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 Scholz; Katrin Horn; Janne Pott; Matthias Wuttke; Andreas Kühnapfel; M Kamal Nasr; Holger Kirsten; Yong Li; Anselm Hoppmann; Mathias Gorski; Sahar Ghasemi; Man Li; Adrienne Tin; Jin-Fang Chai; Massimiliano Cocca; Judy Wang; Teresa Nutile; Masato Akiyama; Bjørn Olav Åsvold; Nisha Bansal; Mary L Biggs; Thibaud Boutin; Hermann Brenner; Ben Brumpton; Ralph Burkhardt; Jianwen Cai; Archie Campbell; Harry Campbell; John Chalmers; Daniel I Chasman; Miao Ling Chee; Miao Li Chee; Xu Chen; Ching-Yu Cheng; Renata Cifkova; Martha Daviglus; Graciela Delgado; Katalin Dittrich; Todd L Edwards; Karlhans Endlich; J Michael Gaziano; Ayush Giri; Franco Giulianini; Scott D Gordon; Daniel F Gudbjartsson; Stein Hallan; Pavel Hamet; Catharina A Hartman; Caroline Hayward; Iris M Heid; Jacklyn N Hellwege; Bernd Holleczek; Hilma Holm; Nina Hutri-Kähönen; Kristian Hveem; Berend Isermann; Jost B Jonas; Peter K Joshi; Yoichiro Kamatani; Masahiro Kanai; Mika Kastarinen; Chiea Chuen Khor; Wieland Kiess; Marcus E Kleber; Antje Körner; Peter Kovacs; Alena Krajcoviechova; Holly Kramer; Bernhard K Krämer; Mikko Kuokkanen; Mika Kähönen; Leslie A Lange; James P Lash; Terho Lehtimäki; Hengtong Li; Bridget M Lin; Jianjun Liu; Markus Loeffler; Leo-Pekka Lyytikäinen; Patrik K E Magnusson; Nicholas G Martin; Koichi Matsuda; Yuri Milaneschi; Pashupati P Mishra; Nina Mononen; Grant W Montgomery; Dennis O Mook-Kanamori; Josyf C Mychaleckyj; Winfried März; Matthias Nauck; Kjell Nikus; Ilja M Nolte; Raymond Noordam; Yukinori Okada; Isleifur Olafsson; Albertine J Oldehinkel; Brenda W J H Penninx; Markus Perola; Nicola Pirastu; Ozren Polasek; David J Porteous; Tanja Poulain; Bruce M Psaty; Ton J Rabelink; Laura M Raffield; Olli T Raitakari; Humaira Rasheed; Dermot F Reilly; Kenneth M Rice; Anne Richmond; Paul M Ridker; Jerome I Rotter; Igor Rudan; Charumathi Sabanayagam; Veikko Salomaa; Neil Schneiderman; Ben Schöttker; Mario Sims; Harold Snieder; Klaus J Stark; Kari Stefansson; Hannah Stocker; Michael Stumvoll; Patrick Sulem; Gardar Sveinbjornsson; Per O Svensson; E-Shyong Tai; Kent D Taylor; Bamidele O Tayo; Andrej Teren; Yih-Chung Tham; Joachim Thiery; Chris H L Thio; Laurent F Thomas; Johanne Tremblay; Anke Tönjes; Peter J van der Most; Veronique Vitart; Uwe Völker; Ya Xing Wang; Chaolong Wang; Wen Bin Wei; John B Whitfield; Sarah H Wild; James F Wilson; Thomas W Winkler; Tien-Yin Wong; Mark Woodward; Xueling Sim; Audrey Y Chu; Mary F Feitosa; Unnur Thorsteinsdottir; Adriana M Hung; Alexander Teumer; Nora Franceschini; Afshin Parsa; Anna Köttgen; Pascal Schlosser; Cristian Pattaro

