Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer’s disease
Year: 2025
Type: article
Study design: Observational Study
Abstract: Depression is a risk factor for the later development of Alzheimer’s disease (AD), but evidence for the genetic relationship is mixed. Assessing depression symptom-specific genetic associations may better clarify this relationship. To address this, we conducted genome-wide meta-analysis (a genome-wide association study, GWAS) of the nine depression symptom items, plus their sum score, on the Patient Health Questionnaire (PHQ-9) (GWAS-equivalent N: 224,535–308,421) using data from UK Biobank, the GLAD study and PROTECT, identifying 37 genomic risk loci. Using six AD GWASs with varying proportions of clinical and proxy (family history) case ascertainment, we identified 20 significant genetic correlations with depression/depression symptoms. However, only one of these was identified with a clinical AD GWAS. Local genetic correlations were detected in 14 regions. No statistical colocalization was identified in these regions. However, the region of the transmembrane protein 106B gene (TMEM106B) showed colocalization between multiple depression phenotypes and both clinical-only and clinical + proxy AD. Mendelian randomization and polygenic risk score analyses did not yield significant results after multiple testing correction in either direction. Our findings do not demonstrate a causal role of depression/depression symptoms on AD and suggest that previous evidence of genetic overlap between depression and AD may be driven by the inclusion of family history-based proxy cases/controls. However, colocalization at TMEM106B warrants further investigation.
Source: Nature Mental Health
Authors: Lachlan Gilchrist, Thomas P. Spargo, Rebecca E. Green, Jonathan R. I. Coleman, David M. Howard, Jackson G. Thorp, Brett N. Adey, Jodie Lord, Helena L. Davies, Jessica Mundy, Abigail R. ter Kuile, Molly R. Davies, Christopher Hübel, Shannon Bristow, Sang Hyuck Lee, Henry Rogers, Charles Curtis, Saakshi Kakar, Chelsea M. Malouf, Gursharan Kalsi, Ryan Arathimos, Anne Corbett, Clive Ballard, Helen Brooker, Byron Creese, Dag Aarsland, Adam Hampshire, Latha Velayudhan, Thalia C. Eley, Gerome Breen, Alfredo Iacoangeli, Sulev Kõks, Cathryn M. Lewis, Petroula Proitsi
Institutions: King's College London, Perron Institute for Neurological and Translational Science, South London and Maudsley NHS Foundation Trust, NIHR Maudsley Biomedical Research Centre, MRC Unit for Lifelong Health and Ageing, University College London, QIMR Berghofer Medical Research Institute, Sankt Hans Hospital, Mental Health Services, Copenhagen University Hospital, Aarhus University, Charité - Universitätsmedizin Berlin, University of Exeter, Brunel University of London, Centre for Healthy Brain Ageing, Murdoch University, Queen Mary University of London
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: U.S. Department of Defense, Foundation for the National Institutes of Health, Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Biogen, University of Southern California, F. Hoffmann-La Roche, Meso Scale Diagnostics, Alzheimer's Disease Neuroimaging Initiative, BioClinica, Novartis Pharmaceuticals Corporation, NHS Blood and Transplant, Northern California Institute for Research and Education, Wellcome Trust, MND Scotland, LifeArc, Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease, Université de Lille, Alzheimer's Society, Spastic Paraplegia Foundation, National Institute for Health and Care Research, Department of Health and Social Care, Motor Neurone Disease Association, University of Cambridge, University of Exeter, King's College London, University College London, European Commission, Rosetrees Trust, Cardiff University, Institut National de la Santé et de la Recherche Médicale, Alzheimer’s Research UK, Bundesministerium für Bildung und Forschung, Erasmus Medisch Centrum, Eisai, Alfried Krupp von Bohlen und Halbach-Stiftung, Servier, Hjartavernd, H. Lundbeck A/S, Centre hospitalier régional universitaire de Lille, IXICO, Multiple Sclerosis Society of Western Australia, National Institutes of Health, Genentech, NIHR BioResource, NIHR Maudsley Biomedical Research Centre, Canadian Institutes of Health Research, Medical Research Council, Economic and Social Research Council, National Institute on Aging, National Institute of Mental Health, Health Data Research UK
Awards: G100845555, G1012222616, G104586243, G1173778324, G1194337659, Kompetenznetz 'Demenzen', G1298807586, G1309605592, G1554142629, G1593117279, G1596937967, G1650819308, G1692888740, G1823308732, G1880935189, Alzheimer's Disease Neuroimaging Initiative, G2100670906, G2105457377, G2152643862, G2189010064, G230712557, G2340207221, G2423387114, G2471646051, G2522063444, G2649392419, G2697093250, NIHR Pre-doctoral Fellowship (Round 2), G2835601961, G2929235049, G29951154, G3131374986, G3146424788, G3161882281, G3173811024, G3216574877, G3392333875, G3402222819, G3420704675, G346328595, G3512028809, G3553156159, G36881302, G3705772492, G3710456697, G3752451908, G3870774570, G3908963977, G3916087950, G3966393351, Using multiple data sources to stratify depression and identify more targeted drug treatments, G4119534169, G4122031276, G43180419, G4475667458, G4501223628, G4591121360, G464279176, G4645372781, G4800177743, G5200159585, G5207404921, G5209990037, Alzheimer's Disease Genetics Consortium, G528601746, G5334218988, G5365730499, EFFECTS OF TRAUMATIC BRAIN INJURY (TBI) AND POST TRAUMATIC STRESS DISORDER (PTSD) ON ALZHEIMER'S DISEASE (AD) IN VETERANS USING IMAGING AND BIOMARKERS IN THE AD NEUROIMAGING INITIATIVE (ADNI)", G5558075022, External Collaboration, Innovation and Entrepreneurism: Translational Medicine in Exeter 2 (EXCITEME2), G5598714753, G5654639750, G5740349702, G5790812223, G5850682332, G6039058924, G613619302, G6173816828, G6210868510, Verbundprojekt: Kompetenznetz Demenzen - Epidemiologie: Teilprojekte der Universität Bonn, G6371410416, G639185302, G6412110892, G6425121803, G6447063303, G6648385527, G6655839575, G6708752960, G6719828067, G6762071588, G6792506723, G6899163935, G6948409098, Verbundprojekt Kompetenznetz Demenzen: Teilprojekte des ZISG Mannheim (2. Förderphase), G7234197675, G72415811, G7298697282, G7373387228, G7414321945, G745803450, G764699806, G7799614282, G781725486, G8228018387, G8281378126, G839208290, G8464022744, G8506111834, Using multiple data sources to stratify depression and identify more targeted drug treatments, G8672444070, G8852128998, G8895907669, G8897063270, G8957659042, G9000010277, G9000030076, G9000039018, G9000044681, G9000106852, G9000122267, G9000122335, G9000159195, G9000354881
OpenAlex ID: W4406400880