Abstract
Background Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts.
Methods Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations.
Results Two genome-wide significant (P<5×10−8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained.
Conclusion This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This study was funded by the National Institutes of Health (NIH) through the H3Africa AWI-Gen project (NIH grant number U54HG006938)). AWI-Gen is supported by the National Human Genome Research Institute (NHGRI), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), and Office of the Director (OD) at the National Institutes of Health. PB is funded by the National Research Foundation/The World Academy of Sciences African Renaissance Doctoral Fellowship (Grant no. 100004). JTB is supported by grants from the National Human Genome Research Institute (U54HG006938) as part of the H3A Consortium (AWI-Gen); and the Science For African Foundation - REACCT-CAN Grant (Del-22-008). MR is the South African Research Chair in Genomics and Bioinformatics of African populations hosted by the University of the Witwatersrand (SARChI), funded by the South African Department of Science and Innovation, and administered by the National Research Foundation. WCC is supported by the Research Networks for Health Innovations in sub-Saharan Africa Funding Initiative of the German Federal Ministry of Education and Research (RHISSA) Grant and the Science For African Foundation - REACCT-CAN Grant (Del-22-008). The ARK study was jointly funded by the South African MRC, MRC UK (via the Newton Fund), and GSK Africa Non-Communicable Disease Open Lab (via a supporting grant; project number 074). The views expressed in this manuscript do not necessarily reflect the views of the funders.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethics committee of University of the Witwatersrand/South Africa gave ethical approval for this work : M121029; M170880; M160939Ethics committee of centre Muraz Institutional Ethics Committee/Burkina Faso gave ethical approval for this work : 15-2014/CE- CM0Ethics committee of National Ethics Committee For Health Research/Burkina Faso gave ethical approval for this work : 2014-08-096Ethics committee of Ghana Health Service Ethics Review Committee gave ethical approval for this work : GHS-ERC:05/05/2015Ethics committee of AMREF Health Ethics and Scientific Review Committee in Kenya gave ethical approval for this work : P114/2014Ethics committee of Navrongo Institutional Review Board gave ethical approval for this work : NHRCIRB178
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Footnotes
Support: National Institutes of Health (NIH) H3Africa AWI-Gen Collaborative Centre (U54HG006938).
Following comment of reviewer minor comment had been done as title and/or eqtl analysis. no major review
Data availability statement
Summary statistics are available in the GWAS catalog (XXX) and scripts are available from the corresponding authors. The AWI-Gen data set is available from the European Genome-phenome Archive (EGA) database (https://ega-archive.org/), accession number EGAS00001002482 (phenotype dataset: EGAD00001006425; genotype dataset: EGAD00010001996). The availability of these datasets is subject to controlled access through the Data and Biospecimen Access Committee of the H3Africa Consortium. ARK data is available in WIReDSpace repository on request (https://wiredspace.wits.ac.za/), https://doi.org/10.54223/uniwitwatersrand-10539-3301635
Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). The processed data generated in this study are provided in Supplementary Material. Permission was obtained to access the genotype and phenotype dataset for UKBB (research project number: 63215).
Publicly available databases include Teumer et al. in CKD-GEN consortium website: https://ckdgen.imbi.uni-freiburg.de/.
