Huijun Qian1, Madeline H Kowalski1, Holly J Kramer2, Ran Tao3,4, James P Lash5, Adrienne M Stilp6, Jianwen Cai2, Yun Li7, Nora Franceschini8. 1. Department of Statistics and Operations Research (H.Q., M.H.K.), University of North Carolina, Chapel Hill. 2. Departments of Biostatistics (J.C.), University of North Carolina, Chapel Hill. 3. Department of Biostatistics (R.T.), Vanderbilt University Medical Center, Nashville, TN. 4. Vanderbilt Genetics Institute (R.T.), Vanderbilt University Medical Center, Nashville, TN. 5. Division of Nephrology, Department of Medicine, University of Illinois, Chicago, IL (J.P.L.). 6. Department of Biostatistics, University of Washington, Seattle (A.M.S.). 7. Department of Genetics (Y.L.), University of North Carolina, Chapel Hill. 8. Department of Epidemiology (N.F.), University of North Carolina, Chapel Hill.
Abstract
BACKGROUND: Genetic factors that influence kidney traits have been understudied for low-frequency and ancestry-specific variants. METHODS: This study used imputed whole-genome sequencing from the Trans-Omics for Precision Medicine project to identify novel loci for estimated glomerular filtration rate and urine albumin-to-creatinine ratio in up to 12 207 Hispanics/Latinos. Replication was performed in the Women's Health Initiative and the UK Biobank when variants were available. RESULTS: Two low-frequency intronic variants were associated with estimated glomerular filtration rate (rs58720902 at AQR, minor allele frequency=0.01, P=1.6×10-8) or urine albumin-to-creatinine ratio (rs527493184 at ZBTB16, minor allele frequency=0.002, P=1.1×10-8). An additional variant at PRNT (rs2422935, minor allele frequency=0.54, P=2.89×10-8) was significantly associated with estimated glomerular filtration rate in meta-analysis with replication samples. We also identified 2 known loci for urine albumin-to-creatinine ratio (BCL2L11 rs116907128, P=5.6×10-8 and HBB rs344, P=9.3×10-11) and validated 8 loci for urine albumin-to-creatinine ratio previously identified in the UK Biobank. CONCLUSIONS: Our study shows gains in gene discovery when using dense imputation from multi-ethnic whole-genome sequencing data in admixed Hispanics/Latinos. It also highlights limitations in genetic research of kidney traits, including the lack of suitable replication samples for variants that are more common in non-European ancestry and those at low frequency in populations.
BACKGROUND: Genetic factors that influence kidney traits have been understudied for low-frequency and ancestry-specific variants. METHODS: This study used imputed whole-genome sequencing from the Trans-Omics for Precision Medicine project to identify novel loci for estimated glomerular filtration rate and urine albumin-to-creatinine ratio in up to 12 207 Hispanics/Latinos. Replication was performed in the Women's Health Initiative and the UK Biobank when variants were available. RESULTS: Two low-frequency intronic variants were associated with estimated glomerular filtration rate (rs58720902 at AQR, minor allele frequency=0.01, P=1.6×10-8) or urine albumin-to-creatinine ratio (rs527493184 at ZBTB16, minor allele frequency=0.002, P=1.1×10-8). An additional variant at PRNT (rs2422935, minor allele frequency=0.54, P=2.89×10-8) was significantly associated with estimated glomerular filtration rate in meta-analysis with replication samples. We also identified 2 known loci for urine albumin-to-creatinine ratio (BCL2L11 rs116907128, P=5.6×10-8 and HBB rs344, P=9.3×10-11) and validated 8 loci for urine albumin-to-creatinine ratio previously identified in the UK Biobank. CONCLUSIONS: Our study shows gains in gene discovery when using dense imputation from multi-ethnic whole-genome sequencing data in admixed Hispanics/Latinos. It also highlights limitations in genetic research of kidney traits, including the lack of suitable replication samples for variants that are more common in non-European ancestry and those at low frequency in populations.
