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