Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants
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.
Authors
- Matthew Palmer (ORCID: https://orcid.org/0000-0002-0534-4289)
- Tyler Joseph (ORCID: https://orcid.org/0000-0001-6013-7285)
- Erin Fuller (ORCID: https://orcid.org/0000-0003-4923-6367)
- Anna Alkelai (ORCID: https://orcid.org/0000-0001-6314-8502)
- Vijay Kumar (ORCID: https://orcid.org/0000-0002-2081-3485)
- Rita Guerreiro (ORCID: https://orcid.org/0000-0001-5879-3486)
- JoEllen Weaver (ORCID: https://orcid.org/0000-0002-0596-0188)
- Jessie A. Brown (ORCID: https://orcid.org/0000-0003-2396-5393)
- Razvan Panea
- Humaira Rasheed (ORCID: https://orcid.org/0000-0002-3331-5864)
- Lauren Gurski
- Gannie Tzoneva (ORCID: https://orcid.org/0000-0001-5784-7796)
- Deepika Sharma (ORCID: https://orcid.org/0000-0002-5840-8266)
- Niek Verweij (ORCID: https://orcid.org/0000-0002-4303-7685)
- Rouel Lanche
- Caitlin Forsythe
- Benjamin Sultan (ORCID: https://orcid.org/0000-0003-0416-0338)
- Matthew Zawistowski (ORCID: https://orcid.org/0000-0002-3005-083X)
- Chengxiang Qiu (ORCID: https://orcid.org/0000-0002-6346-8669)
- David D.K. Rolston (ORCID: https://orcid.org/0000-0002-8707-949X)
- Nirupama Nishtala
- William J. Salerno (ORCID: https://orcid.org/0000-0003-2975-4108)
- Stein Hallan (ORCID: https://orcid.org/0000-0002-9045-3569)
- Alan R. Shuldiner (ORCID: https://orcid.org/0000-0001-9921-4305)
- Muhammad Aqeel (ORCID: https://orcid.org/0000-0003-0690-4783)
- Pasquale Mulé
- Veera M. Rajagopal (ORCID: https://orcid.org/0000-0002-5236-168X)
- Alexander Gorovits (ORCID: https://orcid.org/0000-0002-5067-6557)
- Rujin Wang
- Ju Guan (ORCID: https://orcid.org/0000-0001-7971-8514)
- Blair Zhang
- Anurag Verma (ORCID: https://orcid.org/0000-0002-5063-9107)
- Alexander Lopez (ORCID: https://orcid.org/0000-0002-4769-5650)
- Timothy D. Majarian (ORCID: https://orcid.org/0000-0002-0482-1602)
- Silvia Álvarez (ORCID: https://orcid.org/0000-0003-0664-650X)
- Brian D. Hobbs (ORCID: https://orcid.org/0000-0001-9564-0745)
- George Mitra
- Laura K. Wiley (ORCID: https://orcid.org/0000-0001-6681-9754)
- Manav Kapoor (ORCID: https://orcid.org/0000-0001-6682-940X)
- Zhenhua Gu
- Hossein Khiabanian (ORCID: https://orcid.org/0000-0003-1446-4394)
- Kathy Burch
- Kimberly Skead (ORCID: https://orcid.org/0000-0001-5652-1399)
- Jonas Bovijn (ORCID: https://orcid.org/0000-0001-7436-4446)
- Ned Haubein
- Feng‐Jen Hsieh
- Arkopravo Ghosh (ORCID: https://orcid.org/0000-0003-2342-1441)
- Suying Bao (ORCID: https://orcid.org/0000-0002-6220-0257)
- Melissa P. Wilson (ORCID: https://orcid.org/0000-0001-9176-3131)
- Jingning Zhang (ORCID: https://orcid.org/0000-0003-4698-0676)
- Atlas Khan (ORCID: https://orcid.org/0000-0002-6651-2725)
- Jacqueline M. Otto (ORCID: https://orcid.org/0000-0002-4583-2076)
- Kyoko Watanabe (ORCID: https://orcid.org/0000-0002-3303-8860)
- Pui–Yan Kwok (ORCID: https://orcid.org/0000-0002-5087-3059)
- Charles Paulding (ORCID: https://orcid.org/0000-0002-7918-3561)
