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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 M , Horn K , Pott J , Wuttke M , Kühnapfel A , Nasr MK , Kirsten H , Li Y , Hoppmann A , Gorski M , Ghasemi S , Li M , Tin A , Chai JF , Cocca M , Wang J , Nutile T , Akiyama M , Åsvold BO , Bansal N , Biggs ML , Boutin T , Brenner H , Brumpton B , Burkhardt R , Cai J , Campbell A , Campbell H , Chalmers J , Chasman DI , Chee ML , Chee ML , Chen X , Cheng CY , Cifkova R , Daviglus M , Delgado G , Dittrich K , Edwards TL , Endlich K , Michael Gaziano J , Giri A , Giulianini F , Gordon SD , Gudbjartsson DF , Hallan S , Hamet P , Hartman CA , Hayward C , Heid IM , Hellwege JN , Holleczek B , Holm H , Hutri-Kähönen N , Hveem K , Isermann B , Jonas JB , Joshi PK , Kamatani Y , Kanai M , Kastarinen M , Khor CC , Kiess W , Kleber ME , Körner A , Kovacs P , Krajcoviechova A , Kramer H , Krämer BK , Kuokkanen M , Kähönen M , Lange LA , Lash JP , Lehtimäki T , Li H , Lin BM , Liu J , Loeffler M , Lyytikäinen LP , Magnusson PKE , Martin NG , Matsuda K , Milaneschi Y , Mishra PP , Mononen N , Montgomery GW , Mook-Kanamori DO , Mychaleckyj JC , März W , Nauck M , Nikus K , Nolte IM , Noordam R , Okada Y , Olafsson I , Oldehinkel AJ , Penninx BWJH , Perola M , Pirastu N , Polasek O , Porteous DJ , Poulain T , Psaty BM , Rabelink TJ , Raffield LM , Raitakari OT , Rasheed H , Reilly DF , Rice KM , Richmond A , Ridker PM , Rotter JI , Rudan I , Sabanayagam C , Salomaa V , Schneiderman N , Schöttker B , Sims M , Snieder H , Stark KJ , Stefansson K , Stocker H , Stumvoll M , Sulem P , Sveinbjornsson G , Svensson PO , Tai ES , Taylor KD , Tayo BO , Teren A , Tham YC , Thiery J , Thio CHL , Thomas LF , Tremblay J , Tönjes A , van der Most PJ , Vitart V , Völker U , Wang YX , Wang C , Wei WB , Whitfield JB , Wild SH , Wilson JF , Winkler TW , Wong TY , Woodward M , Sim X , Chu AY , Feitosa MF , Thorsteinsdottir U , Hung AM , Teumer A , Franceschini N , Parsa A , Köttgen A , Schlosser P , Pattaro C , . Nature communications. 2024 1 18; 15(1). 586

ABSTRACT

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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