Local ancestry-aware genome-wide meta-analysis uncovers novel genetic loci for sickle cell disease nephropathy

In the United States, sickle cell disease (SCD) is a rare inherited hemoglobinopathy affecting about 100,000 individuals, mostly with African ancestry. SCD causes damage to multiple organ systems and SCD nephropathy (SCDN) is a common complication associated with early mortality. We previously performed a genome-wide association study (GWAS) for SCDN and identified a modest number of genome-wide significant loci. Here, we leveraged the ancestral composition of participants from two well-characterized adult SCD cohorts to boost statistical power and perform a local ancestry-aware GWAS for estimated glomerular filtration rate (eGFR), resulting in the identification of novel genome-wide significant loci within the African (AFR) and European (EUR) ancestral components of participants. Meta-analysis identified 12 significant genomic regions in the AFR tract, including PPIL6, ARHGAP24, RAB11A, and STEAP3, and 38 regions in the EUR tract, including UBLCP1, ADAMTS6, JAZF1, MYO7B, MYO1C, PDGFA, GPC5, LRP1B, KANK1, and TRPV5. The identified regions encompass genes affecting inflammation, extracellular matrix (ECM) integrity, iron metabolism, magnesium ion homeostasis, B cell apoptosis, tumor necrosis factor (TNF) production, and estrogen signaling. Many of these genes and pathways are important not only for renal function, but also for SCD biology, providing additional support for the hypothesis that SCDN pathophysiology is unique from other forms of kidney disease. This study represents the largest local ancestry-aware analysis of SCDN to date, furthers our understanding of the genetic risk factors underlying SCDN, and proposes new targets that could be useful for the early identification and treatment of kidney dysfunction in SCD patients. KEY POINTSO_LINovel application of local ancestry-aware GWAS in two SCD cohorts identified distinct eGFR loci from the African and European ancestries C_LIO_LIThis application increased power to detect new loci with biologic functions important to renal function, as well as sickle cell disease C_LI