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
Authors: Scholz Markus , Horn Katrin , Pott Janne , Wuttke Matthias , Kühnapfel Andreas , Nasr M. Kamal , Kirsten Holger , Li Yong , Hoppmann Anselm , Gorski Mathias , Ghasemi Sahar , Li Man , Tin Adrienne , Chai Jin-Fang , Cocca Massimiliano , Wang Judy , Nutile Teresa , Akiyama Masato , Åsvold Bjørn Olav , Bansal Nisha , Biggs Mary L. , Boutin Thibaud , Brenner Hermann , Brumpton Ben , Burkhardt Ralph , Cai Jianwen , Campbell Archie , Campbell Harry , Chalmers John , Chasman Daniel I. , Chee Miao Ling , Chee Miao Li , Chen Xu , Cheng Ching-Yu , Cifkova Renata , Daviglus Martha , Delgado Graciela , Dittrich Katalin , Edwards Todd L. , Endlich Karlhans , Michael Gaziano J. , Giri Ayush , Giulianini Franco , Gordon Scott D. , Gudbjartsson Daniel F. , Hallan Stein , Hamet Pavel , Hartman Catharina A. , Hayward Caroline , Heid Iris M. , Hellwege Jacklyn N. , Holleczek Bernd , Holm Hilma , Hutri-Kähönen Nina , Hveem Kristian , Isermann Berend , Jonas Jost B. , Joshi Peter K. , Kamatani Yoichiro , Kanai Masahiro , Kastarinen Mika , Khor Chiea Chuen , Kiess Wieland , Kleber Marcus E. , Körner Antje , Kovacs Peter , Krajcoviechova Alena , Kramer Holly , Krämer Bernhard K. , Kuokkanen Mikko , Kähönen Mika , Lange Leslie A. , Lash James P. , Lehtimäki Terho , Li Hengtong , Lin Bridget M. , Liu Jianjun , Loeffler Markus , Lyytikäinen Leo-Pekka , Magnusson Patrik K. E. , Martin Nicholas G. , Matsuda Koichi , Milaneschi Yuri , Mishra Pashupati P. , Mononen Nina , Montgomery Grant W. , Mook-Kanamori Dennis O. , Mychaleckyj Josyf C. , März Winfried , Nauck Matthias , Nikus Kjell , Nolte Ilja M. , Noordam Raymond , Okada Yukinori , Olafsson Isleifur , Oldehinkel Albertine J. , Penninx Brenda W. J. H. , Perola Markus , Pirastu Nicola , Polasek Ozren , Porteous David J. , Poulain Tanja , Psaty Bruce M. , Rabelink Ton J. , Raffield Laura M. , Raitakari Olli T. , Rasheed Humaira , Reilly Dermot F. , Rice Kenneth M. , Richmond Anne , Ridker Paul M. , Rotter Jerome I. , Rudan Igor , Sabanayagam Charumathi , Salomaa Veikko , Schneiderman Neil , Schöttker Ben , Sims Mario , Snieder Harold , Stark Klaus J. , Stefansson Kari , Stocker Hannah , Stumvoll Michael , Sulem Patrick , Sveinbjornsson Gardar , Svensson Per O. , Tai E-Shyong , Taylor Kent D. , Tayo Bamidele O. , Teren Andrej , Tham Yih-Chung , Thiery Joachim , Thio Chris H. L. , Thomas Laurent F. , Tremblay Johanne , Tönjes Anke , van der Most Peter J. , Vitart Veronique , Völker Uwe , Wang Ya Xing , Wang Chaolong , Wei Wen Bin , Whitfield John B. , Wild Sarah H. , Wilson James F. , Winkler Thomas W. , Wong Tien-Yin , Woodward Mark , Sim Xueling , Chu Audrey Y. , Feitosa Mary F. , Thorsteinsdottir Unnur , Hung Adriana M. , Teumer Alexander , Franceschini Nora , Parsa Afshin , Köttgen Anna , Schlosser Pascal , Pattaro Cristian 
Published: January 2024

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.