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

• DOI: 10.1126/science.adp4753
• Publication Date: 2025-02-06T18:59:31Z
• Authors: 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; ; ; Theodore G. Drivas; ; Ha My T. Vy; Girish N. Nadkarni; Laura K. Wiley; Melissa P. Wilson; Christopher R. Gi...; 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; Aris Baras; Gonçalo Abecasis; Adolfo Ferrando; Giovanni Coppola; Andrew Deubler; Aris Economides; Luca A Lotta; John D Overton; Jeffrey G Reid; Alan Shuldiner; Katherine Siminov...; Jason Portnoy; Marcus B Jones; Lyndon Mitnaul; Alison Fenney; Jonathan Marchini; Manuel Allen Reve...; 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 Sotiropoulo...; 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 Vasir...; 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; Adrian Campos; Liron Ganel; Sheila Gaynor; Benjamin Geraghty; Arkopravo Ghosh; Salvador Romero M...; Christopher Gillies; Lauren Gurski; Joseph Herman; Eric Jorgenson; Tyler Joseph; Michael Kessler; Jack Kosmicki; Adam 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 Wendt; Suganthi Balasubr...; Suying Bao; Kathie Sun; Chuanyi Zhang; Adolfo Ferrando; Giovanni Coppola; Luca A Lotta; Alan Shuldiner; Katherine Siminov...; Brian Hobbs; Jon Silver; William Palmer; Rita Guerreiro; Amit Joshi; Antoine Baldassari; Cristen Willer; Sarah Graham; Ernst Mayerhofer; Erola Pairo Casti...; Mary Haas; Niek Verweij; George Hindy; Jonas Bovijn; Tanima De; Parsa Akbari; Luanluan Sun; Olukayode Sosina; Arthur Gilly; Peter Dornbos; Juan Rodriguez-Fl...; Moeen Riaz; Manav Kapoor; Gannie Tzoneva; Momodou W Jallow; Anna Alkelai; Ariane Ayer; Veera Rajagopal; Sahar Gelfman; Vijay Kumar; Jacqueline Otto; Neelroop Parikshak; Aysegul Guvenek; Jose Bras; Silvia Alvarez; Jessie Brown; Jing He; Hossein Khiabanian; Joana Revez; Kimberly Skead; Valentina 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 Rana; Jaimee Hernandez; Alison Fenney; Randi Schwartz; Jody Hankins; Anna Han; Samuel Hart; Ann Perez-Beals; Gina Solari; Johannie Rivera-P...; Michelle Pagan; Sunilbe Siceron; Adam Buchanan; David J. Carey; Christa L. Martin; Michelle Meyer; Kyle Retterer; David 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 DerOhan...; 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 M. Dudek; Theodore G. Drivas

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.