Entities:
Keywords:
genes; genetic variation; genetics; genome-wide association study; kidney; population
Authors: H C Gerstein; J F Mann; Q Yi; B Zinman; S F Dinneen; B Hoogwerf; J P Hallé; J Young; A Rashkow; C Joyce; S Nawaz; S Yusuf Journal: JAMA Date: 2001-07-25 Impact factor: 56.272
Authors: Paul D Sorlie; Larissa M Avilés-Santa; Sylvia Wassertheil-Smoller; Robert C Kaplan; Martha L Daviglus; Aida L Giachello; Neil Schneiderman; Leopoldo Raij; Gregory Talavera; Matthew Allison; Lisa Lavange; Lloyd E Chambless; Gerardo Heiss Journal: Ann Epidemiol Date: 2010-08 Impact factor: 3.797
Authors: Ana C Ricardo; Michael F Flessner; John H Eckfeldt; Paul W Eggers; Nora Franceschini; Alan S Go; Nathan M Gotman; Holly J Kramer; John W Kusek; Laura R Loehr; Michal L Melamed; Carmen A Peralta; Leopoldo Raij; Sylvia E Rosas; Gregory A Talavera; James P Lash Journal: Clin J Am Soc Nephrol Date: 2015-09-28 Impact factor: 8.237
Authors: Brad C Astor; Kunihiro Matsushita; Ron T Gansevoort; Marije van der Velde; Mark Woodward; Andrew S Levey; Paul E de Jong; Josef Coresh; Brad C Astor; Kunihiro Matsushita; Ron T Gansevoort; Marije van der Velde; Mark Woodward; Andrew S Levey; Paul E de Jong; Josef Coresh; Meguid El-Nahas; Kai-Uwe Eckardt; Bertram L Kasiske; Jackson Wright; Larry Appel; Tom Greene; Adeera Levin; Ognjenka Djurdjev; David C Wheeler; Martin J Landray; John N Townend; Jonathan Emberson; Laura E Clark; Alison Macleod; Angharad Marks; Tariq Ali; Nicholas Fluck; Gordon Prescott; David H Smith; Jessica R Weinstein; Eric S Johnson; Micah L Thorp; Jack F Wetzels; P J Blankestijn; A D van Zuilen; Vandana Menon; Mark Sarnak; Gerald Beck; Florian Kronenberg; Barbara Kollerits; Marc Froissart; Benedicte Stengel; Marie Metzger; Giuseppe Remuzzi; Piero Ruggenenti; Annalisa Perna; H J Lambers Heerspink; Barry Brenner; Dick de Zeeuw; Peter Rossing; Hans-Henrik Parving; Priscilla Auguste; Kasper Veldhuis; Yaping Wang; Laura Camarata; Beverly Thomas; Tom Manley Journal: Kidney Int Date: 2011-02-02 Impact factor: 10.612
Authors: Nora Franceschini; Cara L Carty; Yingchang Lu; Ran Tao; Yun Ju Sung; Ani Manichaikul; Jeff Haessler; Myriam Fornage; Karen Schwander; Niha Zubair; Stephanie Bien; Lucia A Hindorff; Xiuqing Guo; Suzette J Bielinski; Georg Ehret; Joel D Kaufman; Stephen S Rich; Christopher S Carlson; Erwin P Bottinger; Kari E North; D C Rao; Aravinda Chakravarti; Paula Q Barrett; Ruth J F Loos; Steven Buyske; Charles Kooperberg Journal: PLoS One Date: 2016-10-13 Impact factor: 3.240
Authors: Alexander Teumer; Yong Li; Sahar Ghasemi; Bram P Prins; Matthias Wuttke; Tobias Hermle; Ayush Giri; Karsten B Sieber; Chengxiang Qiu; Holger Kirsten; Adrienne Tin; Audrey Y Chu; Nisha Bansal; Mary F Feitosa; Lihua Wang; Jin-Fang Chai; Massimiliano Cocca; Christian Fuchsberger; Mathias Gorski; Anselm Hoppmann; Katrin Horn; Man Li; Jonathan Marten; Damia Noce; Teresa Nutile; Sanaz Sedaghat; Gardar Sveinbjornsson; Bamidele O Tayo; Peter J van der Most; Yizhe Xu; Zhi Yu; Lea Gerstner; Johan Ärnlöv; Stephan J L Bakker; Daniela Baptista; Mary L Biggs; Eric Boerwinkle; Hermann Brenner; Ralph Burkhardt; Robert J Carroll; Miao-Li Chee; Miao-Ling Chee; Mengmeng Chen; Ching-Yu Cheng; James P Cook; Josef Coresh; Tanguy Corre; John Danesh; Martin H de Borst; Alessandro De Grandi; Renée de Mutsert; Aiko P J de Vries; Frauke Degenhardt; Katalin Dittrich; Jasmin Divers; Kai-Uwe Eckardt; Georg Ehret; Karlhans Endlich; Janine F Felix; Oscar H Franco; Andre Franke; Barry I Freedman; Sandra Freitag-Wolf; Ron T Gansevoort; Vilmantas Giedraitis; Martin