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Table 2 Genomic-wide association studies in chronic kidney disease

From: Genomic approaches in the search for molecular biomarkers in chronic kidney disease

PMID Author Year Patients Ethnicity Methodology Main findings
28452372 Gorski 2017 110,517 eGFRcrea
24,063 eGFRcys
Caucasian GWAMA
33 studies
Imputation: 1KG
8,103,124 (SNPs and INDELs)
Identification of 49 genome-wide significant loci for eGFRcrea, including 10 novel loci
All common variants except for one in HOXD8 gene
Confirmation of previously identified loci in or near CST3/CST9 (p = 4.1·10−153), UMOD (p = 2.9·10−10), and ATXN2 (p = 1.6·10−8) associated with eGFRcys
Identification of 127 novel pathways for kidney function
27729571 Parsa 2017 CRIC cohort: 2807 CKD
CKD definition: 20–70 ml/min/1.73 m2
1331 Black
1476 White
Illumina HumanOmni 1-Quad Array Platform The discovery analysis identified 12 SNPs in black patients and 6 SNPs in white patients (p < 10−6)
Followed up 3 SNPs in a replication cohort and 8 SNPs in a validation cohort
In black, non-diabetic patients, variant rs653747 in LINC00923 was replicated (p = 0.039) in the African American Study of Kidney Disease and Hypertension Cohort and was also associated with ESRD (p = 4.90 × 10−6)
Association of eGFR decline with rs931891 in the LINC00923 gene was found in white patients without diabetes (p = 1.44 × 10−4)
26831199 Pattaro 2016 Discovery: 49 population-based studies: 133,413 individuals
Replication: 15 studies
42,166 individuals
Trans-ethnic MA: 12 African studies
48 European studies
Caucasian
African
GWAMA
Discovery: ≈ 2.5million SNPs
The discovery analysis, stratified by diabetes status to account for its influence on CKD susceptibility, confirmed 29 previously identified loci and identified 18 new ones, 21 with genome-wide significance
Overall, 43 SNPs were identified in association with eGFRcrea (nine in the non-diabetes sample), one with eGFRcys and four with CKD
Replication analysis: 24 SNPs out of 48 novel candidates reached genome-wide significant (p < 5.0·10−8). Of these, 23 fulfilled additional replication criteria (q-value < 0.05)
Suggested irrelevance of the estimation method for eGFR, since 22/24 retained significance across eGFR estimation method
Association of 19 loci (13 demonstrated nominal associations) with eGFRcrea in diabetes
The trans-ethnic MA showed that 12 loci (SDCCAG8, LRP2, IGFBP5, SKIL, UNCX, KBTBD2, A1CF, KCNQ1, AP5B1, PTPRO, TP53INP2 and BCAS1) had fully consistent effect direction across the three ethnic groups
For eGFRcrea, 15 out of 24 new loci were also genome-wide significant in the trans-ethnic MA
25082825 Sveinbjornsson 2014 81,656 and their 112,630 relatives
15,594 CKD (1716 Severe CKD)
291,420 non-CKD
Icelandic Icelandic: Illumina, HumanHap300, HumanCNV370, HumanHap610, HumanHap1M, HumanHap660, Omni-1, 
Omni 2.5, 
Omni Express bead chips
≈ 24 million SNPs
Association of 19 SNPs with SCr (5 new)
The genes affected by the novel variants encode either solute carriers (SLC25A45, SLC47A1 and SLC6A19) or E3 ubiquitin ligases (RNF128 and RNF186)
Three of the five novel ones also associated with CKD (p < 0.05)
No association with severe CKD, but consistent directional effect
Replication of 41 out of 45 SNPs previously associated with SCr/CKD
24029420 Parsa 2013 CKDGen:
Discovery: 26 cohorts
74,354 individuals
Replication: 56,246 individuals
Caucasian GWAMA Identified OMIM genes associated with mendelian kidney disease and investigate SNPs within these for association with eGFR/CKD
Identification of 8 independent associations with eGFR
Confirmation of the previously identified variants rs12922822 in UMOD and rs12460876 in SLC7A9
Three SNPs associated with eGFR (rs6433115 in LRP2, rs9827843 in ROBO2, and rs1050700 in TSC1) and one associated with CKD (rs249942 in PALB2) were taken to replication, with no significance achieved
22479191 Pattaro 2012 Discovery: 74,354: 6271 CKD
68,083 non-CKD
2181 CKD45
(eGFR < 45 ml/min/1.73 m2)
72,173 non-CKD45
Replication: 56,246
Ethnicity replication: 8110 (CARe)
Discovery and Replication: Caucasian
Ethnicity replication: African American (CARe)
GWAMA Twenty-one SNPs associated with eGFRcrea selected for replication (5 with genome-wide significance)