- Carlo Sidore (ORCID: https://orcid.org/0000-0001-7504-7477)
- Leah C. Kottyan (ORCID: https://orcid.org/0000-0003-3979-2220)
- Nicole Dittrich Hosni (ORCID: https://orcid.org/0000-0001-5546-3836)
- Sahar Gelfman (ORCID: https://orcid.org/0000-0002-4727-7862)
- John D. Overton (ORCID: https://orcid.org/0000-0001-7650-8634)
- Jennifer Rico‐Varela
- Mary E. Haas (ORCID: https://orcid.org/0000-0002-2816-9268)
- Laura M. Cremona
- Giorgio Sirugo (ORCID: https://orcid.org/0000-0002-0244-6343)
- Ziyuan Ma (ORCID: https://orcid.org/0000-0002-1512-8993)
- Marjorie Risman
- Olga Krasheninina (ORCID: https://orcid.org/0000-0001-7317-6232)
- Olivier Delaneau (ORCID: https://orcid.org/0000-0002-3906-8446)
- Aris Baras (ORCID: https://orcid.org/0000-0002-6830-3396)
- Christina Beechert
- Benjamin Franklin Voight (ORCID: https://orcid.org/0000-0002-6205-9994)
- Xiaodong Bai (ORCID: https://orcid.org/0000-0002-6363-2764)
- George Hindy (ORCID: https://orcid.org/0000-0002-7257-9299)
- Xin Sheng (ORCID: https://orcid.org/0000-0002-3620-3577)
- Lei Chen (ORCID: https://orcid.org/0000-0003-4346-713X)
- Randi Schwartz
- Joseph Dunn
- Kyong‐Mi Chang (ORCID: https://orcid.org/0000-0001-6811-9364)
- Hailong Hu (ORCID: https://orcid.org/0000-0002-0565-7752)
- Nan Lin (ORCID: https://orcid.org/0000-0002-4635-3966)
- Antoine Baldassari (ORCID: https://orcid.org/0000-0003-4818-2512)
- Kyle Retterer (ORCID: https://orcid.org/0000-0001-5252-2001)
- Teo Tran
- Liron Ganel (ORCID: https://orcid.org/0000-0002-8762-622X)
- Olukayode Sosina
- Sujit Gokhale
- Tamás Arányi (ORCID: https://orcid.org/0000-0002-2087-6275)
- Renae Judy (ORCID: https://orcid.org/0000-0003-0915-2222)
- Adam E. Locke (ORCID: https://orcid.org/0000-0001-6227-198X)
- Anthony Marcketta (ORCID: https://orcid.org/0000-0001-6356-3343)
- Chien-Hsiun Chen (ORCID: https://orcid.org/0000-0003-2140-033X)
- Sean O’Keeffe (ORCID: https://orcid.org/0000-0002-0971-1525)
- Sarah E. Graham (ORCID: https://orcid.org/0000-0003-1271-2489)
- Michael D. Kessler (ORCID: https://orcid.org/0000-0003-1258-5221)
- Karl Landheer (ORCID: https://orcid.org/0000-0001-5012-3007)
- Luca A. Lotta (ORCID: https://orcid.org/0000-0002-2619-5956)
- Andrey Ziyatdinov (ORCID: https://orcid.org/0000-0002-6400-6095)
- Amit D. Joshi (ORCID: https://orcid.org/0000-0001-7581-6934)
- Ernst Mayerhofer (ORCID: https://orcid.org/0000-0001-8902-4209)
- Hongbo Liu (ORCID: https://orcid.org/0000-0002-0733-8616)
- Arthur Gilly (ORCID: https://orcid.org/0000-0002-3190-4358)
- Eric Jorgenson (ORCID: https://orcid.org/0000-0002-5829-8191)
- Yuxin Zou (ORCID: https://orcid.org/0000-0001-9816-5847)
- Benjamin Geraghty (ORCID: https://orcid.org/0000-0002-6756-8528)
- Eimear E. Kenny (ORCID: https://orcid.org/0000-0001-9198-759X)
- Anita Pandit (ORCID: https://orcid.org/0000-0001-5474-0993)
- Girish N. Nadkarni (ORCID: https://orcid.org/0000-0001-6319-4314)
- José C. Florez (ORCID: https://orcid.org/0000-0002-1730-9325)
- Esteban Chen
- Ning Shang (ORCID: https://orcid.org/0000-0002-2510-4856)
- Chenggu Wang