Gögele; Franziska Grundner-Culemann; Daniel F Gudbjartsson; Vilmundur Gudnason; Pavel Hamet; Tamara B Harris; Andrew A Hicks; Hilma Holm; Valencia Hui Xian Foo; Shih-Jen Hwang; M Arfan Ikram; Erik Ingelsson; Vincent W V Jaddoe; Johanna Jakobsdottir; Navya Shilpa Josyula; Bettina Jung; Mika Kähönen; Chiea-Chuen Khor; Wieland Kiess; Wolfgang Koenig; Antje Körner; Peter Kovacs; Holly Kramer; Bernhard K Krämer; Florian Kronenberg; Leslie A Lange; Carl D Langefeld; Jeannette Jen-Mai Lee; Terho Lehtimäki; Wolfgang Lieb; Su-Chi Lim; Lars Lind; Cecilia M Lindgren; Jianjun Liu; Markus Loeffler; Leo-Pekka Lyytikäinen; Anubha Mahajan; Joseph C Maranville; Deborah Mascalzoni; Barbara McMullen; Christa Meisinger; Thomas Meitinger; Kozeta Miliku; Dennis O Mook-Kanamori; Martina Müller-Nurasyid; Josyf C Mychaleckyj; Matthias Nauck; Kjell Nikus; Boting Ning; Raymond Noordam; Jeffrey O' Connell; Isleifur Olafsson; Nicholette D Palmer; Annette Peters; Anna I Podgornaia; Belen Ponte; Tanja Poulain; Peter P Pramstaller; Ton J Rabelink; Laura M Raffield; Dermot F Reilly; Rainer Rettig; Myriam Rheinberger; Kenneth M Rice; Fernando Rivadeneira; Heiko Runz; Kathleen A Ryan; Charumathi Sabanayagam; Kai-Uwe Saum; Ben Schöttker; Christian M Shaffer; Yuan Shi; Albert V Smith; Konstantin Strauch; Michael Stumvoll; Benjamin B Sun; Silke Szymczak; E-Shyong Tai; Nicholas Y Q Tan; Kent D Taylor; Andrej Teren; Yih-Chung Tham; Joachim Thiery; Chris H L Thio; Hauke Thomsen; Unnur Thorsteinsdottir; Anke Tönjes; Johanne Tremblay; André G Uitterlinden; Pim van der Harst; Niek Verweij; Suzanne Vogelezang; Uwe Völker; Melanie Waldenberger; Chaolong Wang; Otis D Wilson; Charlene Wong; Tien-Yin Wong; Qiong Yang; Masayuki Yasuda; Shreeram Akilesh; Murielle Bochud; Carsten A Böger; Olivier Devuyst; Todd L Edwards; Kevin Ho; Andrew P Morris; Afshin Parsa; Sarah A Pendergrass; Bruce M Psaty; Jerome I Rotter; Kari Stefansson; James G Wilson; Katalin Susztak; Harold Snieder; Iris M Heid; Markus Scholz; Adam S Butterworth; Adriana M Hung; Cristian Pattaro; Anna Köttgen Journal: Nat Commun Date: 2019-09-11 Impact factor: 17.694
Authors: Andrew P Morris; Thu H Le; Haojia Wu; Artur Akbarov; Peter J van der Most; Gibran Hemani; George Davey Smith; Anubha Mahajan; Kyle J Gaulton; Girish N Nadkarni; Adan Valladares-Salgado; Niels Wacher-Rodarte; Josyf C Mychaleckyj; Nicole D Dueker; Xiuqing Guo; Yang Hai; Jeffrey Haessler; Yoichiro Kamatani; Adrienne M Stilp; Gu Zhu; James P Cook; Johan Ärnlöv; Susan H Blanton; Martin H de Borst; Erwin P Bottinger; Thomas A Buchanan; Sylvia Cechova; Fadi J Charchar; Pei-Lun Chu; Jeffrey Damman; James Eales; Ali G Gharavi; Vilmantas Giedraitis; Andrew C Heath; Eli Ipp; Krzysztof Kiryluk; Holly J Kramer; Michiaki Kubo; Anders Larsson; Cecilia M Lindgren; Yingchang Lu; Pamela A F Madden; Grant W Montgomery; George J Papanicolaou; Leslie J Raffel; Ralph L Sacco; Elena Sanchez; Holger Stark; Johan Sundstrom; Kent D Taylor; Anny H Xiang; Aleksandra Zivkovic; Lars Lind; Erik Ingelsson; Nicholas G Martin; John B Whitfield; Jianwen Cai; Cathy C Laurie; Yukinori Okada; Koichi Matsuda; Charles Kooperberg; Yii-Der Ida Chen; Tatjana Rundek; Stephen S Rich; Ruth J F Loos; Esteban J Parra; Miguel Cruz; Jerome I Rotter; Harold Snieder; Maciej Tomaszewski; Benjamin D Humphreys; Nora Franceschini Journal: Nat Commun Date: 2019-01-03 Impact factor: 14.919
Authors: Andrea R V R Horimoto; Diane Xue; Jianwen Cai; James P Lash; Martha L Daviglus; Nora Franceschini; Timothy A Thornton Journal: J Am Soc Nephrol Date: 2021-10-20 Impact factor: 14.978