Six SNPs showed genome-wide significance after replication: rs3925584 in MPPED2 (overall); rs6431731 in DDX1 (overall); rs2453580 in SLC47A1 (non-diabetic); rs11078903 in CDK12 (younger age); rs12124078 in CASP9 (younger age); rs2928148 in INO80
None of the six SNPs achieved significance in African American patients
Similar results in eGFRcys
Stratification by diabetes, hypertension, age and sex showed 29 SNPs (23 known and 6 novel ones) associated with eGFRcrea
Stratifying by age showed UMOD associated with eGFRcrea in older individuals, and CDK12 with younger
Additional association of 18 out of 29 SNPs with CKD and 11 with CDK45
21355061 Böger 2011 GWAMA and discovery: CKDGen Consortium (20 studies)
GWAMA: 31,580 individuals
Discovery: 27,746 individuals
Ethnicity replication: CARe Consortium
19,499 White
6981 African American
Caucasian
African American
GWAMA and discovery: GWAMA
Ethnicity replication: IBC SNP Chip
Survival analysis: Illumina 1 M SNP chip
No genome-wide association (p < 5.0·10−8) with either UACR or microalbuminuria in both the overall and the nondiabetic analyses
Top 16 independent SNPs taken forward to replication
The combined analysis showed in direction-consistent association of rs1801239 in the CUBN gene with UACR (p = 4.0·10−8)
UACR was also associated with rs17319721 in SHROOM3, whose minor allele (A) indicated lower albuminuria levels
No association with eGFR (p = 0.53) or CKD (p = 0.33) was shown
20466664 Bostrom 2010 Discovery & Replication:
317 ESRD
354 non-nephropathy
African American MassARRAY and DNA sequencing No association with ESRD
Three SNPs in intron 1 of KL associated with age of ESRD onset (association lost after Bonferroni correction)
20532800 Bostrom 2010 Discovery: non-DM ESRD (n = 500), pools
Replication: same cohort, unpooled (n = 464)
Controls: Non-nephropathy (Discovery = 500, Replication = 478)
African American Illumina
HumanHap550-Duo BeadChip and Affymetrix 6.0
Discovery: 166,033 SNPs
Replication: 65 SNPs
Association of 16 SNPs with non-DM ESRD. Twelve out of 16 were located in/near the MYH9 gene
Four out 16 SNPs were not replicated
Approximately 4% of carriers of MYH9 risk allele progressed to ESRD, whereas 57% of non-nephropathy controls carried at least one copy of the risk haplotype, suggesting additional environmental and/or genetic factors contributing to the increased risk for ESRD in this population
20383145 Chambers 2010 Discovery: 23,812 individuals
Replication: 16,626 individuals
Caucasian GWAMA Association of 109 SNPs at p < 5·10−7 level in the discovery stage
Four SNPs (rs10206899, rs3127573, rs8068318, rs4805834) showed strong replication with creatinine concentration
The variants rs10206899 (close to NAT8) and rs4805834 (close to SLC7A9) were associated with SCr, eGFR, cystatin-c and CKD
The variants rs3127573 (near SLC22A2) and rs8068318 (located in TBX2) were only associated with SCr and eGFR
None were associated with other clinical parameters which are known to influence SCr
No association with MYH9
20686651 Gudbjartsson 2010 Discovery: 2903 CKD
35,818 Non-CKD controls
Serum Creatinine: 22,256 individuals
Replication: 300 CKD, 2964 Non-CKD controls
SCr: 4198 Individuals
Discovery: Icelandic
Serum Creatinine: 22,256 Icelandic
Replication:
300 Icelandic (CKD)
2964 Icelandic
SCr: 1819 Dutch 2379 Icelandic
Illumina
HumanHap300 HumanHapCNV370 bead chips
≈ 2.5 million SNPs
Association of rs4293393-T in UMOD with increased risk of CKD (OR = 1.25; 95%CI 1.16–1.34; p = 6.2·10−9) and elevated SCr
This association was replicated consistently
No interaction of UMOD-rs4293393 with sex, but SCr increased 0.09 µmol/l per year in carriers of the T-allele (95%CI 0.07–0.11)
Similar interaction of UMOD-rs4293393 and age with CKD
The effect of UMOD-rs4293393 on SCr also increased with the number of comorbidities
UMOD-rs4293393T was also associated with serum urea (p  =  1.0 × 10−6) and uric acid concentrations (p = 0.0064), and was associated with a lower risk of kidney stones (OR  =  0.88; p  =  0.0053)
20383146 Kottgen 2010 Discovery: CKDGen Consortium (20 studies)
67,093 (5807 CKD)
Replication: 22,982 (1366 CKD)
Caucasian GWAMA Association of 20 novel loci with eGFR and CKD. Thirteen loci were likely linked to renal function/CKD, others to creatinine production
These variants accounted for 1.4% of variation in eGFR
