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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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.

Original language	English
Article number	586
Number of pages	17
Journal	Nature Communications
Volume	15
Issue number	1
Early online date	18-Jan-2024
DOIs	https://doi.org/10.1038/s41467-024-44709-1
Publication status	Published - 2024

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

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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), Article 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, no. 1, 586. https://doi.org/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. / Scholz, Markus; Horn, Katrin; Pott, Janne et al.
In: Nature Communications, Vol. 15, No. 1, 586, 2024.

Research output: Contribution to journal › Article › Academic › peer-review

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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