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

Journal: Molecular Psychiatry

Published: June 18, 2024

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.

Authors

Julie Le Borgne, Lissette Gomez, Sami Heikkinen, Najaf Amin, Shahzad Ahmad, Seung Choi, Joshua Bis, Benjamin Grenier Boley, Omar Rodriguez, Luca Kleineidam, Juan Young, Kumar Tripathi, Lily Wang, Achintya Varma, Rafael Campos Martin, Sven Van Der Lee, Vincent Damotte, Itziar De Rojas, Sagnik Palmal, 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, Thomas Grabowski, Walter Kukull, Sanjay Asthana, Suzanne Craft, Stephen Strittmatter, Carlos Cruchaga, James Leverenz, Alison Goate, M Kamboh, Peter George Hyslop, Otto Valladares, Amanda Kuzma, Laura Cantwell, Matthias Riemenschneider, John Morris, Susan Slifer, Carolina Dalmasso, Atahualpa Castillo, Fahri Küçükali, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Jürgen Deckert, Steffi Riedel Heller, Lucrezia Hausner, Laura Molina Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols Icardo, Fermin Moreno, Jordi Pérez Tur, María Bullido, Pau Pastor, Raquel Sánchez Valle, Victoria Álvarez, Mercè Boada, Pablo García González, Raquel Puerta, Pablo Mir, Luis Real, Gerard Piñol Ripoll, Jose García Alberca, Jose Royo, Eloy Rodriguez, Hilkka Soininen, Alexandre De Mendonça, Shima Mehrabian, Latchezar Traykov, Jakub Hort, Martin Vyhnalek, Jesper Thomassen, Yolande A Pijnenburg, Henne Holstege, John Van Swieten, Inez Ramakers, Frans Verhey, Philip Scheltens, Caroline Graff, Goran Papenberg, Vilmantas Giedraitis, Anne Boland, Jean-françois Deleuze, Gael Nicolas, Carole Dufouil, Florence Pasquier, Olivier Hanon, Stéphanie Debette, Edna Grünblatt, Julius Popp, Roberta Ghidoni, Daniela Galimberti, Beatrice Arosio, Patrizia Mecocci, Vincenzo Solfrizzi, Lucilla Parnetti, Alessio Squassina, Lucio Tremolizzo, Barbara Borroni, Benedetta Nacmias, Marco Spallazzi, Davide Seripa, Innocenzo Rainero, Antonio Daniele, Paola Bossù, Carlo Masullo, Giacomina Rossi, Frank Jessen, Victoria Fernandez, Patrick Kehoe, Ruth Frikke Schmidt, Magda Tsolaki, Pascual Sánchez Juan, Kristel Sleegers, Martin Ingelsson, Jonathan Haines, Lindsay Farrer, Richard Mayeux, Li-san Wang, Rebecca Sims, Anita Destefano, Gerard Schellenberg, Sudha Seshadri, Philippe Amouyel, Julie Williams, Wiesje Van Der Flier, Alfredo Ramirez, Margaret Pericak Vance, Ole Andreassen, Cornelia Van Duijn, Mikko Hiltunen, Agustín Ruiz, Josée Dupuis, Eden Martin, Jean-charles Lambert, Brian Kunkle, Céline Bellenguez

Relevant Conditions

Alzheimer's Disease, Dementia

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

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