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

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

doi:10.1038/s41467-024-44709-1

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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

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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

M Scholz, K Horn, J Pott, M Wuttke, A Kühnapfel, MK Nasr, H Kirsten, Y Li, A Hoppmann, M Gorski, …

Nature Communications, Vol.15

18/01/2024

DOI: https://doi.org/10.1038/s41467-024-44709-1

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https://hdl.handle.net/10863/38258

PMID: 38233393

Abstract

Biostatistics & Epidemiology

CKD

Genetics

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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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
Creators: M Scholz - Leipzig University
K Horn - Leipzig University
J Pott - Leipzig University
M Wuttke - University of Freiburg
A Kühnapfel - Leipzig University
MK Nasr - Greifswald University Hospital
H Kirsten - Leipzig University
Y Li
A Hoppmann - University of Freiburg
M Gorski - University of Regensburg
S Ghasemi - Greifswald University Hospital
M Li - University of Utah
A Tin - University of Mississippi Medical Center
JF Chai - National University Health System
M Cocca - IRCCS Materno Infantile Burlo Garofolo
J Wang
T Nutile - Institute of Genetics and Biophysics
M Akiyama - RIKEN Center for Integrative Medical Sciences
BO Åsvold - Norwegian University of Science and Technology
N Bansal - University of Washington
ML Biggs - University of Washington
T Boutin - Medical Research Council
H Brenner - German Cancer Research Center
B Brumpton - Norwegian University of Science and Technology
R Burkhardt
J Cai - University of North Carolina at Chapel Hill
A Campbell - Edinburgh Cancer Research
H Campbell - University of Edinburgh
J Chalmers - The George Institute for Global Health
DI Chasman - Brigham and Women's Hospital
ML Chee - Singapore National Eye Center
ML Chee - Singapore National Eye Center
CY Cheng - Singapore Eye Research Institute
R Cifkova - Charles University
M Daviglus - University of Illinois at Chicago
G Delgado - Heidelberg University
K Dittrich - University Hospital Leipzig
TL Edwards - VA Tennessee Valley Healthcare System
K Endlich - German Centre for Cardiovascular Research
MJ Gaziano
A Giri - Vanderbilt University Medical Center
F Giulianini - Brigham and Women's Hospital
SD Gordon - QIMR Berghofer Medical Research Institute
DF Gudbjartsson
S Hallan - Norwegian University of Science and Technology
P Hamet
CA Hartman - University Medical Center Groningen
C Hayward - MRC Institute of Genetics and Molecular Medicine
IM Heid - University of Regensburg
JN Hellwege - VA Tennessee Valley Healthcare System
B Holleczek - German Cancer Research Center
H Holm - deCODE Genetics
N Hutri-Kähönen
K Hveem - Norwegian University of Science and Technology
B Isermann
JB Jonas - University Medical Centre Mannheim
PK Joshi - Centre for Global Health Research
Y Kamatani - RIKEN Center for Integrative Medical Sciences
M Kanai - RIKEN Center for Integrative Medical Sciences
M Kastarinen - Finnish Medicines Agency Fimea
W Kiess
ME Kleber - Heidelberg University
A Körner
P Kovacs - Leipzig University
A Krajcoviechova - Charles University
H Kramer - Loyola University Chicago
BK Krämer - Heidelberg University
M Kuokkanen - Finnish Institute for Health and Welfare
M Kähönen - Tampere University Hospital
LA Lange - University of Colorado Denver
JP Lash - University of Illinois at Chicago
T Lehtimäki - Fimlab
H Li - National University Health System
BM Lin - University of North Carolina at Chapel Hill
J Liu - Agency for Science, Technology and Research
M Loeffler
LP Lyytikäinen - Fimlab
PKE Magnusson
NG Martin - QIMR Berghofer Medical Research Institute
K Matsuda - The University of Tokyo
Y Milaneschi - GGZ inGeest
PP Mishra - Fimlab
N Mononen - Fimlab
GW Montgomery - University of Queensland
DO Mook-Kanamori
JC Mychaleckyj - University of Virginia
W März - Heidelberg University
M Nauck - German Centre for Cardiovascular Research
K Nikus - Tampere University
IM Nolte - University Medical Center Groningen
R Noordam - Leiden University Medical Center
Y Okada - RIKEN Center for Integrative Medical Sciences
I Olafsson - National University Hospital of Iceland
AJ Oldehinkel - University Medical Center Groningen
BWJH Penninx
M Perola - Finnish Institute for Health and Welfare
N Pirastu - Centre for Global Health Research
O Polasek - University of Split
DJ Porteous - Edinburgh Cancer Research
T Poulain - University Hospital Leipzig
BM Psaty - University of Washington
TJ Rabelink - Leiden University Medical Center
LM Raffield - University of North Carolina at Chapel Hill
OT Raitakari - University of Turku
H Rasheed - University of Bristol
DF Reilly - Janssen
KM Rice - University of Washington
A Richmond - MRC Institute of Genetics and Molecular Medicine
PM Ridker - Harvard University
JI Rotter - Harbor–UCLA Medical Center
I Rudan - Centre for Global Health Research
C Sabanayagam - Duke-NUS Medical School
V Salomaa - Finnish Institute for Health and Welfare
N Schneiderman - University of Miami
B Schöttker - Heidelberg University
M Sims - University of California, Riverside
H Snieder - University Medical Center Groningen
KJ Stark - University of Regensburg
K Stefansson - deCODE Genetics
H Stocker - Heidelberg University
M Stumvoll - Leipzig University
P Sulem - deCODE Genetics
G Sveinbjornsson - deCODE Genetics
PO Svensson - Stockholm South General Hospital
ES Tai - National University Health System
KD Taylor - UCLA Medical Center
BO Tayo - Loyola University Chicago
A Teren - Klinikum Bielefeld
YC Tham - National University Health System
J Thiery - Leipzig University
CHL Thio
LF Thomas - Norwegian University of Science and Technology
J Tremblay
A Tönjes - Leipzig University
PJ van der Most - University Medical Center Groningen
V Vitart - MRC Institute of Genetics and Molecular Medicine
U Völker - Greifswald University Hospital
YX Wang - Beijing Tongren Hospital
C Wang - Agency for Science, Technology and Research
WB Wei
JB Whitfield - QIMR Berghofer Medical Research Institute
SH Wild - University of Edinburgh
JF Wilson - Centre for Global Health Research
TW Winkler - University of Regensburg
TY Wong - Duke-NUS Medical School
M Woodward - The George Institute for Global Health
X Sim - National University Health System
AY Chu - MSD
MF Feitosa
U Thorsteinsdottir
AM Hung - VA Tennessee Valley Healthcare System
A Teumer - Medical University of Białystok
N Franceschini - University of North Carolina at Chapel Hill
A Parsa - National Institute of Diabetes and Digestive and Kidney Diseases
A Köttgen - Johns Hopkins University
P Schlosser - Johns Hopkins University
Cristian Pattaro - Institute for Biomedicine
Publication Details: Nature Communications, Vol.15
EISSN: 2041-1723
Series / Volume: 15
Publisher: Nature Research
Identifiers: (EURAC)27992336
991006696598201241
Web of Science ID: WOS:001187887400001
Copyright: CC BY 4.0 DEED
Academic Unit: Institute for Biomedicine
Language: English
Resource Type: Journal article
Description coverage: international
Description audience: Scientific
Local Fields: Scientific
Author Names String: 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, ChenX, Cheng CY, Cifkova R, Daviglus M, Delgado G, Dittrich K, Edwards TL, Endlich K, Gaziano MJ, 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, KhorCC, 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

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