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First GWAS of Cystatin-C Kidney Function in Continental Africa Identifies Novel Loci & Refines Known Associations
18 Pages Posted: 8 Jun 2023
More...Abstract
Background: Chronic kidney disease is becoming more prevalent in Africa, and its genetic determinants are poorly understood. Creatinine-based estimated glomerular filtration rate (eGFR) is commonly used to estimate kidney function, modelling the excretion of the endogenous biomarker (creatinine). However, eGFR based on creatinine has been shown to inadequately detect individuals with low kidney function in Sub-Saharan Africa, with eGFR based on cystatin-C (eGFRcys) exhibiting significantly superior performance. Therefore, we opted to conduct a GWAS for eGFRcys.
Methods: Using the Uganda Genomic Resource, we performed a genome-wide association study (GWAS) of eGFRcys in 5,877 Ugandans and evaluated replication in independent studies. Subsequently, putative causal variants were screened through Bayesian fine-mapping. Functional annotation of the GWAS loci was performed using Functional Mapping and Annotation (FUMA).
Findings: Three independent lead single nucleotide polymorphisms (SNPs) (P-value<5x10-8) were identified; rs59288815 (ANK3), rs4277141 (OR51B5) and rs911119 (CST3). From fine-mapping, rs59288815 and rs911119 each had a posterior probability of causality of >99%. The rs911119 SNP maps to the cystatin C gene and has been previously associated with eGFRcys among Europeans. With gene-set enrichment analyses of the olfactory receptor family 51 overlapping genes, we identified an association with the G-alpha-S signalling events.
Interpretation: Our study found two novel candidate eGFRcys SNPs for eGFRcys in continental Africans (rs59288815 and rs4277141) and validated a previously well-established SNP (rs911119) for eGFRcys. The identified gene-set enrichment for the G-protein signaling pathways relates to the capacity of the kidney to readily adapt to an ever-changing environment. This is the first GWAS of eGFRcys in continental Africa. Additional GWASs are required to represent the diverse regions in Africa.
Funding: This work was supported by the Wellcome Trust [grant number: 220740/Z/20/Z] awarded to Segun Fatumo. This work was supported by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, through core funding to the MRC/UVRI and LSHTM Uganda Research Unit. SF and EZ acknowledge the Humboldt‐Forschungsstipendium für (AvH) Georg Forster Research Fellowship to SF for experienced researchers.
Declaration of Interest: None declared.
Ethical Approval: The GPC study was approved by the Science and Ethics Committee of the UVRI, the Ugandan National Council for Science and Technology, and the East of England-Cambridge South NHS Research Ethics Committee in the United Kingdom. The study utilized samples that were acquired from the GPC study. The individuals who participated in the study had previously consented to their samples being used in future genetic research.
Keywords: Cystatin-C, Estimated glomerular filtration rate, Kidney Function, Genome-wide association study, Fine-mapping, Continental Africa
Suggested Citation: Suggested Citation