X‐chromosome-wide association study for Alzheimer’s disease
Authors: Le Borgne Julie , Gomez Lissette , Heikkinen Sami , Amin Najaf , Ahmad Shahzad , Choi Seung Hoan , Bis Joshua , Grenier-Boley Benjamin , Rodriguez Omar Garcia , Kleineidam Luca , Young Juan , Tripathi Kumar Parijat , Wang Lily , Varma Achintya , Campos-Martin Rafael , van der Lee Sven , Damotte Vincent , de Rojas Itziar , Palmal Sagnik ,   EADB, GR@ACE, DEGESCO, EADI, GERAD, DemGene, FinnGen, ADGC, CHARGE, Lipton Richard , Reiman Eric , McKee Ann , De Jager Philip , Bush William , Small Scott , Levey Allan , Saykin Andrew , Foroud Tatiana , Albert Marilyn , Hyman Bradley , Petersen Ronald , Younkin Steven , Sano Mary , Wisniewski Thomas , Vassar Robert , Schneider Julie , Henderson Victor , Roberson Erik , DeCarli Charles , LaFerla Frank , Brewer James , Swerdlow Russell , Van Eldik Linda , Hamilton-Nelson Kara , Paulson Henry , Naj Adam , Lopez Oscar , Chui Helena , Crane Paul , Grabowski Thomas , Kukull Walter , Asthana Sanjay , Craft Suzanne , Strittmatter Stephen , Cruchaga Carlos , Leverenz James , Goate Alison , Kamboh M. Ilyas , George-Hyslop Peter St , Valladares Otto , Kuzma Amanda , Cantwell Laura , Riemenschneider Matthias , Morris John , Slifer Susan , Dalmasso Carolina , Castillo Atahualpa , Küçükali Fahri , Peters Oliver , Schneider Anja , Dichgans Martin , Rujescu Dan , Scherbaum Norbert , Deckert Jürgen , Riedel-Heller Steffi , Hausner Lucrezia , Molina-Porcel Laura , Düzel Emrah , Grimmer Timo , Wiltfang Jens , Heilmann-Heimbach Stefanie , Moebus Susanne , Tegos Thomas , Scarmeas Nikolaos , Dols-Icardo Oriol , Moreno Fermin , Pérez-Tur Jordi , Bullido María J. , Pastor Pau , Sánchez-Valle Raquel , Álvarez Victoria , Boada Mercè , García-González Pablo , Puerta Raquel , Mir Pablo , Real Luis M. , Piñol-Ripoll Gerard , García-Alberca Jose María , Royo Jose Luís , Rodriguez-Rodriguez Eloy , Soininen Hilkka , de Mendonça Alexandre , Mehrabian Shima , Traykov Latchezar , Hort Jakub , Vyhnalek Martin , Thomassen Jesper Qvist , Pijnenburg Yolande A. L. , Holstege Henne , van Swieten John , Ramakers Inez , Verhey Frans , Scheltens Philip , Graff Caroline , Papenberg Goran , Giedraitis Vilmantas , Boland Anne , Deleuze Jean-François , Nicolas Gael , Dufouil Carole , Pasquier Florence , Hanon Olivier , Debette Stéphanie , Grünblatt Edna , Popp Julius , Ghidoni Roberta , Galimberti Daniela , Arosio Beatrice , Mecocci Patrizia , Solfrizzi Vincenzo , Parnetti Lucilla , Squassina Alessio , Tremolizzo Lucio , Borroni Barbara , Nacmias Benedetta , Spallazzi Marco , Seripa Davide , Rainero Innocenzo , Daniele Antonio , Bossù Paola , Masullo Carlo , Rossi Giacomina , Jessen Frank , Fernandez Victoria , Kehoe Patrick Gavin , Frikke-Schmidt Ruth , Tsolaki Magda , Sánchez-Juan Pascual , Sleegers Kristel , Ingelsson Martin , Haines Jonathan , Farrer Lindsay , Mayeux Richard , Wang Li-San , Sims Rebecca , DeStefano Anita , Schellenberg Gerard D. , Seshadri Sudha , Amouyel Philippe , Williams Julie , van der Flier Wiesje , Ramirez Alfredo , Pericak-Vance Margaret , Andreassen Ole A. , Van Duijn Cornelia , Hiltunen Mikko , Ruiz Agustín , Dupuis Josée , Martin Eden , Lambert Jean-Charles , Kunkle Brian , Bellenguez Céline 
Published: December 2024

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.