X‐chromosome-wide association study for Alzheimer’s disease
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<sup>-</sup><sup>8</sup>) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10<sup>-</sup><sup>6</sup>). 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
- Richard B. Lipton (ORCID: https://orcid.org/0000-0003-2652-2897)
- Emrah Düzel (ORCID: https://orcid.org/0000-0002-0139-5388)
- Anita L. DeStefano (ORCID: https://orcid.org/0000-0002-9335-2819)
- Laura Molina‐Porcel (ORCID: https://orcid.org/0000-0003-4068-8578)
- Najaf Amin (ORCID: https://orcid.org/0000-0002-8944-1771)
- Jean‐Charles Lambert (ORCID: https://orcid.org/0000-0003-0829-7817)
- Martin Ingelsson (ORCID: https://orcid.org/0000-0001-5466-8370)
- Jens Wiltfang (ORCID: https://orcid.org/0000-0003-1492-5330)
- Luís Miguel Real (ORCID: https://orcid.org/0000-0003-4932-7429)
- Juan I. Young
- Olivier Hanon (ORCID: https://orcid.org/0000-0002-4697-122X)
- Sudha S. Seshadri (ORCID: https://orcid.org/0000-0001-6135-2622)
- Caroline Graff (ORCID: https://orcid.org/0000-0002-9949-2951)
- Giacomina Rossi (ORCID: https://orcid.org/0000-0001-6680-2725)
- Agustı́n Ruiz (ORCID: https://orcid.org/0000-0003-2633-2495)
- Kristel Sleegers (ORCID: https://orcid.org/0000-0002-0283-2332)
- Cornelia M. van Duijn (ORCID: https://orcid.org/0000-0002-2374-9204)
- Patrizia Mecocci (ORCID: https://orcid.org/0000-0003-0729-5246)
- Pablo Mir (ORCID: https://orcid.org/0000-0003-1656-302X)
- Suzanne Craft (ORCID: https://orcid.org/0000-0003-0591-8657)
- Oliver Peters (ORCID: https://orcid.org/0000-0003-0568-2998)
- Otto Valladares (ORCID: https://orcid.org/0000-0001-8055-2187)
- Lucilla Parnetti (ORCID: https://orcid.org/0000-0001-5722-3967)
- Ole A. Andreassen (ORCID: https://orcid.org/0000-0002-4461-3568)
- Vilmantas Giedraitis (ORCID: https://orcid.org/0000-0003-3423-2021)
- Jonathan L. Haines (ORCID: https://orcid.org/0000-0002-4351-4728)
- Julius Popp (ORCID: https://orcid.org/0000-0002-0068-0312)
- Julie A. Schneider (ORCID: https://orcid.org/0000-0002-9482-1752)
- Omar Garcia Rodriguez
- Marilyn Albert (ORCID: https://orcid.org/0000-0002-8167-8985)
- Allan I. Levey (ORCID: https://orcid.org/0000-0002-3153-502X)
- Linda J. Van Eldik (ORCID: https://orcid.org/0000-0002-8139-6400)
- Eloy Rodríguez‐Rodríguez (ORCID: https://orcid.org/0000-0001-7742-677X)
- Philip Scheltens (ORCID: https://orcid.org/0000-0002-1046-6408)
- Stephen M. Strittmatter (ORCID: https://orcid.org/0000-0001-8188-3092)
- Andrew J. Saykin (ORCID: https://orcid.org/0000-0002-1376-8532)
- Frank M. LaFerla (ORCID: https://orcid.org/0000-0003-2324-6911)
- Norbert Scherbaum (ORCID: https://orcid.org/0000-0003-1759-6990)
- Itziar de Rojas (ORCID: https://orcid.org/0000-0002-2148-381X)
- Patrick G. Kehoe (ORCID: https://orcid.org/0000-0002-7542-1139)
- Pau Pástor (ORCID: https://orcid.org/0000-0002-7493-8777)
- Lily Wang (ORCID: https://orcid.org/0000-0002-8311-4251)
- Robert Vassar (ORCID: https://orcid.org/0000-0002-1358-504X)
- Marco Spallazzi (ORCID: https://orcid.org/0000-0002-8091-2063)
- Alfredo Ramı́rez (ORCID: https://orcid.org/0000-0003-4991-763X)
- Wiesje M. van der Flier (ORCID: https://orcid.org/0000-0001-8766-6224)
- Philippe Amouyel (ORCID: https://orcid.org/0000-0001-9088-234X)
- Carlos Cruchaga (ORCID: https://orcid.org/0000-0002-5261-689X)
- José Luís Royo (ORCID: https://orcid.org/0000-0003-2024-4363)