- Moeen Riaz (ORCID: https://orcid.org/0000-0001-5858-3788)
- Yi-An Ko (ORCID: https://orcid.org/0000-0002-0066-358X)
- Ha My T. Vy (ORCID: https://orcid.org/0000-0002-5117-3740)
- Jason Mighty
- Joseph Herman (ORCID: https://orcid.org/0000-0003-4561-6151)
- Colleen Morse Kripke (ORCID: https://orcid.org/0009-0007-3117-685X)
- Chunhua Weng (ORCID: https://orcid.org/0000-0002-0761-3104)
- Valentina A. Zavala (ORCID: https://orcid.org/0000-0003-2040-1760)
- Scott Dudek (ORCID: https://orcid.org/0000-0003-2904-3824)
- Michelle Pagan
- Nilanjana Banerjee (ORCID: https://orcid.org/0000-0001-8022-8598)
- Sailaja Vedantam (ORCID: https://orcid.org/0000-0003-3892-7461)
- Frank R. Wendt (ORCID: https://orcid.org/0000-0002-2108-6822)
- Aaron Zhang (ORCID: https://orcid.org/0000-0003-2788-5008)
- Amin Abedini (ORCID: https://orcid.org/0000-0002-8875-0070)
- Boris Boutkov (ORCID: https://orcid.org/0000-0002-9134-0769)
- Jonathan Ross (ORCID: https://orcid.org/0000-0002-4193-6919)
- Mei‐Yueh Lee (ORCID: https://orcid.org/0000-0001-8950-064X)
- Jianfu Zhou (ORCID: https://orcid.org/0000-0002-1996-9503)
- Tanima De (ORCID: https://orcid.org/0000-0001-9240-3744)
- Dadong Li
- Nawar Naseer (ORCID: https://orcid.org/0000-0002-0700-7155)
- Katalin Suszták (ORCID: https://orcid.org/0000-0002-1005-3726)
- Sameer Malhotra
- Suganthi Balasubramanian (ORCID: https://orcid.org/0000-0003-2243-5948)
- Arden Moscati
- Joanne B. Cole (ORCID: https://orcid.org/0000-0001-9520-2788)
- John J. Connolly (ORCID: https://orcid.org/0000-0003-4396-1226)
- Cristen J. Willer (ORCID: https://orcid.org/0000-0001-5645-4966)
- Momodou W. Jallow (ORCID: https://orcid.org/0000-0001-9748-538X)
- Sean Yu (ORCID: https://orcid.org/0000-0002-1434-8556)
- Lance Zhang
- Daniel James Rader (ORCID: https://orcid.org/0000-0002-9245-9876)
- Samantha Zarate (ORCID: https://orcid.org/0000-0001-5570-2059)
- Joelle Mbatchou (ORCID: https://orcid.org/0000-0002-2245-3743)
- Kathie Sun (ORCID: https://orcid.org/0000-0003-1200-452X)
- Sheila M. Gaynor (ORCID: https://orcid.org/0000-0002-7869-5223)
- Bjørn Olav Åsvold (ORCID: https://orcid.org/0000-0003-3837-2101)
- Maya Ghoussaini (ORCID: https://orcid.org/0000-0002-2415-2143)
- Samuel F. M. Hart (ORCID: https://orcid.org/0000-0002-5068-2199)
- Anna Han (ORCID: https://orcid.org/0000-0001-8180-6214)
- Joana Revez (ORCID: https://orcid.org/0000-0003-3204-5396)
- Eli Stahl
- Jie Zheng (ORCID: https://orcid.org/0000-0002-6623-6839)
- Aditeya Pandey (ORCID: https://orcid.org/0000-0003-3216-9997)
- Theodore G. Drivas (ORCID: https://orcid.org/0000-0002-8717-0111)
- Prathyusha Challa
- José Brás (ORCID: https://orcid.org/0000-0001-8186-0333)
- Manasi Pradhan
- Stephanie DerOhannessian
- Sebastian Zöllner (ORCID: https://orcid.org/0000-0001-7362-156X)
- Kuan-Han Wu (ORCID: https://orcid.org/0000-0001-7872-3485)
- Michael Lattari
- Amelia Averitt (ORCID: https://orcid.org/0000-0003-1221-1123)
- Erola Pairó Castiñeira
- Jack A. Kosmicki (ORCID: https://orcid.org/0000-0003-1252-6192)
- Colin Wollack
