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.; Kühnapfel, A.; Nasr, M.K.; ... ; Pattaro, C. (2024)

Article / Letter to editor

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.

• All authors: Scholz, M.; Horn, K.; Pott, J.; Wuttke, M.; Kühnapfel, 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.W.; Campbell, A.; Campbell, H.; Chalmers, J.; Chasman, D.; Chee, M.L.; Li Chee, M.; Chen, X.; Cheng, C.Y.; Cifkova, R.; Daviglus, M.; Delgado, G.; Dittrich, K.; Edwards, T.L.; Endlich, K.; Gaziano, J.M.; 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-Kähönen, 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.; Körner, A.; Kovacs, P.; Krajcoviechova, A.; Kramer, H.; Krämer, B.K.; Kuokkanen, M.; Kähönen, M.; Lange, L.A.; Lash, J.P.; Lehtimäki, T.; Li, H.T.; Lin, B.M.; Liu, J.J.; Loeffler, M.; Lyytikäinen, 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.; März, 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.; 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.; Tönjes, A.; Most, P.J. van der; Vitart, V.; Völker, U.; Wang, Y.X.; Wang, C.L.; 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.; Köttgen, A.; Schlosser, P.; Pattaro, C.
• Date: 2024-01-18
• Journal: Nature Communications
• Volume: 15
• Issue: 1
• DOI: doi:10.1038/s41467-024-44709-1