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

Scholz, M.; Horn, K.; Pott, J.; Wuttke, M.; Kuhnapfel, A.; Nasr, M. K.; Kirsten, H.; Li, Y.; Hoppmann, A.; Gorski, M.; Ghasemi, S.; Li, M.; Tin, A.; Chai, J. -F.; Cocca, M.; Wang, J.; Nutile, T.; Akiyama, M.; Asvold, B. O.; Bansal, N.; Biggs, M. L.; Boutin, T.; Brenner, H.; Brumpton, B.; Burkhardt, R.; Cai, J.; Campbell, A.; Campbell, H.; Chalmers, J.; Chasman, D. I.; Chee, M. L.; Chee, M. L.; Chen, X.; Cheng, C. -Y.; Cifkova, R.; Daviglus, M.; Delgado, G.; Dittrich, K.; Edwards, T. L.; Endlich, K.; Michael Gaziano, J.; Giri, A.; Giulianini, F.; Gordon, S. D.; Gudbjartsson, D. F.; Hallan, S.; Hamet, P.; Hartman, C. A.; Hayward, C.; Heid, I. M.; Hellwege, J. N.; Holleczek, B.; Holm, H.; Hutri-Kahonen, N.; Hveem, K.; Isermann, B.; Jonas, J. B.; Joshi, P. K.; Kamatani, Y.; Kanai, M.; Kastarinen, M.; Khor, C. C.; Kiess, W.; Kleber, M. E.; Korner, A.; Kovacs, P.; Krajcoviechova, A.; Kramer, H.; Kramer, B. K.; Kuokkanen, M.; Kahonen, M.; Lange, L. A.; Lash, J. P.; Lehtimaki, T.; Li, H.; Lin, B. M.; Liu, J.; Loeffler, M.; Lyytikainen, L. -P.; Magnusson, P. K. E.; Martin, N. G.; Matsuda, K.; Milaneschi, Y.; Mishra, P. P.; Mononen, N.; Montgomery, G. W.; Mook-Kanamori, D. O.; Mychaleckyj, J. C.; Marz, W.; Nauck, M.; Nikus, K.; Nolte, I. M.; Noordam, R.; Okada, Y.; Olafsson, I.; Oldehinkel, A. J.; Penninx, B. W. J. H.; Perola, M.; Pirastu, N.; Polasek, O.; Porteous, D. J.; Poulain, T.; Psaty, B. M.; Rabelink, T. J.; Raffield, L. M.; Raitakari, O. T.; Rasheed, H.; Reilly, D. F.; Rice, K. M.; Richmond, A.; Ridker, P. M.; Rotter, J. I.; Rudan, I.; Sabanayagam, C.; Salomaa, V.; Schneiderman, N.; Schottker, B.; Sims, M.; Snieder, H.; Stark, K. J.; Stefansson, K.; Stocker, H.; Stumvoll, M.; Sulem, P.; Sveinbjornsson, G.; Svensson, P. O.; Tai, E. -S.; Taylor, K. D.; Tayo, B. O.; Teren, A.; Tham, Y. -C.; Thiery, J.; Thio, C. H. L.; Thomas, L. F.; Tremblay, J.; Tonjes, A.; van der Most, P. J.; Vitart, V.; Volker, U.; Wang, Y. X.; Wang, C.; Wei, W. B.; Whitfield, J. B.; Wild, S. H.; Wilson, J. F.; Winkler, T. W.; Wong, T. -Y.; Woodward, M.; Sim, X.; Chu, A. Y.; Feitosa, M. F.; Thorsteinsdottir, U.; Hung, A. M.; Teumer, A.; Franceschini, N.; Parsa, A.; Kottgen, A.; Schlosser, P.; Pattaro, C.

doi:10.1038/s41467-024-44709-1

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.