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.
Originalsprog | Engelsk |
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Artikelnummer | 113386 |
Tidsskrift | Molecular Psychiatry |
ISSN | 1359-4184 |
DOI | |
Status | E-pub ahead of print - 2024 |
Bibliografisk note
Funding Information:EADB: This study was supported by grants from the Fondation pour la Recherche sur Alzheimer (convention 2022-A-01 and cluster grant), and the JPco-fuND-2 \u2018Multinational research projects on Personalized Medicine for Neurodegenerative Diseases\u2019 PREADAPT project (ANR-19-JPW2-0004). We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). This work was funded by a grant (EADB) from the EU Joint Programme\u2014Neurodegenerative Disease Research. Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille M\u00E9tropole Communaut\u00E9 Urbaine and French government\u2019s LABEX DISTALZ program (Development of Innovative Strategies for a Transdisciplinary Approach to ALZheimer\u2019s disease). This work was also supported by the Research Council of Finland grants 338182 and 334802, the Sigrid Jus\u00E9lius Foundation, and the Strategic Neuroscience Funding of the University of Eastern Finland. ADGC: The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; Samples from the National Cell Repository for Alzheimer\u2019s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer\u2019s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01) in cooperation with NACC (U24 AG072122) and additional studies described in the . Full consortium acknowledgments and funding are in the .
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© The Author(s) 2024.