Genetic association and transferability for urinary albumin-creatinine ratio as a marker of kidney disease in four Sub-Saharan African populations and non-continental individuals of African ancestry

Jean-Tristan Brandenburg; Wenlong Carl Chen; Palwende Romuald Boua; Melanie A Govender; Godfred Agongo; Lisa K Micklesfield; Hermann Sorgho; Stephen Tollman; Gershim Asiki; Felistas Mashinya; Scott Hazelhurst; Andrew P Morris; June Fabian; Michèle Ramsay

doi:10.3389/fgene.2024.1372042

Genetic association and transferability for urinary albumin-creatinine ratio as a marker of kidney disease in four Sub-Saharan African populations and non-continental individuals of African ancestry

Front Genet. 2024 May 15:15:1372042. doi: 10.3389/fgene.2024.1372042. eCollection 2024.

Authors

Jean-Tristan Brandenburg^{1

2}, Wenlong Carl Chen^{1

2

3}, Palwende Romuald Boua^{1

4}, Melanie A Govender^{1

2

3

4

5

6

7

8

9

10

11

12

13

14

15}, Godfred Agongo^{6

7}, Lisa K Micklesfield⁸, Hermann Sorgho⁴, Stephen Tollman⁹, Gershim Asiki^{10

11}, Felistas Mashinya¹², Scott Hazelhurst^{1

13}, Andrew P Morris¹⁴, June Fabian^#^{9

15}, Michèle Ramsay^#^{1

5}

Affiliations

¹ Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
² Strengthening Oncology Services Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
³ National Cancer Registry, National Health Laboratory Service, Johannesburg, South Africa.
⁴ Clinical Research Unit of Nanoro, Institut de Recherche en Sciences de la Santé, Nanoro, Burkina Faso.
⁵ Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
⁶ Navrongo Health Research Centre, Navrongo, Ghana.
⁷ Department of Biochemistry and Forensic Sciences, School of Chemical and Biochemical Sciences, C. K. Tedam University of Technology and Applied Sciences, Navrongo, Ghana.
⁸ SAMRC/Wits Developmental Pathways for Health Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
⁹ Medical Research Council/Wits University Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
¹⁰ African Population and Health Research Center, Nairobi, Kenya.
¹¹ Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
¹² Department of Pathology and Medical Sciences, School of Healthcare Sciences, Faculty of Health Sciences, University of Limpopo, Polokwane, South Africa.
¹³ School of Electrical and Information Engineering, University of the Witwatersrand, Johannesburg, South Africa.
¹⁴ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, United Kingdom.
¹⁵ Wits Donald Gordon Medical Centre, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

^# Contributed equally.

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.

Keywords: African diversity; GWAS; Polygenic score; UACR; chronic kidney disease.

Grants and funding

U54 HG006938/HG/NHGRI NIH HHS/United States