Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants
IF 45.8 1区 综合性期刊Q1 MULTIDISCIPLINARY SCIENCESSciencePub Date : 2025-02-07
Hongbo Liu, Amin Abedini, Eunji Ha, Ziyuan Ma, Xin Sheng, Bernhard Dumoulin, Chengxiang Qiu, Tamas Aranyi, Shen Li, Nicole Dittrich, 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 Kottyan, John J. Connolly, Gail P. Jarvik, Chunhua Weng, Ning Shang, Joanne B. Cole, Josep M. Mercader, Ravi Mandla, Timothy D. Majarian, Jose C. Florez, Mary E. Haas, Luca A. Lotta, Regeneron Genetics Center, GHS-RGC DiscovEHR Collaboration, 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 M. Brumpton, Stein I. 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 Susztak
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引用次数: 0
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.
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