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

• 成果类型: Article
• 署名作者: Liu, Hongbo; Abedini, Amin; Ha, Eunji; Ma, Ziyuan; Sheng, Xin; Dumoulin, Bernhard; Qiu, Chengxiang; Aranyi, Tamas; Li, Shen; Dittrich, Nicole; Chen, Hua-Chang; Tao, Ran; Tarng, Der-Cherng; Hsieh, Feng-Jen; Chen, Shih-Ann; Yang, Shun-Fa; Lee, Mei-Yueh; Kwok, Pui-Yan; Wu, Jer-Yuarn; Chen, Chien-Hsiun; Khan, Atlas; Limdi, Nita A.; Wei, Wei-Qi; Walunas, Theresa L.; Karlson, Elizabeth W.; Kenny, Eimear E.; Luo, Yuan; Kottyan, Leah; Connolly, John J.; Jarvik, Gail P.; Weng, Chunhua; Shang, Ning; Cole, Joanne B.; Mercader, Josep M.; Mandla, Ravi; Majarian, Timothy D.; Florez, Jose C.; Haas, Mary E.; Lotta, Luca A.; Drivas, Theodore G.; Vy, Ha My T.; Nadkarni, Girish N.; Wiley, Laura K.; Wilson, Melissa P.; Gignoux, Christopher R.; Rasheed, Humaira; Thomas, Laurent F.; Asvold, Bjrn Olav; Brumpton, Ben M.; Hallan, Stein I.; Hveem, Kristian; Zheng, Jie; Hellwege, Jacklyn N.; Zawistowski, Matthew; Zoellner, Sebastian; Franceschini, Nora; Hu, Hailong; Zhou, Jianfu; Kiryluk, Krzysztof; Ritchie, Marylyn D.; Palmer, Matthew; Edwards, Todd L.; Voight, Benjamin F.; Hung, Adriana M.; Susztak, Katalin
• 署名单位: University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Zhejiang University; Liangzhu Laboratory; HUN-REN; HUN-REN Research Centre for Natural Sciences; Semmelweis University; Universidade Federal de Sao Paulo (UNIFESP); Vanderbilt University; Vanderbilt University; National Yang Ming Chiao Tung University; Taipei Veterans General Hospital; Academia Sinica - Taiwan; Taichung Veterans General Hospital; National Chung Hsing University; Taipei Veterans General Hospital; National Yang Ming Chiao Tung University; Chung Shan Medical University; Chung Shan Medical University; Chung Shan Medical University Hospital; Kaohsiung Medical University; Kaohsiung Medical University Hospital; Kaohsiung Medical University; Kaohsiung Medical University; University of California System; University of California San Francisco; Columbia University; University of Alabama System; University of Alabama Birmingham; Vanderbilt University; Northwestern University; Feinberg School of Medicine; Northwestern University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Northwestern University; Feinberg School of Medicine; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Washington; University of Washington Seattle; Columbia University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; University of Colorado System; University of Colorado Anschutz Medical Campus; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of Pennsylvania; Vertex Pharmaceuticals; Regeneron; University of Pennsylvania; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; University of Colorado System; University of Colorado Anschutz Medical Campus; University of Colorado System; University of Colorado Anschutz Medical Campus; Norwegian University of Science & Technology (NTNU); University of Bristol; Norwegian University of Science & Technology (NTNU); Norwegian University of Science & Technology (NTNU); Norwegian University of Science & Technology (NTNU); Norwegian University of Science & Technology (NTNU); Norwegian University of Science & Technology (NTNU); Norwegian University of Science & Technology (NTNU); Shanghai Jiao Tong University; Shanghai Jiao Tong University; Vanderbilt University; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of North Carolina; University of North Carolina Chapel Hill; University of Pennsylvania; University of Pennsylvania; Vanderbilt University; University of Pennsylvania; University of Pennsylvania; Vanderbilt University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Tennessee Valley Healthcare System; University of Rochester
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11158
• DOI: 10.1126/science.adp4753
• 发表日期: 2025-02-07
• 关键词: genome-wide association; genotype imputation; web server; count data; DISCOVERY; disease; generation; regression; eqtl; transcriptome

摘要

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.