X‐chromosome-wide association study for Alzheimer’s disease

EADB, GR@ACE, DEGESCO, EADI, GERAD, DemGene, FinnGen, ADGC, CHARGE

doi:10.1038/s41380-024-02838-5

X‐chromosome-wide association study for Alzheimer’s disease

EADB, GR@ACE, DEGESCO, EADI, GERAD, DemGene, FinnGen, ADGC, CHARGE

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

1 Scopus citations

Abstract

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10⁻⁸) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10⁻⁶). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

Original language	English
Article number	113386
Pages (from-to)	2335-2346
Number of pages	12
Journal	Molecular Psychiatry
Volume	30
Issue number	6
DOIs	https://doi.org/10.1038/s41380-024-02838-5
State	Published - Jun 2025

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10.1038/s41380-024-02838-5

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@article{ce2f7ad5c97a44298c0baafa10d02095,

title = "X‐chromosome-wide association study for Alzheimer{\textquoteright}s disease",

abstract = "Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer{\textquoteright}s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10−8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10−6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.",

author = "{EADB, GR@ACE, DEGESCO, EADI, GERAD, DemGene, FinnGen, ADGC, CHARGE} and {Le Borgne}, Julie and Lissette Gomez and Sami Heikkinen and Najaf Amin and Shahzad Ahmad and Choi, {Seung Hoan} and Joshua Bis and Benjamin Grenier-Boley and Rodriguez, {Omar Garcia} and Luca Kleineidam and Juan Young and Tripathi, {Kumar Parijat} and Lily Wang and Achintya Varma and Rafael Campos-Martin and {van der Lee}, Sven and Vincent Damotte and {de Rojas}, Itziar and Sagnik Palmal and Richard Lipton and Eric Reiman and Ann McKee and {De Jager}, Philip and William Bush and Scott Small and Allan Levey and Andrew Saykin and Tatiana Foroud and Marilyn Albert and Bradley Hyman and Ronald Petersen and Steven Younkin and Mary Sano and Thomas Wisniewski and Robert Vassar and Julie Schneider and Victor Henderson and Erik Roberson and Charles DeCarli and Frank LaFerla and James Brewer and Russell Swerdlow and {Van Eldik}, Linda and Kara Hamilton-Nelson and Henry Paulson and Adam Naj and Oscar Lopez and Helena Chui and Paul Crane and Thomas Grabowski and Walter Kukull and Sanjay Asthana and Suzanne Craft and Stephen Strittmatter and Carlos Cruchaga and James Leverenz and Alison Goate and Kamboh, {M. Ilyas} and George-Hyslop, {Peter St} and Otto Valladares and Amanda Kuzma and Laura Cantwell and Matthias Riemenschneider and John Morris and Susan Slifer and Carolina Dalmasso and Atahualpa Castillo and Fahri K{\"u}{\c c}{\"u}kali and Oliver Peters and Anja Schneider and Martin Dichgans and Dan Rujescu and Norbert Scherbaum and J{\"u}rgen Deckert and Steffi Riedel-Heller and Lucrezia Hausner and Laura Molina-Porcel and Emrah D{\"u}zel and Timo Grimmer and Jens Wiltfang and Stefanie Heilmann-Heimbach and Susanne Moebus and Thomas Tegos and Nikolaos Scarmeas and Oriol Dols-Icardo and Fermin Moreno and Jordi P{\'e}rez-Tur and Bullido, {Mar{\'i}a J.} and Pau Pastor and Raquel S{\'a}nchez-Valle and Victoria {\'A}lvarez and Merc{\`e} Boada and Pablo Garc{\'i}a-Gonz{\'a}lez and Raquel Puerta and Pablo Mir and Real, {Luis M.} and Gerard Pi{\~n}ol-Ripoll and Garc{\'i}a-Alberca, {Jose Mar{\'i}a} and Royo, {Jose Lu{\'i}s} and Eloy Rodriguez-Rodriguez and Hilkka Soininen and {de Mendon{\c c}a}, Alexandre and Shima Mehrabian and Latchezar Traykov and Jakub Hort and Martin Vyhnalek and Thomassen, {Jesper Qvist} and Pijnenburg, {Yolande A.L.} and Henne Holstege and {van Swieten}, John and Inez Ramakers and Frans Verhey and Philip Scheltens and Caroline Graff and Goran Papenberg and Vilmantas Giedraitis and Anne Boland and Deleuze, {Jean Fran{\c c}ois} and Gael Nicolas and Carole Dufouil and Florence Pasquier and Olivier Hanon and St{\'e}phanie Debette and Edna Gr{\"u}nblatt and Julius Popp and Roberta Ghidoni and Daniela Galimberti and Beatrice Arosio and Patrizia Mecocci and Vincenzo Solfrizzi and Lucilla Parnetti and Alessio Squassina and Lucio Tremolizzo and Barbara Borroni and Benedetta Nacmias and Marco Spallazzi and Davide Seripa and Innocenzo Rainero and Antonio Daniele and Paola Boss{\`u} and Carlo Masullo and Giacomina Rossi and Frank Jessen and Victoria Fernandez and Kehoe, {Patrick Gavin} and Ruth Frikke-Schmidt and Magda Tsolaki and Pascual S{\'a}nchez-Juan and Kristel Sleegers and Martin Ingelsson and Jonathan Haines and Lindsay Farrer and Richard Mayeux and Wang, {Li San} and Rebecca Sims and Anita DeStefano and Schellenberg, {Gerard D.} and Sudha Seshadri and Philippe Amouyel and Julie Williams and {van der Flier}, Wiesje and Alfredo Ramirez and Margaret Pericak-Vance and Andreassen, {Ole A.} and {Van Duijn}, Cornelia and Mikko Hiltunen and Agust{\'i}n Ruiz and Jos{\'e}e Dupuis and Eden Martin and Lambert, {Jean Charles} and Brian Kunkle and C{\'e}line Bellenguez",