- Ann Carolyn McKee (ORCID: https://orcid.org/0000-0003-2961-7488)
- Li‐San Wang (ORCID: https://orcid.org/0000-0002-3684-0031)
- Lindsay A. Farrer (ORCID: https://orcid.org/0000-0001-5533-4225)
- Antonio Daniele (ORCID: https://orcid.org/0000-0003-1641-5852)
- Charles DeCarli
- Alexandre de Mendonça (ORCID: https://orcid.org/0000-0002-0488-1453)
- Amanda B Kuzma (ORCID: https://orcid.org/0000-0002-6064-5420)
- Victoria Álvarez (ORCID: https://orcid.org/0000-0002-1916-2523)
- Rebecca Sims (ORCID: https://orcid.org/0000-0002-3885-1199)
- Luca Kleineidam (ORCID: https://orcid.org/0009-0006-3309-6856)
- Kumar Parijat Tripathi (ORCID: https://orcid.org/0000-0002-3998-599X)
- Seung Hoan Choi (ORCID: https://orcid.org/0000-0002-2797-3190)
- Julie Le Borgne
- Dan Rujescu (ORCID: https://orcid.org/0000-0002-1432-313X)
- Thomas Tegos
- Ronald Carl Petersen (ORCID: https://orcid.org/0000-0002-8178-6601)
- Gerard Piñol‐Ripoll (ORCID: https://orcid.org/0000-0002-4495-2113)
- Lucrezia Hausner (ORCID: https://orcid.org/0000-0001-9009-2356)
- Thomas J. Grabowski (ORCID: https://orcid.org/0000-0002-7425-6610)
- Raquel Sánchez‐Valle (ORCID: https://orcid.org/0000-0001-7750-896X)
- Eric M. Reiman (ORCID: https://orcid.org/0000-0002-0705-3696)
- Henne Holstege (ORCID: https://orcid.org/0000-0002-7688-3087)
- Philip L. De Jager (ORCID: https://orcid.org/0000-0002-8057-2505)
- José María García‐Alberca (ORCID: https://orcid.org/0000-0003-2951-6644)
- Carlo Masullo (ORCID: https://orcid.org/0000-0001-7798-3410)
- Julie Williams (ORCID: https://orcid.org/0000-0002-4069-0259)
- Paul K. Crane (ORCID: https://orcid.org/0000-0003-4278-7465)
- Russell Howard Swerdlow (ORCID: https://orcid.org/0000-0003-2948-7230)
- Merçé Boada (ORCID: https://orcid.org/0000-0003-2617-3009)
- James B. Leverenz (ORCID: https://orcid.org/0000-0002-0896-0749)
- Laura Cantwell
- Josée Dupuis (ORCID: https://orcid.org/0000-0003-2871-3603)
- Davide Seripa (ORCID: https://orcid.org/0000-0001-7331-0470)
- Alessio Squassina (ORCID: https://orcid.org/0000-0001-7415-7607)
- Adam C. Naj (ORCID: https://orcid.org/0000-0002-9621-2942)
- Henry L. Paulson (ORCID: https://orcid.org/0000-0002-0382-7535)
- Stefanie Heilmann‐Heimbach (ORCID: https://orcid.org/0000-0003-1057-465X)
- Florence Pasquier (ORCID: https://orcid.org/0000-0001-9880-9788)
- Inez H.G.B. Ramakers (ORCID: https://orcid.org/0000-0002-4747-2879)
- Fahri Küçükali (ORCID: https://orcid.org/0000-0002-3835-9639)
- Sven J. van der Lee (ORCID: https://orcid.org/0000-0003-1606-8643)
- María J. Bullido (ORCID: https://orcid.org/0000-0002-6477-1117)
- Jesper Qvist Thomassen (ORCID: https://orcid.org/0000-0003-3484-9531)
- Carole Dufouil (ORCID: https://orcid.org/0000-0003-2442-4476)
- Walter A. Kukull (ORCID: https://orcid.org/0000-0001-8761-9014)
- Thomas Wısnıewskı (ORCID: https://orcid.org/0000-0002-3379-8966)
- Benedetta Nacmias (ORCID: https://orcid.org/0000-0001-9338-9040)
- Martin Dichgans (ORCID: https://orcid.org/0000-0002-0654-387X)
- Magda Tsolaki (ORCID: https://orcid.org/0000-0002-2072-8010)
- Pascual Sánchez‐Juan (ORCID: https://orcid.org/0000-0002-6081-8037)
- Joshua C. Bis (ORCID: https://orcid.org/0000-0002-3409-1110)
- Jürgen Deckert
- John C. Morris (ORCID: https://orcid.org/0000-0001-9820-5618)
- Martin Vyhnálek (ORCID: https://orcid.org/0000-0002-5976-4932)
- Lucio Tremolizzo (ORCID: https://orcid.org/0000-0003-0473-6560)
