X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Markus Scholz,Katrin Horn,Janne Pott,Matthias Wuttke,Andreas Kühnapfel, M. Kamal Nasr,Holger Kirsten,Yong Li,Anselm Hoppmann,Mathias Gorski,Sahar Ghasemi,Man Li,Adrienne Tin,Jin-Fang Chai,Massimiliano Cocca,Judy Wang, Teresa Nutile,Masato Akiyama, Bjørn Olav Åsvold,Nisha Bansal,Mary L. Biggs,Thibaud Boutin,Hermann Brenner,Ben Brumpton,Ralph Burkhardt,Jianwen Cai,Archie Campbell,Harry Campbell,John Chalmers, Daniel I. Chasman, Miao Ling Chee,Miao Li Chee,Xu Chen,Ching-Yu Cheng,Renata Cifkova,Martha Daviglus,Graciela Delgado,Katalin Dittrich,Todd L. Edwards,Karlhans Endlich,J. Michael Gaziano,Ayush Giri, Franco Giulianini,Scott D. Gordon,Daniel F. Gudbjartsson,Stein Hallan,Pavel Hamet,Catharina A. Hartman,Caroline Hayward,Iris M. Heid,Jacklyn N. Hellwege, Bernd Holleczek,Hilma Holm,Nina Hutri-Kähönen,Kristian Hveem,Berend Isermann,Jost B. Jonas,Peter K. Joshi,Yoichiro Kamatani,Masahiro Kanai,Mika Kastarinen,Chiea Chuen Khor,Wieland Kiess,Marcus E. Kleber,Antje Körner,Peter Kovacs,Alena Krajcoviechova,Holly Kramer,Bernhard K. Krämer,Mikko Kuokkanen,Mika Kähönen,Leslie A. Lange,James P. Lash,Terho Lehtimäki,Hengtong Li,Bridget M. Lin,Jianjun Liu, Markus Loeffler,Leo-Pekka Lyytikäinen,Patrik K. E. Magnusson,Nicholas G. Martin,Koichi Matsuda,Yuri Milaneschi,Pashupati P. Mishra,Nina Mononen,Grant W. Montgomery,Dennis O. Mook-Kanamori,Josyf C. Mychaleckyj,Winfried März,Matthias Nauck,Kjell Nikus,Ilja M. Nolte,Raymond Noordam,Yukinori Okada,Isleifur Olafsson,Albertine J. Oldehinkel,Brenda W. J. H. Penninx,Markus Perola,Nicola Pirastu,Ozren Polasek, David J. Porteous,Tanja Poulain, Bruce M. Psaty, Ton J. Rabelink,Laura M. Raffield,Olli T. Raitakari, Humaira Rasheed, Dermot F. Reilly, Kenneth M. Rice, Anne Richmond, Paul M. Ridker,Jerome I. Rotter, Igor Rudan, Charumathi Sabanayagam, Veikko Salomaa, Neil Schneiderman, Ben Schöttker, Mario Sims, Harold Snieder, Klaus J. Stark, Kari Stefansson, Hannah Stocker, Michael Stumvoll, Patrick Sulem, Gardar Sveinbjornsson, Per O. Svensson, E-Shyong Tai, Kent D. Taylor, Bamidele O. Tayo, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Laurent F. Thomas, Johanne Tremblay, Anke Tönjes, Peter J. van der Most, Veronique Vitart, Uwe Völker, Ya Xing Wang, Chaolong Wang, Wen Bin Wei, John B. Whitfield, Sarah H. Wild,James F. Wilson, Thomas W. Winkler, Tien-Yin Wong, Mark Woodward, Xueling Sim, Audrey Y. Chu, Mary F. Feitosa, Unnur Thorsteinsdottir, Adriana M. Hung, Alexander Teumer, Nora Franceschini, Afshin Parsa, Anna Köttgen, Pascal Schlosser, Cristian Pattaro

Nature Communications（2024）

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摘要

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits ( n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4 , CLDN2 , TSPAN6 and the female-specific DRP2 . Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R , and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1 . All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

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