Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

Abstract

Genome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288 Ugandans and replicated the findings in 8224 African Americans. We identified two loci associated with eGFR at genome-wide significance (p<5x10 -8 ). The most significantly associated variant (rs2433603, p=2.4x10 -9 ) in GATM was distinct from previously reported signals. A second association signal mapping near HBB (rs141845179, p=3.0x10 -8 ) was not significant after conditioning on a previously reported SNP (rs334) for eGFR. However, fine-mapping analyses highlighted rs141845179 to be the most likely causal variant at the HBB locus (posterior probability of 0.61). A trans-ethnic GRS of eGFR constructed from previously reported lead SNPs was not predictive into the Ugandan population, indicating that additional large-scale efforts in Africa are necessary to gain further insight into the genetic architecture of kidney disease.

A roadmap to increase diversity in genomic studies

“…Underrepresentation is driven by inequitable resource allocation, which is an ethical issue, as are potential healthcare disparities stemming from imbalanced research. Here, we focus on the major missed scientific opportunities that arise as a consequence of underrepresentation, opportunities such as identification of new associations with population-enriched variants, pinpointing causal variants for functional follow-up, improving genetic risk prediction accuracy for all populations (particularly underrepresented populations) and understanding shared versus unique genetic and environmental population risk factors that influence health outcomes [10][11][12] .…”

“…During this training, he was strategically positioned to take a lead role in analyses of the UGR. Following this training and research, Segun Fatumo has since continued to maintain the genomic resources locally, in addition to leading other genomic studies [10][11][12]44 . Furthermore, this resource has enabled significant new insights for population genetics and genetic epidemiology.…”

Measurement of kidney function in Malawi, South Africa, and Uganda: a multicentre cohort study

“…36 Renal tubular handling of creatinine might be affected by antiretroviral therapy (which is particularly relevant in countries in which HIV is highly prevalent, such as South Africa) and by variants in genes affecting creatinine production and tubular secretion. 37 These issues, as well as prevalence of comorbidities such as hypertension, affect the likeli hood of individuals developing kidney dysfunction. Furthermore, normative ranges for GFR have not been established in African populations and whether a cutoff of GFR of less than 60 mL/min per 1•73 m² is appropriate is unknown.…”

The flashfm approach for fine-mapping multiple quantitative traits

“…Another source for African ancestry LD is the AFR superpopulation of 1000 Genomes 37 that consists of 1,418 samples of African ancestry from both Africa and the United States; data are available for download from http://grch37.ensembl.org/Homo_sapiens/Tools/DataSlicer. As African Americans reflect admixture of people of West and Central-West African descent 38 , the AFR superpopulation of 1000 Genomes or the African ancestry cohort from UK Biobank would be an appropriate source of LD for either African or African American samples.…”