- Anne Boland (ORCID: https://orcid.org/0000-0001-8789-5676)
- William S. Bush (ORCID: https://orcid.org/0000-0002-9729-6519)
- Steffi Gerlinde Riedel-Heller (ORCID: https://orcid.org/0000-0003-4321-6090)
- Céline Bellenguez (ORCID: https://orcid.org/0000-0002-1240-7874)
- Roberta Ghidoni (ORCID: https://orcid.org/0000-0002-7691-1957)
- Peter St George‐Hyslop (ORCID: https://orcid.org/0000-0003-0796-7209)
- Bradley T. Hyman (ORCID: https://orcid.org/0000-0002-7959-9401)
- Sami Heikkinen (ORCID: https://orcid.org/0000-0002-6083-2402)
- Jordi Pérez‐Tur (ORCID: https://orcid.org/0000-0002-9111-1712)
- Atahualpa Castillo-Morales (ORCID: https://orcid.org/0000-0001-9733-6923)
- Rafael Campos-Martín (ORCID: https://orcid.org/0000-0002-1395-8571)
- Edna Grünblatt (ORCID: https://orcid.org/0000-0001-8505-7265)
- Scott A. Small (ORCID: https://orcid.org/0000-0002-4777-1502)
- Beatrice Arosio (ORCID: https://orcid.org/0000-0002-0615-3580)
- Markus J. Riemenschneider (ORCID: https://orcid.org/0000-0001-7658-1022)
- Anja Schneider (ORCID: https://orcid.org/0000-0001-9540-8700)
- Carolina Dalmasso (ORCID: https://orcid.org/0000-0002-4901-9955)
- Sagnik Palmal (ORCID: https://orcid.org/0000-0003-1318-7444)
- Stéphanie Debette (ORCID: https://orcid.org/0000-0001-8675-7968)
- Richard P Mayeux (ORCID: https://orcid.org/0000-0001-6519-9696)
- Susanne Moebus (ORCID: https://orcid.org/0000-0002-0072-5410)
- Hilkka Soininen (ORCID: https://orcid.org/0000-0002-2785-9937)
- Raquel Puerta (ORCID: https://orcid.org/0000-0002-1191-5893)
- Innocenzo Rainero (ORCID: https://orcid.org/0000-0001-6074-9628)
- Jakub Hort (ORCID: https://orcid.org/0000-0002-1080-3726)
- Ruth Frikke‐Schmidt (ORCID: https://orcid.org/0000-0003-4084-5027)
- Daniela Galimberti (ORCID: https://orcid.org/0000-0002-9284-5953)
- Erik D. Roberson (ORCID: https://orcid.org/0000-0002-1810-9763)
- M. Ilyas Kamboh (ORCID: https://orcid.org/0000-0002-3453-1438)
- Shima Mehrabian (ORCID: https://orcid.org/0000-0002-3146-6001)
- Oriol Dols‐Icardo (ORCID: https://orcid.org/0000-0003-2656-8748)
- Eden R. Martin (ORCID: https://orcid.org/0000-0002-4035-9152)
- Brian W. Kunkle (ORCID: https://orcid.org/0000-0002-9515-5157)
- Pablo García‐González (ORCID: https://orcid.org/0000-0003-0125-5403)
- Gaël Nicolas (ORCID: https://orcid.org/0000-0001-9391-7800)
- Achintya Varma
- Victor W. Henderson (ORCID: https://orcid.org/0000-0003-1198-9240)
- Fermín Moreno (ORCID: https://orcid.org/0000-0001-5200-3164)
- María Victoria Fernández (ORCID: https://orcid.org/0000-0002-9669-5147)
- Vincent Damotte (ORCID: https://orcid.org/0000-0002-7321-8575)
- Alison Goate (ORCID: https://orcid.org/0000-0002-0576-2472)
- Barbara Borroni (ORCID: https://orcid.org/0000-0001-9340-9814)
- Vincenzo Solfrizzi (ORCID: https://orcid.org/0000-0002-8524-0315)
- Oscar L. López (ORCID: https://orcid.org/0000-0002-8546-8256)
- Shahzad Ahmad (ORCID: https://orcid.org/0000-0002-8658-3790)
- Nikolaos Scarmeas
- Yolande A.L. Pijnenburg (ORCID: https://orcid.org/0000-0003-2464-1905)
- Frans Verhey
- Margaret A. Pericak‐Vance
- Steven G. Younkin
- Gerard D. Schellenberg
- John van Swieten
- Mikko Hiltunen
- Sanjay Asthana (ORCID: https://orcid.org/0000-0002-3298-6324)
- Helena C. Chui
- Paola Bossù
- Mary Sano
- Jean-François Deleuze
- James Brewer
- Kara L. Hamilton‐Nelson
- Timo Grimmer
- Goran Papenberg
- Lissette Gomez
- Tatiana Foroud
