Gorski et al., 2021
https://pubmed.ncbi.nlm.nih.gov/33137338/
Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Data set description
- GWAS meta-analysis across 42 longitudinal studies of rapid eGFRcrea decline: Rapid3 and CKDi25
- Within each file, the data are presented as follows:
- Chr: chromosome
- Pos_b37: position (build 37)
- RSID: rs identifier
- Allele1: coded (effect) allele
- Allele2: noncoded allele
- Freq1: frequency of allele 1
- OR: odds ratio of association of allele 1
- StdErr: Standard error, 2nd GC corrected
- P-value: P value, 2nd GC corrected
- N_total_sum: Number of subjects in analysis
Phenotypes
- CKDi25 overall, N(19,901 cases and 175,244 controls)
- Rapid3 overall, N(34,874 cases and 107,090 controls)