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

year = "2025",

month = jun,

doi = "10.1038/s41380-024-02838-5",

language = "English",

volume = "30",

pages = "2335--2346",

journal = "Molecular Psychiatry",

issn = "1359-4184",

number = "6",

}

TY - JOUR

T1 - X‐chromosome-wide association study for Alzheimer’s disease

AU - EADB, GR@ACE, DEGESCO, EADI, GERAD, DemGene, FinnGen, ADGC, CHARGE

AU - Le Borgne, Julie

AU - Gomez, Lissette

AU - Heikkinen, Sami

AU - Amin, Najaf

AU - Ahmad, Shahzad

AU - Choi, Seung Hoan

AU - Bis, Joshua

AU - Grenier-Boley, Benjamin

AU - Rodriguez, Omar Garcia

AU - Kleineidam, Luca

AU - Young, Juan

AU - Tripathi, Kumar Parijat

AU - Wang, Lily

AU - Varma, Achintya

AU - Campos-Martin, Rafael

AU - van der Lee, Sven

AU - Damotte, Vincent

AU - de Rojas, Itziar

AU - Palmal, Sagnik

AU - Lipton, Richard

AU - Reiman, Eric

AU - McKee, Ann

AU - De Jager, Philip

AU - Bush, William

AU - Small, Scott

AU - Levey, Allan

AU - Saykin, Andrew

AU - Foroud, Tatiana

AU - Albert, Marilyn

AU - Hyman, Bradley

AU - Petersen, Ronald

AU - Younkin, Steven

AU - Sano, Mary

AU - Wisniewski, Thomas

AU - Vassar, Robert

AU - Schneider, Julie

AU - Henderson, Victor

AU - Roberson, Erik

AU - DeCarli, Charles

AU - LaFerla, Frank

AU - Brewer, James

AU - Swerdlow, Russell

AU - Van Eldik, Linda

AU - Hamilton-Nelson, Kara

AU - Paulson, Henry

AU - Naj, Adam

AU - Lopez, Oscar

AU - Chui, Helena

AU - Crane, Paul

AU - Grabowski, Thomas

AU - Kukull, Walter

AU - Asthana, Sanjay

AU - Craft, Suzanne

AU - Strittmatter, Stephen

AU - Cruchaga, Carlos

AU - Leverenz, James

AU - Goate, Alison

AU - Kamboh, M. Ilyas

AU - George-Hyslop, Peter St

AU - Valladares, Otto

AU - Kuzma, Amanda

AU - Cantwell, Laura

AU - Riemenschneider, Matthias

AU - Morris, John

AU - Slifer, Susan

AU - Dalmasso, Carolina

AU - Castillo, Atahualpa

AU - Küçükali, Fahri

AU - Peters, Oliver

AU - Schneider, Anja

AU - Dichgans, Martin

AU - Rujescu, Dan

AU - Scherbaum, Norbert

AU - Deckert, Jürgen

AU - Riedel-Heller, Steffi

AU - Hausner, Lucrezia

AU - Molina-Porcel, Laura

AU - Düzel, Emrah

AU - Grimmer, Timo

AU - Wiltfang, Jens

AU - Heilmann-Heimbach, Stefanie

AU - Moebus, Susanne

AU - Tegos, Thomas

AU - Scarmeas, Nikolaos

AU - Dols-Icardo, Oriol

AU - Moreno, Fermin

AU - Pérez-Tur, Jordi

AU - Bullido, María J.

AU - Pastor, Pau

AU - Sánchez-Valle, Raquel

AU - Álvarez, Victoria

AU - Boada, Mercè

AU - García-González, Pablo

AU - Puerta, Raquel

AU - Mir, Pablo

AU - Real, Luis M.

AU - Piñol-Ripoll, Gerard