- Latchezar Traykov
- Susan Slifer
- Benjamin Grenier‐Boley (ORCID: https://orcid.org/0009-0004-3412-3997)
- Frank Jessen
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Broad Institute (US)
- Tunis University (TN)
- Boston University (US)
- Northwestern University (US)
- University of Southern California (US)
- Uppsala University (SE)
- University of Copenhagen (DK)
- University of Parma (IT)
- Alzheimer's Association (US)
- Oslo University Hospital (NO)
- Brigham and Women's Hospital (US)
- Translational Genomics Research Institute (US)
- Rush University Medical Center (US)
- Albert Einstein College of Medicine (US)
- Universidad de Cantabria (ES)
- Cleveland Clinic (US)
- University Health Network (CA)
- Karolinska University Hospital (SE)
- University of Bonn (DE)
- University of Wisconsin–Madison (US)
- Harvard University (US)
- University of Arizona (US)
- University of Lisbon (PT)
- University of Kentucky (US)
- Johns Hopkins University (US)
- University of Miami (US)
- University of Antwerp (BE)
- Emory University (US)
- Université de Bordeaux (FR)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Inserm (FR)
- Stockholm University (SE)
- University of Pittsburgh (US)
- University of Cagliari (IT)
- University of Eastern Finland (FI)
- University of Phoenix (US)
- University of Cologne (DE)
- University of Oslo (NO)
- University of Toronto (CA)
- University of Milan (IT)
- National and Kapodistrian University of Athens (GR)
- University of Washington (US)
- University of Zurich (CH)
- University of California, Irvine (US)
- Washington University in St. Louis (US)
- Université Paris Cité (FR)
- Charles University (CZ)
- Aristotle University of Thessaloniki (GR)
- Heidelberg University (DE)
- Université de Lille (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- University of Perugia (IT)
- Université Paris-Saclay (FR)
- University of Michigan (US)
- Alexandrovska Hospital (BG)
- University Hospital Bonn (DE)
- Columbia University Irving Medical Center (US)
- Lou Ruvo Brain Institute (US)
- Institut Pasteur de Lille (FR)
- Instituto de Salud Carlos III (ES)
- German Center for Neurodegenerative Diseases (DE)
- Hospital de Sant Pau (ES)
- Erasmus MC (NL)
- Agostino Gemelli University Polyclinic (IT)
- Copenhagen University Hospital (DK)
- TUM Klinikum (DE)
- Rigshospitalet (DK)
- Health Net (US)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Karolinska Institutet (SE)
- Medical University of Sofia (BG)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- LMU Klinikum (DE)
- University of Alabama at Birmingham (US)
- Yale University (US)
- Maastricht University (NL)
- ETH Zurich (CH)
- University of Bristol (GB)
- University of California San Diego (US)
- Humboldt-Universität zu Berlin (DE)
- University of Oxford (GB)
- Centre National de Recherche en Génomique Humaine (FR)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Massachusetts General Hospital (US)
- Hospital Universitari de Santa Maria (ES)
- University Hospital Mútua de Terrassa (ES)
- Assistance Publique – Hôpitaux de Paris (FR)
- Marqués de Valdecilla University Hospital (ES)
- Biogipuzkoa Health Research Institute (ES)
- University Hospital of Zurich (CH)
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- Hospital La Paz Institute for Health Research (ES)
- Central Institute of Mental Health (DE)
- Normandie Université (FR)
- Bordeaux Population Health (FR)
