X-chromosome-wide association study for Alzheimer's disease

Julie Le Borgne; Lissette Gomez; Sami Heikkinen; Najaf Amin; Shahzad Ahmad; Seung Hoan Choi; Joshua Bis; Benjamin Grenier-Boley; Omar Garcia Rodriguez; Luca Kleineidam; Juan Young; Kumar Parijat Tripathi; Lily Wang; Achintya Varma; Rafael Campos-Martin; Sven van der Lee; Vincent Damotte; Itziar de Rojas; Sagnik Palmal; Richard Lipton; Eric Reiman; Ann McKee; Philip De Jager; William Bush; Scott Small; Allan Levey; Andrew Saykin; Tatiana Foroud; Marilyn Albert; Bradley Hyman; Ronald Petersen; Steven Younkin; Mary Sano; Thomas Wisniewski; Robert Vassar; Julie Schneider; Victor Henderson; Erik Roberson; Charles DeCarli; Frank LaFerla; James Brewer; Russell Swerdlow; Linda Van Eldik; Kara Hamilton-Nelson; Henry Paulson; Adam Naj; Oscar Lopez; Helena Chui; Paul Crane; Inez Ramakers; Frans Verhey; EADB; GR@ACE study group; DEGESCO consortium; EADI; GERAD; DemGene; FinnGen Investigators; Alzheimer's Disease Genetics Consortium (ADGC); CHARGE Consortium; Céline Bellenguez

doi:10.1038/s41380-024-02838-5

X-chromosome-wide association study for Alzheimer's disease

Julie Le Borgne, Lissette Gomez, Sami Heikkinen, Najaf Amin, Shahzad Ahmad, Seung Hoan Choi, Joshua Bis, Benjamin Grenier-Boley, Omar Garcia Rodriguez, Luca Kleineidam, Juan Young, Kumar Parijat Tripathi, Lily Wang, Achintya Varma, Rafael Campos-Martin, Sven van der Lee, Vincent Damotte, Itziar de Rojas, Sagnik Palmal, Richard LiptonEric Reiman, Ann McKee, Philip De Jager, William Bush, Scott Small, Allan Levey, Andrew Saykin, Tatiana Foroud, Marilyn Albert, Bradley Hyman, Ronald Petersen, Steven Younkin, Mary Sano, Thomas Wisniewski, Robert Vassar, Julie Schneider, Victor Henderson, Erik Roberson, Charles DeCarli, Frank LaFerla, James Brewer, Russell Swerdlow, Linda Van Eldik, Kara Hamilton-Nelson, Henry Paulson, Adam Naj, Oscar Lopez, Helena Chui, Paul Crane, Inez Ramakers, Frans Verhey, EADB, GR@ACE study group, DEGESCO consortium, EADI, GERAD, DemGene, FinnGen Investigators, Alzheimer's Disease Genetics Consortium (ADGC), CHARGE Consortium, Céline Bellenguez^*

^*Corresponding author for this work

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

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
Journal	Molecular Psychiatry
DOIs	https://doi.org/10.1038/s41380-024-02838-5
Publication status	E-pub ahead of print - 4 Dec 2024

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Le Borgne, J., Gomez, L., Heikkinen, S., Amin, N., Ahmad, S., Choi, S. H., Bis, J., Grenier-Boley, B., Rodriguez, O. G., Kleineidam, L., Young, J., Tripathi, K. P., Wang, L., Varma, A., Campos-Martin, R., van der Lee, S., Damotte, V., de Rojas, I., Palmal, S., ... Bellenguez, C. (2024). X-chromosome-wide association study for Alzheimer's disease. Molecular Psychiatry, Article 113386. Advance online publication. https://doi.org/10.1038/s41380-024-02838-5

@article{831cb6f3919d4aaf82c1382b3fc0cf73,

title = "X-chromosome-wide association study for Alzheimer'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 = "{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 Inez Ramakers and Frans Verhey and EADB and {GR@ACE study group} and {DEGESCO consortium} and EADI and GERAD and DemGene and {FinnGen Investigators} and {Alzheimer's Disease Genetics Consortium (ADGC)} and {CHARGE Consortium} and C{\'e}line Bellenguez",

year = "2024",

month = dec,

day = "4",

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

language = "English",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer",

}

Le Borgne, J, Gomez, L, Heikkinen, S, Amin, N, Ahmad, S, Choi, SH, Bis, J, Grenier-Boley, B, Rodriguez, OG, Kleineidam, L, Young, J, Tripathi, KP, Wang, L, Varma, A, Campos-Martin, R, van der Lee, S, Damotte, V, de Rojas, I, Palmal, S, Lipton, R, Reiman, E, McKee, A, De Jager, P, Bush, W, Small, S, Levey, A, Saykin, A, Foroud, T, Albert, M, Hyman, B, Petersen, R, Younkin, S, Sano, M, Wisniewski, T, Vassar, R, Schneider, J, Henderson, V, Roberson, E, DeCarli, C, LaFerla, F, Brewer, J, Swerdlow, R, Van Eldik, L, Hamilton-Nelson, K, Paulson, H, Naj, A, Lopez, O, Chui, H, Crane, P, Ramakers, I , Verhey, F, EADB, GR@ACE study group, DEGESCO consortium, EADI, GERAD, DemGene, FinnGen Investigators, Alzheimer's Disease Genetics Consortium (ADGC), CHARGE Consortium & Bellenguez, C 2024, 'X-chromosome-wide association study for Alzheimer's disease', Molecular Psychiatry. https://doi.org/10.1038/s41380-024-02838-5

TY - JOUR

T1 - X-chromosome-wide association study for Alzheimer's disease

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 - Ramakers, Inez

AU - Verhey, Frans

AU - EADB

AU - GR@ACE study group

AU - DEGESCO consortium

AU - EADI

AU - GERAD

AU - DemGene

AU - FinnGen Investigators

AU - Alzheimer's Disease Genetics Consortium (ADGC)

AU - CHARGE Consortium

AU - Bellenguez, Céline

PY - 2024/12/4

Y1 - 2024/12/4

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.

U2 - 10.1038/s41380-024-02838-5

DO - 10.1038/s41380-024-02838-5

M3 - Article

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

M1 - 113386

ER -

X-chromosome-wide association study for Alzheimer's disease

Abstract

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