阿尔茨海默病的全X染色体关联研究。

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

作者信息

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, 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

机构信息

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, LabEx DISTALZ - U1167-RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Lille, France.

The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.

出版信息

Mol Psychiatry. 2025 Jun;30(6):2335-2346. doi: 10.1038/s41380-024-02838-5. Epub 2024 Dec 4.

DOI:10.1038/s41380-024-02838-5

PMID:39633006

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12092188/

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) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10). 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.

摘要

由于方法学原因，X染色体未在阿尔茨海默病（AD）的主要全基因组关联研究中得到关注。为解决这一问题并更好地描绘AD的遗传图谱，我们对115,841例AD病例或AD替代病例进行了深入的全X染色体关联研究（XWAS），其中包括52,214例临床诊断的AD病例和613,671例对照。我们考虑了三种方法来解释女性中不同的X染色体失活（XCI）状态，即随机XCI、偏态XCI和逃逸XCI。我们未检测到任何全基因组显著信号（P≤5×10），但鉴定出了7个全X染色体显著位点（P≤1.6×10）。索引变异在Xp22.32、FRMPD4、DMD和Xq25位点较为常见，而在WNK3、PJA1和DACH2位点较为罕见。总体而言，这项样本量充足的XWAS研究未在X染色体的非假常染色体区域发现AD的遗传风险因素，但识别出了值得进一步研究的提示性信号。