- Manisha Goyal (ORCID: https://orcid.org/0000-0001-7064-7617)
- Michelle N. Meyer (ORCID: https://orcid.org/0000-0001-5497-8803)
- Neelroop Parikshak (ORCID: https://orcid.org/0000-0003-2027-1871)
- Adam H. Buchanan (ORCID: https://orcid.org/0000-0002-6518-2453)
- Ariane Ayer
- Luanluan Sun
- Ben Michael Brumpton (ORCID: https://orcid.org/0000-0002-3058-1059)
- William Hunt Palmer (ORCID: https://orcid.org/0000-0002-0348-6339)
- Marylyn DeRiggi Ritchie (ORCID: https://orcid.org/0000-0002-1208-1720)
- Laurent F. Thomas (ORCID: https://orcid.org/0000-0003-0548-2486)
- Elizabeth W. Karlson (ORCID: https://orcid.org/0000-0001-5455-7443)
- Scott M. Damrauer (ORCID: https://orcid.org/0000-0001-8009-1632)
- Priyanka Nakka (ORCID: https://orcid.org/0000-0002-6572-0338)
- Bernhard Dumoulin (ORCID: https://orcid.org/0000-0003-4728-4250)
- Evan K. Maxwell (ORCID: https://orcid.org/0000-0002-7325-7531)
- Christopher R. Gignoux (ORCID: https://orcid.org/0000-0001-9728-6567)
- Theresa L. Walunas (ORCID: https://orcid.org/0000-0002-7653-3650)
- Parsa Akbari (ORCID: https://orcid.org/0000-0001-9210-4760)
- Joshua Backman (ORCID: https://orcid.org/0000-0001-7262-0880)
- Christopher E. Gillies (ORCID: https://orcid.org/0000-0002-5290-3880)
- Michelle G. LeBlanc (ORCID: https://orcid.org/0000-0001-5039-5491)
- Mona Nafde
- Christa Lese Martin (ORCID: https://orcid.org/0000-0002-8071-5780)
- Peter Dornbos
- Ravi Mandla (ORCID: https://orcid.org/0000-0002-0782-0138)
- Sanjay Sreeram
- Alison Fenney
- Jody Hankins
- Raymond Reynoso
- Justin Mower
- Evan Edelstein
- Afiya Poindexter
- Fred Vadivieso
- Krishna Pawan Punuru
- Sunilbe Siceron
- Ann Perez-Beals
- Gina Solari
- Johannie Rivera-Picart
- Julia Stephanowski
- Kyle P. Nerz
- Ran Tao (ORCID: https://orcid.org/0000-0001-5461-5930)
- Adrián I. Campos (ORCID: https://orcid.org/0000-0003-3468-8619)
- Bin Ye (ORCID: https://orcid.org/0000-0001-8127-1707)
- Mira Tang
- Chuanyi Zhang
- Eunji Ha (ORCID: https://orcid.org/0000-0001-8618-8347)
- Gail P. Jarvik
- Salma Santos
- Nora Franceschini
- Li Shen (ORCID: https://orcid.org/0009-0006-2736-0892)
- Shih‐Ann Chen (ORCID: https://orcid.org/0000-0001-9085-0823)
- Jing He (ORCID: https://orcid.org/0000-0003-0816-3843)
- David J. Carey
- Todd L. Edwards
- Adam J. Mansfield
- Manuel Allen Revez Ferreira
- Juan Rodriguez-Flores
- Nita A. Limdi
- Ayesha Rasool
- Katherine Siminovitch
- Jer-Yuarn Wu
- Sarah E. Wolf
- Timothy Thornton
- Maria Sotiropoulos Padilla
- Jacklyn N. Hellwege
- Jason Portnoy
- Andrew Deubler
- Adriana M. Hung
- Giovanni Coppola
- Jonathan Marchini
- Wei-Qi Wei
- Shefali Setia-Verma (ORCID: https://orcid.org/0000-0002-0766-1253)
- Gisu Eom
- Yuan Luo
- Mudasar Sarwar
- Alicia Hawes
- Amy Damask (ORCID: https://orcid.org/0000-0003-4995-908X)
- Kristian Hveem
- Lukas Habegger
- Sam Choi
- Jaimee Hernandez
- Vrushali Mahajan
- Nadia A. Rana
- Lyndon J. Mitnaul
- Der-Cherng Tarng
- Yuki Bradford
- Aris Economides
- Josep M. Mercader
- Kia Manoochehri
- Eliot Austin
- Ricardo Schiavo
- Meghan Livingstone
- Shun-Fa Yang
