Local ancestry–aware genome-wide meta-analysis uncovers novel genetic loci for sickle cell disease nephropathy
5 affiliations
- 1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC
- 2Department of Medicine, University of Pittsburgh, Pittsburgh, PA
- 3School of Medicine, University of Maryland, Baltimore, MD
- 4Department of Medicine, University of Illinois at Chicago, Chicago, IL
- 5Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC
Abstract
In the United States, sickle cell disease (SCD) is a rare inherited hemoglobinopathy affecting ∼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 2 well-characterized adult SCD cohorts to boost statistical power and perform a local ancestry–aware GWAS for estimated glomerular filtration rate, resulting in the identification of novel genome-wide significant loci within the African and European ancestral components of participants. Meta-analysis identified 12 significant genomic regions in the African tract, including peptidylprolyl isomerase like 6, ARHGAP24, RAB11A, and STEAP3, and 38 regions in the European tract, including UBLCP1, a disintegrin and metalloproteinase with thrombospondin motifs 6, JAZF1, MYO7B, MYO1C, PDGFA, GPC5, LRP1B, KANK1, and TRPV5. The identified regions encompass genes affecting inflammation, extracellular matrix integrity, iron metabolism, magnesium ion homeostasis, B-cell apoptosis, tumor necrosis factor 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 patients with SCD.
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BibTeX
@article{garrett2026local,
title = {{Local ancestry–aware genome-wide meta-analysis uncovers novel genetic loci for sickle cell disease nephropathy}},
author = {Melanie E. Garrett and Seyed Mehdi Nouraie and Roberto F. Machado and Victor R. Gordeuk and Mark T. Gladwin and Marilyn J. Telen and Allison E. Ashley-Koch and Gonçalo Abecasis and Gonçalo Abecasis and Francois Aguet and Christine Albert and Laura Almasy and Alvaro Alonso and Seth Ament and Peter Anderson and Pramod Anugu and Kristin Ardlie and Dan Arking and Donna K. Arnett and Allison Ashley-Koch and Stella Aslibekyan and Tim Assimes and Paul Auer and Dimitrios Avramopoulos and Najib Ayas and John Barnard and Kathleen Barnes and R. Graham Barr and Emily Barron-Casella and Terri Beaty and Gerald Beck and Diane Becker and Lewis Becker and Amber Beitelshees and Panagiotis Benos and Marcos Bezerra and Larry Bielak and Joshua Bis and John Blangero and Nathan Blue and Donald W. Bowden and Russell Bowler and Jennifer Brody and Ulrich Broeckel and Deborah Brown and Esteban Burchard and Carlos Bustamante and Brian Cade and Jonathan Cardwell and Vincent Carey and April P. Carson and Cara Carty and Richard Casaburi and James Casella and Peter Castaldi and Mark Chaffin and Yi-Cheng Chang and Daniel Chasman and Wei Min Chen and Yii-Der Ida Chen},
journal = {Blood Advances},
year = {2026},
month = oct,
doi = {10.1182/bloodadvances.2026020894},
url = {https://doi.org/10.1182/bloodadvances.2026020894},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Local ancestry–aware genome-wide meta-analysis uncovers novel genetic loci for sickle cell disease nephropathy
AU - Melanie E. Garrett
AU - Seyed Mehdi Nouraie
AU - Roberto F. Machado
AU - Victor R. Gordeuk
AU - Mark T. Gladwin
AU - Marilyn J. Telen
AU - Allison E. Ashley-Koch
AU - Gonçalo Abecasis
AU - Gonçalo Abecasis
AU - Francois Aguet
AU - Christine Albert
AU - Laura Almasy
AU - Alvaro Alonso
AU - Seth Ament
AU - Peter Anderson
AU - Pramod Anugu
AU - Kristin Ardlie
AU - Dan Arking
AU - Donna K. Arnett
AU - Allison Ashley-Koch
AU - Stella Aslibekyan
AU - Tim Assimes
AU - Paul Auer
AU - Dimitrios Avramopoulos
AU - Najib Ayas
AU - John Barnard
AU - Kathleen Barnes
AU - R. Graham Barr
AU - Emily Barron-Casella
AU - Terri Beaty
AU - Gerald Beck
AU - Diane Becker
AU - Lewis Becker
AU - Amber Beitelshees
AU - Panagiotis Benos
AU - Marcos Bezerra
AU - Larry Bielak
AU - Joshua Bis
AU - John Blangero
AU - Nathan Blue
AU - Donald W. Bowden
AU - Russell Bowler
AU - Jennifer Brody
AU - Ulrich Broeckel
AU - Deborah Brown
AU - Esteban Burchard
AU - Carlos Bustamante
AU - Brian Cade
AU - Jonathan Cardwell
AU - Vincent Carey
AU - April P. Carson
AU - Cara Carty
AU - Richard Casaburi
AU - James Casella
AU - Peter Castaldi
AU - Mark Chaffin
AU - Yi-Cheng Chang
AU - Daniel Chasman
AU - Wei Min Chen
AU - Yii-Der Ida Chen
PY - 2026
DA - 2026/10/17
JO - Blood Advances
DO - 10.1182/bloodadvances.2026020894
UR - https://doi.org/10.1182/bloodadvances.2026020894
AB - In the United States, sickle cell disease (SCD) is a rare inherited hemoglobinopathy affecting ∼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 2 well-characterized adult SCD cohorts to boost statistical power and perform a local ancestry–aware GWAS for estimated glomerular filtration rate, resulting in the identification of novel genome-wide significant loci within the African and European ancestral components of participants. Meta-analysis identified 12 significant genomic regions in the African tract, including peptidylprolyl isomerase like 6, ARHGAP24, RAB11A, and STEAP3, and 38 regions in the European tract, including UBLCP1, a disintegrin and metalloproteinase with thrombospondin motifs 6, JAZF1, MYO7B, MYO1C, PDGFA, GPC5, LRP1B, KANK1, and TRPV5. The identified regions encompass genes affecting inflammation, extracellular matrix integrity, iron metabolism, magnesium ion homeostasis, B-cell apoptosis, tumor necrosis factor 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 patients with SCD.
SN - 2473-9529
SN - 2473-9537
ER -