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
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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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Publisher Copyright: © 2024, The Author(s). © 2024. The Author(s).
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Humans, Male, Female, Androgens/genetics, Genome-Wide Association Study, Kidney, Chromosomes, Human, X/genetics, Response Elements, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Tetraspanins/genetics, General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
Citation
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, Åsvold, 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-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, Lin, B M, Liu, 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, Ólafsson, Í, 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, Schöttker, B, Sims, M, Snieder, H, Stark, K J, Stefánsson, 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, van der Most, P J, Vitart, V, Völker, 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, Þorsteinsdóttir, U, Hung, A M, Teumer, A, Franceschini, N, Parsa, A, Köttgen, A, Schlosser, P & Pattaro, C 2024, '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', Nature Communications, vol. 15, no. 1, 586, pp. 586. https://doi.org/10.1038/s41467-024-44709-1