A map of blood regulatory variation in South Africans enables GWAS interpretation

Stephane E Castel; Furahini D Tluway; Anne-Katrin Emde; Natalie Smyth; Mohd Karim; Dhriti Sengupta; Olivia A Gray; Melissa Hendershott; Sarah LeBaron von Baeyer; Erin E Burke; Sarah Kaewert; Khanh-Dung H Nguyen; Solomon S R Choma; Reneilwe G Mashaba; Lisa K Micklesfield; Chodziwadziwa Kabudula; Kathleen Kahn; F Xavier Gomez-Olive; Stephen Tollman; Ananyo Choudhury; Phelelani T Mpangase; Scott Hazelhurst; Kaja A Wasik; Laura Yerges-Armstrong; Michèle Ramsay

doi:10.1038/s41588-025-02223-0

A map of blood regulatory variation in South Africans enables GWAS interpretation

Nat Genet. 2025 Jun 11. doi: 10.1038/s41588-025-02223-0. Online ahead of print.

Authors

Stephane E Castel¹, Furahini D Tluway², Anne-Katrin Emde³, Natalie Smyth², Mohd Karim³, Dhriti Sengupta², Olivia A Gray³, Melissa Hendershott³, Sarah LeBaron von Baeyer³, Erin E Burke³, Sarah Kaewert³, Khanh-Dung H Nguyen³, Solomon S R Choma^{4

5}, Reneilwe G Mashaba⁵, Lisa K Micklesfield⁶, Chodziwadziwa Kabudula⁷, Kathleen Kahn⁷, F Xavier Gomez-Olive⁷, Stephen Tollman⁷, Ananyo Choudhury², Phelelani T Mpangase², Scott Hazelhurst^{2

8}, Kaja A Wasik³, Laura Yerges-Armstrong³, Michèle Ramsay⁹

Affiliations

¹ Variant Bio, Seattle, WA, USA. stephane@variantbio.com.
² Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
³ Variant Bio, Seattle, WA, USA.
⁴ Department of Pathology, University of Limpopo, Mankweng, South Africa.
⁵ DIMAMO PHRC, University of Limpopo, Mankweng, South Africa.
⁶ SAMRC/Wits Developmental Pathways for Health Research Unit, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
⁷ SAMRC/Wits University Rural Public Health and Health Transitions Research Unit, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
⁸ School of Electrical & Information Engineering, University of the Witwatersrand, Johannesburg, South Africa.
⁹ Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. michele.ramsay@wits.ac.za.

PMID: 40500424
DOI: 10.1038/s41588-025-02223-0

Abstract

Functional genomics resources are critical for interpreting human genetic studies, but currently they are predominantly from European-ancestry individuals. Here we present the South African Blood Regulatory (SABR) resource, a map of blood regulatory variation that includes three South Eastern Bantu-speaking groups. Using paired whole-genome and blood transcriptome data from over 600 individuals, we map the genetic architecture of 40 blood cell traits derived from deconvolution analysis, as well as expression, splice and cell-type interaction quantitative trait loci. We comprehensively compare SABR to the Genotype Tissue Expression Project and characterize thousands of regulatory variants only observed in African-ancestry individuals. Finally, we demonstrate the increased utility of SABR for interpreting African-ancestry association studies by identifying putatively causal genes and molecular mechanisms through colocalization analysis of blood-relevant traits from the Pan-UK Biobank. Importantly, we make full SABR summary statistics publicly available to support the African genomics community.