doi:10.1038/s41467-024-44709-1

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 Scholz, Katrin Horn, Janne Pott, Matthias Wuttke, Andreas Kühnapfel, M Kamal Nasr, Holger Kirsten, Yong Li, Anselm Hoppmann, Mathias Gorski, Sahar Ghasemi, Man Li, Adrienne Tin, Jin-Fang Chai, Massimiliano Cocca, Judy Wang, Teresa Nutile, Masato Akiyama, Bjørn Olav Åsvold, Nisha BansalMary L Biggs, Thibaud Boutin, Hermann Brenner, Ben Brumpton, Ralph Burkhardt, Jianwen Cai, Archie Campbell, Harry Campbell, John Chalmers, Daniel I Chasman, Miao Ling Chee, Miao Li Chee, Xu Chen, Ching-Yu Cheng, Renata Cifkova, Martha Daviglus, Graciela Delgado, Katalin Dittrich, Todd L Edwards, Karlhans Endlich, J Michael Gaziano, Ayush Giri, Franco Giulianini, Scott D Gordon, Daniel F Gudbjartsson, Stein Hallan, Pavel Hamet, Catharina A Hartman, Caroline Hayward, Iris M Heid, Jacklyn N Hellwege, Bernd Holleczek, Hilma Holm, Nina Hutri-Kähönen, Kristian Hveem, Berend Isermann, Jost B Jonas, Peter K Joshi, Yoichiro Kamatani, Masahiro Kanai, Mika Kastarinen, Chiea Chuen Khor, Wieland Kiess, Marcus E Kleber, Antje Körner, Peter Kovacs, Alena Krajcoviechova, Holly Kramer, Bernhard K Krämer, Mikko Kuokkanen, Mika Kähönen, Leslie A Lange, James P Lash, Terho Lehtimäki, Hengtong Li, Bridget M Lin, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Patrik K E Magnusson, Nicholas G Martin, Koichi Matsuda, Yuri Milaneschi, Pashupati P Mishra, Nina Mononen, Grant W Montgomery, Dennis O Mook-Kanamori, Josyf C Mychaleckyj, Winfried März, Matthias Nauck, Kjell Nikus, Ilja M Nolte, Raymond Noordam, Yukinori Okada, Isleifur Olafsson, Albertine J Oldehinkel, Brenda W J H Penninx, Markus Perola, Nicola Pirastu, Ozren Polasek, David J Porteous, Tanja Poulain, Bruce M Psaty, Ton J Rabelink, Laura M Raffield, Olli T Raitakari, Humaira Rasheed, Dermot F Reilly, Kenneth M Rice, Anne Richmond, Paul M Ridker, Jerome I Rotter, Igor Rudan, Charumathi Sabanayagam, Veikko Salomaa, Neil Schneiderman, Ben Schöttker, Mario Sims, Harold Snieder, Klaus J Stark, Kari Stefansson, Hannah Stocker, Michael Stumvoll, Patrick Sulem, Gardar Sveinbjornsson, Per O Svensson, E-Shyong Tai, Kent D Taylor, Bamidele O Tayo, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H L Thio, Laurent F Thomas, Johanne Tremblay, Anke Tönjes, Peter J van der Most, Veronique Vitart, Uwe Völker, Ya Xing Wang, Chaolong Wang, Wen Bin Wei, John B Whitfield, Sarah H Wild, James F Wilson, Thomas W Winkler, Tien-Yin Wong, Mark Woodward, Xueling Sim, Audrey Y Chu, Mary F Feitosa, Unnur Thorsteinsdottir, Adriana M Hung, Alexander Teumer, Nora Franceschini, Afshin Parsa, Anna Köttgen, Pascal Schlosser, Cristian Pattaro

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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.

Originele taal-2	English
Artikelnummer	586
Aantal pagina's	17
Tijdschrift	Nature Communications
Volume	15
Nummer van het tijdschrift	1
Vroegere onlinedatum	18-jan.-2024
DOI's	https://doi.org/10.1038/s41467-024-44709-1
Status	Published - 2024

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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., ... 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, 15(1), Artikel 586. https://doi.org/10.1038/s41467-024-44709-1

