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 PattaroX-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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