Le Borgne, JulieHeikkinen, SamiAmin, NajafAhmad, ShahzadChoi, Seung HoanBis, JoshuaMir Rivera, PabloReal Navarrete, Luis MiguelRodriguez-Rodriguez, Eloy2025-07-022025-07-022024-12-04Le Borgne, J., Heikkinen, S., Amin, N., Ahmad, S., Choi, S.H., Bis, J.,...,Rodriguez-Rodriguez, E. (2024). X-chromosome-wide association study for Alzheimer's disease. Molecular psychiatry, 30 (6), 2335-2346. https://doi.org/10.1038/s41380-024-02838-5.1359-41841476-55781476-5578https://hdl.handle.net/11441/174866Due 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.application/pdf12 p.engMild cognitive impairmentDementia incidenceSex-differencesInactivation patternsfamily-historyRisk LociProgressionPrevalenceMetaanalysisTauinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10.1038/s41380-024-02838-5