- Hôpital Broca (FR)
- Amsterdam Neuroscience (NL)
- Geriatric Research Education and Clinical Center (US)
- Occupational Cancer Research Centre (CA)
- Institute for Neurodegenerative Disorders (US)
- Instituto de Investigación Marqués de Valdecilla (ES)
- Munich Cluster for Systems Neurology (DE)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- Hospital Clínic de Barcelona (ES)
- Don Carlo Gnocchi Foundation (IT)
- Framingham Heart Study (US)
- Hope Center for Neurological Disorders (US)
- Swiss Integrative Center for Human Health (CH)
- Fundació ACE (ES)
- Mayo Clinic in Arizona (US)
- Universitätsklinikum Würzburg (DE)
- UK Dementia Research Institute (GB)
- CEA Paris-Saclay (FR)
- University of Kansas Medical Center (US)
- Mútua Terrassa (ES)
- Dr. John T. Macdonald Foundation (US)
- VIB-UAntwerp Center for Molecular Neurology (BE)
- Instituto de Biomedicina de Sevilla (ES)
- Instituto de Investigación Biomédica de Lleida (ES)
- Hospital Universitario Central de Asturias (ES)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Eginition Hospital (GR)
- Centro de Biología Molecular Severo Ochoa (ES)
- Mayo Clinic in Florida (US)
- Klinik und Poliklinik für Psychiatrie und Psychotherapie (DE)
- Hospital Universitario de Valme (ES)
- Instituto de Biomedicina de Valencia (ES)
- Fondazione Santa Lucia (IT)
- Amsterdam University Medical Centers (NL)
- Ospedale Vito Fazzi (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Hospital Universitario Virgen del Rocío (ES)
- University Hospital Cologne (DE)
- Fundacion Centro De Investigacion De Enfermedades Neurologicas (ES)
- Fundació Clínic per a la Recerca Biomèdica (ES)
- Ontario Brain Institute (CA)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Instituto de Investigación Sanitaria La Fe (ES)
- Instituto de Investigación Sanitaria del Principado de Asturias (ES)
- Banner Alzheimer’s Institute
- Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement
- Arizona Alzheimer’s Consortium
- University of Florence (IT)
- Wake Forest University (US)
- McGill University (CA)
- University of Turin (IT)
- University of Bari Aldo Moro (IT)
- Indiana University – Purdue University Indianapolis (US)
- New York University (US)
- Case Western Reserve University (US)
- University of Duisburg-Essen (DE)
- Université de Rouen Normandie (FR)
- Technical University of Munich (DE)
- Tunis El Manar University (TN)
- Universidad Autónoma de Madrid (ES)
- University of Milano-Bicocca (IT)
- Martin Luther University Halle-Wittenberg (DE)
- Universitat de Barcelona (ES)
- Columbia University (US)
- Universidad de Sevilla (ES)
- Cardiff University (GB)
- University of Pennsylvania (US)
- University of Brescia (IT)
- Ludwig-Maximilians-Universität München (DE)
- Universidad de Málaga (ES)
- University of California, Davis (US)
- Vrije Universiteit Amsterdam (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Erasmus University Rotterdam (NL)
- Leipzig University (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- Stanford University (US)
- University of Lausanne (CH)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1038/s41380-024-02838-5
- Citations
- 6
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.30
Funders
- Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
- Université de Lille
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche sur Alzheimer
- Medical Research Council