AU - García-Alberca, Jose María

AU - Royo, Jose Luís

AU - Rodriguez-Rodriguez, Eloy

AU - Soininen, Hilkka

AU - de Mendonça, Alexandre

AU - Mehrabian, Shima

AU - Traykov, Latchezar

AU - Hort, Jakub

AU - Vyhnalek, Martin

AU - Thomassen, Jesper Qvist

AU - Pijnenburg, Yolande A.L.

AU - Holstege, Henne

AU - van Swieten, John

AU - Ramakers, Inez

AU - Verhey, Frans

AU - Scheltens, Philip

AU - Graff, Caroline

AU - Papenberg, Goran

AU - Giedraitis, Vilmantas

AU - Boland, Anne

AU - Deleuze, Jean François

AU - Nicolas, Gael

AU - Dufouil, Carole

AU - Pasquier, Florence

AU - Hanon, Olivier

AU - Debette, Stéphanie

AU - Grünblatt, Edna

AU - Popp, Julius

AU - Ghidoni, Roberta

AU - Galimberti, Daniela

AU - Arosio, Beatrice

AU - Mecocci, Patrizia

AU - Solfrizzi, Vincenzo

AU - Parnetti, Lucilla

AU - Squassina, Alessio

AU - Tremolizzo, Lucio

AU - Borroni, Barbara

AU - Nacmias, Benedetta

AU - Spallazzi, Marco

AU - Seripa, Davide

AU - Rainero, Innocenzo

AU - Daniele, Antonio

AU - Bossù, Paola

AU - Masullo, Carlo

AU - Rossi, Giacomina

AU - Jessen, Frank

AU - Fernandez, Victoria

AU - Kehoe, Patrick Gavin

AU - Frikke-Schmidt, Ruth

AU - Tsolaki, Magda

AU - Sánchez-Juan, Pascual

AU - Sleegers, Kristel

AU - Ingelsson, Martin

AU - Haines, Jonathan

AU - Farrer, Lindsay

AU - Mayeux, Richard

AU - Wang, Li San

AU - Sims, Rebecca

AU - DeStefano, Anita

AU - Schellenberg, Gerard D.

AU - Seshadri, Sudha

AU - Amouyel, Philippe

AU - Williams, Julie

AU - van der Flier, Wiesje

AU - Ramirez, Alfredo

AU - Pericak-Vance, Margaret

AU - Andreassen, Ole A.

AU - Van Duijn, Cornelia

AU - Hiltunen, Mikko

AU - Ruiz, Agustín

AU - Dupuis, Josée

AU - Martin, Eden

AU - Lambert, Jean Charles

AU - Kunkle, Brian

AU - Bellenguez, Céline

PY - 2025/6

Y1 - 2025/6

N2 - Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10−8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10−6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

AB - Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10−8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10−6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

UR - http://www.scopus.com/inward/record.url?scp=85211480840&partnerID=8YFLogxK

U2 - 10.1038/s41380-024-02838-5

DO - 10.1038/s41380-024-02838-5

M3 - Article

C2 - 39633006

AN - SCOPUS:85211480840

SN - 1359-4184

VL - 30

SP - 2335

EP - 2346

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 6

M1 - 113386

ER -

X‐chromosome-wide association study for Alzheimer’s disease

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