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.
X‐chromosome-wide association study for Alzheimer’s disease / J. Le Borgne, L. Gomez, S. Heikkinen, N. Amin, S. Ahmad, S.H. Choi, J. Bis, B. Grenier-Boley, O.G. Rodriguez, L. Kleineidam, J. Young, K.P. Tripathi, L. Wang, A. Varma, R. Campos-Martin, S. Van Der Lee, V. Damotte, I. De Rojas, S. Palmal, N. Null, R. Lipton, E. Reiman, A. Mckee, P. De Jager, W. Bush, S. Small, A. Levey, A. Saykin, T. Foroud, M. Albert, B. Hyman, R. Petersen, S. Younkin, M. Sano, T. Wisniewski, R. Vassar, J. Schneider, V. Henderson, E. Roberson, C. Decarli, F. Laferla, J. Brewer, R. Swerdlow, L. Van Eldik, K. Hamilton-Nelson, H. Paulson, A. Naj, O. Lopez, H. Chui, P. Crane, T. Grabowski, W. Kukull, S. Asthana, S. Craft, S. Strittmatter, C. Cruchaga, J. Leverenz, A. Goate, M.I. Kamboh, P.S. George-Hyslop, O. Valladares, A. Kuzma, L. Cantwell, M. Riemenschneider, J. Morris, S. Slifer, C. Dalmasso, A. Castillo, F. Küçükali, O. Peters, A. Schneider, M. Dichgans, D. Rujescu, N. Scherbaum, J. Deckert, S. Riedel-Heller, L. Hausner, L. Molina-Porcel, E. Düzel, T. Grimmer, J. Wiltfang, S. Heilmann-Heimbach, S. Moebus, T. Tegos, N. Scarmeas, O. Dols-Icardo, F. Moreno, J. Pérez-Tur, M.J. Bullido, P. Pastor, R. Sánchez-Valle, V. Álvarez, M. Boada, P. García-González, R. Puerta, P. Mir, L.M. Real, G. Piñol-Ripoll, J.M. García-Alberca, J.L. Royo, E. Rodriguez-Rodriguez, H. Soininen, A. De Mendonça, S. Mehrabian, L. Traykov, J. Hort, M. Vyhnalek, J.Q. Thomassen, Y.A.L. Pijnenburg, H. Holstege, J. Van Swieten, I. Ramakers, F. Verhey, P. Scheltens, C. Graff, G. Papenberg, V. Giedraitis, A. Boland, J. Deleuze, G. Nicolas, C. Dufouil, F. Pasquier, O. Hanon, S. Debette, E. Grünblatt, J. Popp, R. Ghidoni, D. Galimberti, B. Arosio, P. Mecocci, V. Solfrizzi, L. Parnetti, A. Squassina, L. Tremolizzo, B. Borroni, B. Nacmias, M. Spallazzi, D. Seripa, I. Rainero, A. Daniele, P. Bossù, C. Masullo, G. Rossi, F. Jessen, V. Fernandez, P.G. Kehoe, R. Frikke-Schmidt, M. Tsolaki, P. Sánchez-Juan, K. Sleegers, M. Ingelsson, J. Haines, L. Farrer, R. Mayeux, L. Wang, R. Sims, A. Destefano, G.D. Schellenberg, S. Seshadri, P. Amouyel, J. Williams, W. Van Der Flier, A. Ramirez, M. Pericak-Vance, O.A. Andreassen, C. Van Duijn, M. Hiltunen, A. Ruiz, J. Dupuis, E. Martin, J. Lambert, B. Kunkle, C. Bellenguez. - In: MOLECULAR PSYCHIATRY. - ISSN 1359-4184. - 30:6(2025), pp. 2335-2346. [10.1038/s41380-024-02838-5]
X‐chromosome-wide association study for Alzheimer’s disease
D. Galimberti;B. Arosio;
2025
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.
| File | Dimensione | Formato | |
|---|---|---|---|
|
41380_2024_Article_2838.pdf
accesso aperto
Tipologia:
Publisher's version/PDF
Licenza:
Creative commons
Dimensione
4.27 MB
Formato
Adobe PDF
|
4.27 MB | Adobe PDF | Visualizza/Apri |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