- Salvador Romero Martinez
- Jae Soon Sul
- Aysegul Guvenek
- Krzysztof Kiryluk
- Hang Du
- Marylyn D. Ritchie
- Jon Silver
- Sai Lakshmi Vasireddy
- Eugene Kalyuskin
Institutions
- Semmelweis University (HU)
- Broad Institute (US)
- Northwestern University (US)
- University of North Carolina at Chapel Hill (US)
- Brigham and Women's Hospital (US)
- Cincinnati Children's Hospital Medical Center (US)
- Boston Children's Hospital (US)
- Children's Hospital of Philadelphia (US)
- Harvard University (US)
- National Yang Ming Chiao Tung University (TW)
- Kaohsiung Medical University (TW)
- National Chung Hsing University (TW)
- University of California, San Francisco (US)
- Shanghai Jiao Tong University (CN)
- Regeneron (United States) (US)
- Norwegian University of Science and Technology (NO)
- University of Michigan (US)
- Hospital of the University of Pennsylvania (US)
- Ruijin Hospital (CN)
- University of Washington Medical Center (US)
- Kaohsiung Medical University Chung-Ho Memorial Hospital (TW)
- Taipei Veterans General Hospital (TW)
- University of Alabama at Birmingham (US)
- University of Bristol (GB)
- Massachusetts General Hospital (US)
- Taichung Veterans General Hospital (TW)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- VA Tennessee Valley Healthcare System (US)
- St Olav's University Hospital (NO)
- Chung Shan Medical University Hospital (TW)
- Children's Hospital of Zhejiang University (CN)
- Translational Therapeutics (United States) (US)
- Penn Center for AIDS Research (US)
- Statistical Research (United States) (US)
- Genomic Health (United States) (US)
- University of Colorado Anschutz Medical Campus (US)
- Vertex Pharmaceuticals (United States) (US)
- Zhejiang University (CN)
- Columbia University (US)
- University of Pennsylvania (US)
- HUN-REN Research Centre for Natural Sciences (HU)
- Universidade Federal de São Paulo (BR)
- Vanderbilt University Medical Center (US)
- Chung Shan Medical University (TW)
- University of Colorado Denver (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1126/science.adp4753
- Citations
- 30
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 54.52
Funders
- Massachusetts General Hospital
- Gilead Sciences
- Children's Hospital of Philadelphia
- Vanderbilt University
- University of Pennsylvania
- Northwestern University
- Cincinnati Children's Hospital Medical Center
- University of Washington
- Norges Teknisk-Naturvitenskapelige Universitet
- Regeneron Pharmaceuticals
- Vanderbilt University Medical Center
- Georgia Clinical and Translational Science Alliance
- University of Pennsylvania Health System
- National Natural Science Foundation of China
- Novo Nordisk
- Helse Midt-Norge
- Nemzeti Kutatási Fejlesztési és Innovációs Hivatal
- National Institutes of Health
- Perelman School of Medicine, University of Pennsylvania
- Medical School, University of Michigan
- Norwegian Institute of Public Health
- National Human Genome Research Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Advancing Translational Sciences