@article{148112112df84721ad624d6aecb0bc1d,

title = "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",

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.",

keywords = "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",

author = "Markus Scholz and Katrin Horn and Janne Pott and Matthias Wuttke and Andreas K{\"u}hnapfel and Nasr, {M Kamal} and Holger Kirsten and Yong Li and Anselm Hoppmann and Mathias Gorski and Sahar Ghasemi and Man Li and Adrienne Tin and Jin-Fang Chai and Massimiliano Cocca and Judy Wang and Teresa Nutile and Masato Akiyama and {\AA}svold, {Bj{\o}rn Olav} and Nisha Bansal and Biggs, {Mary L} and Thibaud Boutin and Hermann Brenner and Ben Brumpton and Ralph Burkhardt and Jianwen Cai and Archie Campbell and Harry Campbell and John Chalmers and Chasman, {Daniel I} and Chee, {Miao Ling} and Chee, {Miao Li} and Xu Chen and Ching-Yu Cheng and Renata Cifkova and Martha Daviglus and Graciela Delgado and Katalin Dittrich and Edwards, {Todd L} and Karlhans Endlich and {Michael Gaziano}, J and Ayush Giri and Franco Giulianini and Gordon, {Scott D} and Gudbjartsson, {Daniel F} and Stein Hallan and Pavel Hamet and Hartman, {Catharina A} and Caroline Hayward and Heid, {Iris M} and Hellwege, {Jacklyn N} and Bernd Holleczek and Hilma Holm and Nina Hutri-K{\"a}h{\"o}nen and Kristian Hveem and Berend Isermann and Jonas, {Jost B} and Joshi, {Peter K} and Yoichiro Kamatani and Masahiro Kanai and Mika Kastarinen and Khor, {Chiea Chuen} and Wieland Kiess and Kleber, {Marcus E} and Antje K{\"o}rner and Peter Kovacs and Alena Krajcoviechova and Holly Kramer and Kr{\"a}mer, {Bernhard K} and Mikko Kuokkanen and Mika K{\"a}h{\"o}nen and Lange, {Leslie A} and Lash, {James P} and Terho Lehtim{\"a}ki and Hengtong Li and Lin, {Bridget M} and Jianjun Liu and Markus Loeffler and Leo-Pekka Lyytik{\"a}inen and Magnusson, {Patrik K E} and Martin, {Nicholas G} and Koichi Matsuda and Yuri Milaneschi and Mishra, {Pashupati P} and Nina Mononen and Montgomery, {Grant W} and Mook-Kanamori, {Dennis O} and Mychaleckyj, {Josyf C} and Winfried M{\"a}rz and Matthias Nauck and Kjell Nikus and Nolte, {Ilja M} and Raymond Noordam and Yukinori Okada and Isleifur Olafsson and Oldehinkel, {Albertine J} and Penninx, {Brenda W J H} and Markus Perola and Nicola Pirastu and Ozren Polasek and Porteous, {David J} and Tanja Poulain and Psaty, {Bruce M} and Rabelink, {Ton J} and Raffield, {Laura M} and Raitakari, {Olli T} and Humaira Rasheed and Reilly, {Dermot F} and Rice, {Kenneth M} and Anne Richmond and Ridker, {Paul M} and Rotter, {Jerome I} and Igor Rudan and Charumathi Sabanayagam and Veikko Salomaa and Neil Schneiderman and Ben Sch{\"o}ttker and Mario Sims and Harold Snieder and Stark, {Klaus J} and Kari Stefansson and Hannah Stocker and Michael Stumvoll and Patrick Sulem and Gardar Sveinbjornsson and Svensson, {Per O} and E-Shyong Tai and Taylor, {Kent D} and Tayo, {Bamidele O} and Andrej Teren and Yih-Chung Tham and Joachim Thiery and Thio, {Chris H L} and Thomas, {Laurent F} and Johanne Tremblay and Anke T{\"o}njes and {van der Most}, {Peter J} and Veronique Vitart and Uwe V{\"o}lker and Wang, {Ya Xing} and Chaolong Wang and Wei, {Wen Bin} and Whitfield, {John B} and Wild, {Sarah H} and Wilson, {James F} and Winkler, {Thomas W} and Tien-Yin Wong and Mark Woodward and Xueling Sim and Chu, {Audrey Y} and Feitosa, {Mary F} and Unnur Thorsteinsdottir and Hung, {Adriana M} and Alexander Teumer and Nora Franceschini and Afshin Parsa and Anna K{\"o}ttgen and Pascal Schlosser and Cristian Pattaro",

note = "Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

doi = "10.1038/s41467-024-44709-1",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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, J-F, 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, C-Y, 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, L-P, 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, E-S, Taylor, KD, Tayo, BO, Teren, A, Tham, Y-C, 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, T-Y, Woodward, M, Sim, X, Chu, AY, Feitosa, MF, Thorsteinsdottir, U, Hung, AM, 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, nr. 1, 586. https://doi.org/10.1038/s41467-024-44709-1