Most of the SNPs (65%) in the analyses were located in or within 3.7 kb upstream of genes
Pathway analysis identified genes involved in nephrogenesis, glomerular function, podocyte function, solute transport, angiogenesis, or metabolic kidney function
19430482 Köttgen 2009 Discovery: 2388 CKD
17,489 non-CKD
Cohorts: ARIC, CHS, FHS, RS
Replication: 1932 CKD
19,534 non-CKD
Cohorts: AGES
WGHS
European GWAMA: 300,000–900,000 SNPs SNPs with suggestive (p < 4·10−7) or significant (p < 5·10−8) genome-wide
associations identified in the discovery were tested for in silico replication
All the significant loci from the discovery analysis replicated for eGFRcrea except for the intronic SNP rs6040055 in JAG1 on chromosome 20 (p-overall = 0.006)
Variants in 5 different genes (UMOD, SHROOM3, SPATA5L1/GATM, STC1 and CST3/CST9) showed significant association (p < 5 × 10−8) with CKD, eGFRcrea or eGFRcys, with several variants showing association with more than one of these traits
18522750 Kottgen 2008 ARIC Cohort: 15,111 11,217 White
3894 Black
iPLEX gold assay
Taq-Man: 16 SNPs
The intronic SNP rs6495446 in the MTHFS gene was significantly associated with CKD among white ARIC participants (p = 0.001)
17903292 Hwang 2007 FHS cohort: 1345 individuals
1010 eGFR: 981 Cystatin-C
822 UAE
Caucasian Affymetrix GeneChip Human Mapping 100 K (70,987 SNPs) Identified several SNPs associated with each phenotype
The top SNP associated with each trait was listed: eGFR (rs2829235, p = 1.6 × 10−05), Cystatin-C (rs1158167, p = 8.5 × 10−09) which is found near the cystatin-C precursor gene family (CST3, CST4, CST9), and UAE (rs1712790, p = 1.9 × 10−06) in NXPE2
  1. 1KG: 1000 genomes (1KG) reference panel; A1CF: APOBEC1 complementation factor; AGES: Age Gene/Environment Susceptibility-Reykjavik Study; AP5B1: adaptor related protein complex 5 subunit beta 1; ARIC: Atherosclerosis in Communities; BCAS1: breast carcinoma amplified sequence 1; CARe: Candidate-gene Association Resource Consortium; CASP9: caspase 9; CDK12: cyclin dependent kinase 12; CHS: Cardiovascular Health Study; CI: Confidence interval; CKD: Chronic Kidney Disease; CKDGen: CKDGen Consortium;CRIC: Chronic Renal Insufficiency Cohort; CST3: cystatin C; CST4: cystatin S; CST9: cystatin 9; CUBN: cubilin; DDX1: DEAD-box helicase 1; DM: Diabetes mellitus; eGFR: estimated glomerular filtration rate; eGFRcrea: GFR estimated using serum creatinine concentration; eGFRcys: GFR estimated using serum cystatin-c concentration; ESRD: end-stage renal disease; FHS: Framingham Heart Study; GATM: glycine amidinotransferase; GWAMA: genome-wide association meta-analysis; HOXD8: homeobox D8; IBC: ITMAT/Broad/CARE Vascular Disease 50 k (IBC) single-nucleotide polymorphism (SNP) chip arrayI; GFBP5: insulin like growth factor binding protein 5; INDEL(s): insertion/deletion(s); INO80: INO80 complex subunit; JAG1: jagged 1; KBTBD2: kelch repeat and BTB domain containing 2; KCNQ1: potassium voltage-gated channel subfamily Q member 1; KL: klotho; LINC00923: long intergenic non-protein coding RNA 923; LRP2: LDL receptor related protein 2; MA: meta-analysis; MPPED2: metallophosphoesterase domain containing 2; MTHFS: methenyltetrahydrofolate synthetase; MYH9: myosin heavy chain 9; NAT8: N-acetyltransferase 8 (putative); NXPE2: neurexophilin and PC-esterase domain family member 2; OMIM: Online Mendelian Inheritance in Man; OR: Odds ratio; PALB2: partner and localizer of BRCA2; PTPRO: protein tyrosine phosphatase, receptor type O; RNF128: ring finger protein 128; E3 ubiquitin protein ligase; RNF186: ring finger protein 186; ROBO2: roundabout guidance receptor 2; RS: Rotterdam Study; SDCCAG8: serologically defined colon cancer antigen 8; SCr: Serum creatinine; SHROOM3: shroom family member 3; SKIL: SKI like proto-oncogene; SLC22A2: solute carrier family 22 member 2; SLC25A45: solute carrier family 25 member 45; SLC47A1: solute carrier family 47 member 1; SLC6A19: solute carrier family 6 member 19; SLC7A9: solute carrier family 7 member 9; SPATA5L1: spermatogenesis associated 5 like 1; SNP: single nucleotide polymorphism; STC1: stanniocalcin 1; TBX2: T-box 2; TP53INP2: tumor protein p53 inducible nuclear protein 2; TSC1: TSC complex subunit 1; UACR: Urinary albumin-to-creatinine ratio; UNCX: UNC homeobox; WGHS: Women’s Genome Health Study