Local ancestry–aware genome-wide meta-analysis uncovers novel genetic loci for sickle cell disease nephropathy
Year: 2026
Type: article
Study design: Observational Study
Abstract: 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.
Source: Blood Advances
Authors: Melanie E. Garrett, Seyed Mehdi Nouraie, Roberto F. Machado, Victor R. Gordeuk, Mark T. Gladwin, Marilyn J. Telen, Allison E. Ashley-Koch, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Amber Beitelshees, Panagiotis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, John Blangero, Nathan Blue, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Deborah Brown, Esteban Burchard, Carlos Bustamante, Brian Cade, Jonathan Cardwell, Vincent Carey, April P. Carson, Cara Carty, Richard Casaburi, James Casella, Peter Castaldi, Mark Chaffin, Yi-Cheng Chang, Daniel Chasman, Wei Min Chen, Yii-Der Ida Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentas, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Serpil Erzurum, Charles Farber, Tasha Fingerlin, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Mark Gladwin, David Glahn, Stephanie Gogarten, Harald Goring, Sharon Graw, Kathryn J. Gray, C. Charles Gu, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Karin Hoth, Chao (Agnes) Hsiung, Chii Min Hwu, Marguerite Ryan Irvin, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Wonji Kim, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Cathy Laurie, Meryl LeBoff, Wen-Jane Lee, Jonathon LeFaive, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Becky McNeil, Hao Mei, James Meigs, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Yuan-I Min, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, May Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Pradeep Natarajan, Sergei Nekhai, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Allan Pack, Nicholette Palmer, James Pankow, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Richa Saxena, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Sylvia Smoller, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Adam Szpiro, Hua Tang, Margaret Taub, Kent D. Taylor, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Scott Vrieze, Tarik Walker, Robert Wallace, Heming Wang, Jiongming Wang, Karol Watson, Daniel E. Weeks, Joshua Weinstock, Lu-Chen Weng, Jennifer Wessel, L. Keoki Williams, Scott Williams, Carla Wilson, Lara Winterkorn, Baojun Wu, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ronit Yarden, Seyedeh Maryam Zekavat, Yingze Zhang, Wei Zhao, Xiaofeng Zhu, Elad Ziv, Michael Zody
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
OpenAlex ID: W7162865381
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