TY - JOUR

T1 - X-chromosome and kidney function

T2 - 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

AU - Scholz, Markus

AU - Horn, Katrin

AU - Pott, Janne

AU - Wuttke, Matthias

AU - Kühnapfel, Andreas

AU - Nasr, M Kamal

AU - Kirsten, Holger

AU - Li, Yong

AU - Hoppmann, Anselm

AU - Gorski, Mathias

AU - Ghasemi, Sahar

AU - Li, Man

AU - Tin, Adrienne

AU - Chai, Jin-Fang

AU - Cocca, Massimiliano

AU - Wang, Judy

AU - Nutile, Teresa

AU - Akiyama, Masato

AU - Åsvold, Bjørn Olav

AU - Bansal, Nisha

AU - Biggs, Mary L

AU - Boutin, Thibaud

AU - Brenner, Hermann

AU - Brumpton, Ben

AU - Burkhardt, Ralph

AU - Cai, Jianwen

AU - Campbell, Archie

AU - Campbell, Harry

AU - Chalmers, John

AU - Chasman, Daniel I

AU - Chee, Miao Ling

AU - Chee, Miao Li

AU - Chen, Xu

AU - Cheng, Ching-Yu

AU - Cifkova, Renata

AU - Daviglus, Martha

AU - Delgado, Graciela

AU - Dittrich, Katalin

AU - Edwards, Todd L

AU - Endlich, Karlhans

AU - Michael Gaziano, J

AU - Giri, Ayush

AU - Giulianini, Franco

AU - Gordon, Scott D

AU - Gudbjartsson, Daniel F

AU - Hallan, Stein

AU - Hamet, Pavel

AU - Hartman, Catharina A

AU - Hayward, Caroline

AU - Heid, Iris M

AU - Hellwege, Jacklyn N

AU - Holleczek, Bernd

AU - Holm, Hilma

AU - Hutri-Kähönen, Nina

AU - Hveem, Kristian

AU - Isermann, Berend

AU - Jonas, Jost B

AU - Joshi, Peter K

AU - Kamatani, Yoichiro

AU - Kanai, Masahiro

AU - Kastarinen, Mika

AU - Khor, Chiea Chuen

AU - Kiess, Wieland

AU - Kleber, Marcus E

AU - Körner, Antje

AU - Kovacs, Peter

AU - Krajcoviechova, Alena

AU - Kramer, Holly

AU - Krämer, Bernhard K

AU - Kuokkanen, Mikko

AU - Kähönen, Mika

AU - Lange, Leslie A

AU - Lash, James P

AU - Lehtimäki, Terho

AU - Li, Hengtong

AU - Lin, Bridget M

AU - Liu, Jianjun

AU - Loeffler, Markus

AU - Lyytikäinen, Leo-Pekka

AU - Magnusson, Patrik K E

AU - Martin, Nicholas G

AU - Matsuda, Koichi

AU - Milaneschi, Yuri

AU - Mishra, Pashupati P

AU - Mononen, Nina

AU - Montgomery, Grant W

AU - Mook-Kanamori, Dennis O

AU - Mychaleckyj, Josyf C

AU - März, Winfried

AU - Nauck, Matthias

AU - Nikus, Kjell

AU - Nolte, Ilja M

AU - Noordam, Raymond

AU - Okada, Yukinori

AU - Olafsson, Isleifur

AU - Oldehinkel, Albertine J

AU - Penninx, Brenda W J H

AU - Perola, Markus

AU - Pirastu, Nicola

AU - Polasek, Ozren

AU - Porteous, David J

AU - Poulain, Tanja

AU - Psaty, Bruce M

AU - Rabelink, Ton J

AU - Raffield, Laura M

AU - Raitakari, Olli T

AU - Rasheed, Humaira

AU - Reilly, Dermot F

AU - Rice, Kenneth M

AU - Richmond, Anne

AU - Ridker, Paul M

AU - Rotter, Jerome I

AU - Rudan, Igor

AU - Sabanayagam, Charumathi

AU - Salomaa, Veikko

AU - Schneiderman, Neil

AU - Schöttker, Ben

AU - Sims, Mario

AU - Snieder, Harold

AU - Stark, Klaus J

AU - Stefansson, Kari

AU - Stocker, Hannah

AU - Stumvoll, Michael

AU - Sulem, Patrick

AU - Sveinbjornsson, Gardar

AU - Svensson, Per O

AU - Tai, E-Shyong

AU - Taylor, Kent D

AU - Tayo, Bamidele O

AU - Teren, Andrej

AU - Tham, Yih-Chung

AU - Thiery, Joachim

AU - Thio, Chris H L

AU - Thomas, Laurent F

AU - Tremblay, Johanne

AU - Tönjes, Anke

AU - van der Most, Peter J

AU - Vitart, Veronique

AU - Völker, Uwe

AU - Wang, Ya Xing

AU - Wang, Chaolong

AU - Wei, Wen Bin

AU - Whitfield, John B

AU - Wild, Sarah H

AU - Wilson, James F

AU - Winkler, Thomas W

AU - Wong, Tien-Yin

AU - Woodward, Mark

AU - Sim, Xueling

AU - Chu, Audrey Y

AU - Feitosa, Mary F

AU - Thorsteinsdottir, Unnur

AU - Hung, Adriana M

AU - Teumer, Alexander

AU - Franceschini, Nora

AU - Parsa, Afshin

AU - Köttgen, Anna

AU - Schlosser, Pascal

AU - Pattaro, Cristian

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - Humans

KW - Male

KW - Female

KW - Androgens/genetics

KW - Genome-Wide Association Study

KW - Kidney

KW - Chromosomes, Human, X/genetics

KW - Response Elements

KW - Polymorphism, Single Nucleotide

KW - Genetic Predisposition to Disease

KW - Tetraspanins/genetics

UR - http://www.scopus.com/inward/record.url?scp=85182684565&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-44709-1

DO - 10.1038/s41467-024-44709-1

M3 - Article

C2 - 38233393

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 586

ER -

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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