC / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
P30 DK017047 / DK / NIDDK NIH HHS / United States
R01 HL088119 / HL / NHLBI NIH HHS / United States
MH081802 / MH / NIMH NIH HHS / United States