Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants

作者：Hongbo Liu, Amin Abedini, Eunji Ha, Ziyuan Ma, Xin Sheng, Bernhard Dumoulin, Chengxiang Qiu, Tamás Arányi, Li Shen, Nicole Dittrich Hosni, Hua-Chang Chen, Ran Tao, Der-Cherng Tarng, Feng‐Jen Hsieh, Shih‐Ann Chen, Shun-Fa Yang, Mei‐Yueh Lee, Pui–Yan Kwok, Jer-Yuarn Wu, Chien-Hsiun Chen, Atlas Khan, Nita A. Limdi, Wei-Qi Wei, Theresa L. Walunas, Elizabeth W. Karlson, Eimear E. Kenny, Yuan Luo, Leah C. Kottyan, John J. Connolly, Gail P. Jarvik, Chunhua Weng, Ning Shang, Joanne B. Cole, Josep M. Mercader, Ravi Mandla, Timothy D. Majarian, José C. Florez, Mary E. Haas, Luca A. Lotta, Theodore G. Drivas, Penn Medicine BioBank¶, Ha My T. Vy, Girish N. Nadkarni, Laura K. Wiley, Melissa P. Wilson, Christopher R. Gignoux, Humaira Rasheed, Laurent F. Thomas, Bjørn Olav Åsvold, Ben Brumpton, Stein Hallan, Kristian Hveem, Jie Zheng, Jacklyn N. Hellwege, Matthew Zawistowski, Sebastian Zöllner, Nora Franceschini, Hailong Hu, Jianfu Zhou, Krzysztof Kiryluk, Marylyn D. Ritchie, Matthew Palmer, Todd L. Edwards, Benjamin F. Voight, Adriana M. Hung, Katalin Suszták, Aris Baras, Gonçalo Abecasis, Adolfo Ferrando, Giovanni Coppola, Andrew Deubler, Aris Economides, Luca A Lotta, John D. Overton, Jeffrey G Reid, Alan R. Shuldiner, Katherine Siminovitch, Jason Portnoy, Marcus B Jones, Lyndon J. Mitnaul, Alison Fenney, Jonathan Marchini, Manuel Allen Revez Ferreira, Maya Ghoussaini, Mona Nafde, William Salerno, John D. Overton, Christina Beechert, Erin Fuller, Laura M. Cremona, Eugene Kalyuskin, Hang Du, Caitlin Forsythe, Zhenhua Gu, Kristy Guevara, Michael Lattari, Alexander Lopez, Kia Manoochehri, Prathyusha Challa, Manasi Pradhan, Raymond Reynoso, Ricardo Schiavo, Maria Sotiropoulos Padilla, Chenggu Wang, Sarah E. Wolf, Hang Du, Kristy Guevara, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Justin Mower, Mudasar Sarwar, Deepika Sharma, Sean Yu, Aaron Zhang, Muhammad Aqeel, Jeffrey G Reid, Mona Nafde, Manan Goyal, George Mitra, Sanjay Sreeram, Rouel Lanche, Vrushali Mahajan, Sai Lakshmi Vasireddy, Gisu Eom, Krishna Pawan Punuru, Sujit Gokhale, Benjamin Sultan, Pooja Mule, Eliot Austin, Xiaodong Bai, Lance Zhang, Sean O’Keeffe, Razvan Panea, Evan Edelstein, Ayesha Rasool, William Salerno, Evan K. Maxwell, Boris Boutkov, Alexander Gorovits, Ju Guan, Lukas Habegger, Alicia Hawes, Olga Krasheninina, Samantha Zarate, Adam J. Mansfield, Lukas Habegger, Gonçalo Abecasis, Joshua Backman, Kathy Burch, Adrián I. Campos, Liron Ganel, Sheila M. Gaynor, Benjamin Geraghty, Arkopravo Ghosh, Salvador Romero Martinez, Christopher E. Gillies, Lauren Gurski, Joseph Herman, Eric Jorgenson, Tyler Joseph, Michael D. Kessler, Jack A. Kosmicki, Adam E. Locke, Priyanka Nakka, Jonathan Marchini, Karl Landheer, Olivier Delaneau, Maya Ghoussaini, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Aditeya Pandey, Anita Pandit, Jonathan Ross, Carlo Sidore, Eli Stahl, Timothy Thornton, Sailaja Vedantam, Rujin Wang, Kuan-Han Wu, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Yuxin Zou, Jingning Zhang, Kyoko Watanabe, Mira Tang, Frank R. Wendt, Suganthi Balasubramanian, Suying Bao, Kathie Sun, Chuanyi Zhang, Adolfo Ferrando, Giovanni Coppola, Luca A Lotta, Alan R. Shuldiner, Katherine Siminovitch, Brian D. Hobbs, Jon Silver, William Palmer, Rita Guerreiro, Amit D. Joshi, Antoine Baldassari, Cristen J. Willer, Sarah E. Graham, Ernst Mayerhofer, Erola Pairó Castiñeira, Mary E. Haas, Niek Verweij, George Hindy, Jonas Bovijn, Tanima De, Parsa Akbari, Luanluan Sun, Olukayode Sosina, Arthur Gilly, Peter Dornbos, Juan Rodriguez-Flores, Moeen Riaz, Manav Kapoor, Gannie Tzoneva, Momodou W. Jallow, Anna Alkelai, Ariane Ayer, Veera M. Rajagopal, Sahar Gelfman, Vijay Kumar, Jacqueline M. Otto, Neelroop Parikshak, Ayşegül Güvenek, José Brás, Silvia Álvarez, Jessie Brown, Jing He, Hossein Khiabanian, Joana Revez, Kimberly Skead, Valentina A. Zavala, Jae Soon Sul, Lei Chen, Sam Choi, Amy Damask, Nan Lin, Charles Paulding, Marcus B Jones, Esteban Chen, Michelle G. LeBlanc, Jason Mighty, Jennifer Rico‐Varela, Nirupama Nishtala, Nadia A. Rana, Jaimee Hernandez, Alison Fenney, Randi Schwartz, Jody Hankins, Anna Han, Samuel F. M. Hart, Ann Perez-Beals, Gina Solari, Johannie Rivera-Picart, Michelle Pagan, Sunilbe Siceron, Adam H. Buchanan, David J. Carey, Christa Lese Martin, Michelle N. Meyer, Kyle Retterer, David D.K. Rolston, Daniel J. Rader, Marylyn D. Ritchie, JoEllen Weaver, Nawar Naseer, Giorgio Sirugo, Afiya Poindexter, Yi-An Ko, Kyle P. Nerz, Meghan Livingstone, Fred Vadivieso, Stephanie DerOhannessian, Teo Tran, Julia Stephanowski, Salma Santos, Ned Haubein, Joseph Dunn, Anurag Verma, Colleen Morse Kripke, Marjorie Risman, Renae Judy, Colin Wollack, Shefali S. Verma, Scott M. Damrauer, Yuki Bradford, Scott Dudek, Theodore G. Drivas · 发表于：Science · 年份：2025 · DOI：10.1126/science.adp4753 · 被引用次数：57 · 研究领域：Genetic Associations and Epidemiology、Renal Diseases and Glomerulopathies、Genetic Syndromes and Imprinting

Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on allele-specific gene expression and regulatory circuitries in more than 700 human kidneys and 237,000 cells. We found 1363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, we present the "Kidney Disease Genetic Scorecard" for prioritizing potentially causal genes, cell types, and druggable targets for kidney disease.