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 3.7Â 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 |