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.
Markus ScholzKatrin HornJanne PottMatthias WuttkeAndreas KühnapfelM Kamal NasrHolger KirstenYong LiAnselm HoppmannMathias GorskiSahar GhasemiMan LiAdrienne TinJin-Fang ChaiMassimiliano CoccaJudy WangTeresa NutileMasato AkiyamaBjørn Olav ÅsvoldNisha BansalMary L BiggsThibaud BoutinHermann BrennerBen Michael BrumptonRalph BurkhardtJianwen CaiArchie I CampbellHarry CampbellJohn ChalmersDaniel I ChasmanMiao Ling CheeMiao Li CheeXu ChenChing-Yu ChengRenata CifkovaMartha DaviglusGraciela DelgadoKatalin DittrichTodd L EdwardsKarlhans EndlichJ Michael GazianoAyush GiriFranco GiulianiniScott D GordonDaniel F GudbjartssonStein HallanPavel HametCatharina A HartmanCaroline HaywardIris M HeidJacklyn N HellwegeBernd HolleczekHilma HólmNina Hutri-KähönenKristian HveemBerend IsermannJost Bruno JonasPeter K JoshiYoichiro KamataniMasahiro KanaiMika KastarinenChiea Chuen KhorWieland KiessMarcus Edi KleberAntje KörnerPeter KovacsAlena KrajcoviechovaHolly J KramerBernhard K KrämerMikko KuokkanenMika KähönenLeslie A LangeJames P LashTerho LehtimäkiHengtong LiBridget M LinJian-Jun LiuMarkus LoefflerLeo-Pekka LyytikainenPatrik K E MagnussonNicholas G MartinKoichi MatsudaYuri MilaneschiPashupati P MishraNina MononenGrant W MontgomeryDennis O Mook-KanamoriJosyf C MychaleckyiWinfried MärzMatthias NauckKjell NikusIlja Maria NolteRaymond NoordamYukinori OkadaIsleifur OlafssonAlbertine J OldehinkelBrenda W J H PenninxMarkus PerolaNicola PirastuOzren PolasekDavid J PorteousTanja PoulainBruce M PsatyTon J RabelinkLaura M RaffieldOlli T RaitakariHumaira RasheedDermot F ReillyKenneth M RiceAnne RichmondPaul M RidkerJerome I RotterIgor RudanCharumathi SabanayagamVeikko V SalomaaNeil SchneidermanBen SchöttkerMario SimsHarold SniederKlaus J StarkKári StefánssonHannah R StockerMichael StumvollPatrick SulemGardar SveinbjornssonPer O SvenssonE-Shyong TaiKent D TaylorBamidele O TayoAndrej TerenYih-Chung ThamJoachim ThieryChris H L ThioLaurent F ThomasJohanne TremblayAnke TönjesPeter J van der MostVeronique VitartLinus VölkerYa-Xing WangChaolong WangWen Bin WeiJohn B WhitfieldSarah D WildJames F WilsonThomas W WinklerTien-Yin WongMark WoodwardXueling S SimAudrey Y ChuMary F FeitosaUnnur ThorsteinsdottirAdriana M HungAlexander TeumerNora FranceschiniAfshin ParsaAnna KottgenPascal SchlosserCristian PattaroPublished in: Nature communications (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.