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

Melanie E Garrett1, Seyed Mehdi Nouraie2, Roberto F Machado3

  • 1Duke University Medical Center, Durham, North Carolina, United States.

Blood Advances
|August 19, 2026
PubMed

Insights

This study identified new genetic regions linked to kidney disease in sickle cell disease (SCD) patients by analyzing ancestral components. These findings offer novel targets for early detection and treatment of SCD nephropathy (SCDN).

Area of Science:

  • Genetics
  • Nephrology
  • Hematology

Background:

  • Sickle cell disease (SCD) is a genetic blood disorder affecting ~100,000 individuals in the US, primarily of African ancestry.
  • SCD can lead to multi-organ damage, with sickle cell disease nephropathy (SCDN) being a frequent and life-threatening complication.
  • Previous genome-wide association studies (GWAS) for SCDN identified limited significant genetic loci.

Purpose of the Study:

  • To conduct the largest local ancestry-aware GWAS for estimated glomerular filtration rate (eGFR) in adult SCD cohorts.
  • To identify novel genetic loci associated with SCDN by leveraging ancestral composition to increase statistical power.
  • To explore the genetic underpinnings of SCDN and its unique pathophysiology compared to other kidney diseases.

Main Methods:

  • Utilized two well-characterized adult SCD cohorts with detailed ancestral composition data.
  • Performed a local ancestry-aware GWAS for eGFR, analyzing African (AFR) and European (EUR) ancestral components separately.
  • Conducted a meta-analysis of identified significant genomic regions.

Main Results:

  • Identified 12 significant genomic regions in the AFR ancestral component, including genes like PPIL6, ARHGAP24, RAB11A, and STEAP3.
  • Discovered 38 significant genomic regions in the EUR ancestral component, including genes such as UBLCP1, ADAMTS6, JAZF1, MYO7B, MYO1C, PDGFA, GPC5, LRP1B, KANK1, and TRPV5.
  • The identified genes are involved in inflammation, extracellular matrix integrity, iron metabolism, magnesium homeostasis, B cell apoptosis, TNF production, and estrogen signaling.

Conclusions:

  • This study significantly advances the understanding of genetic risk factors for SCDN, the most extensive local ancestry-aware analysis to date.
  • The identified genes and pathways highlight the unique pathophysiology of SCDN, distinct from other forms of kidney disease.
  • These findings propose potential new targets for the early identification and therapeutic intervention of kidney dysfunction in SCD patients.

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