Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer's disease

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 Huebel; 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 Koks; Cathryn M. Lewis; Petroula Proitsi

doi:10.1038/s44220-024-00369-0

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Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer's disease

Journal article

Open access

Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer's disease

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, …

Nature mental health, Vol.3(2), pp.212-228

2025

DOI: https://doi.org/10.1038/s44220-024-00369-0

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Abstract

Life Sciences & Biomedicine

Psychiatry

Science & Technology

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.

Details

Title: Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer's disease
Authors/Creators: Lachlan Gilchrist - King's College London
Thomas P. Spargo - King's College London
Rebecca E. Green - MRC Unit for Lifelong Health and Ageing
Jonathan R. I. Coleman - King's College London
David M. Howard - King's College London
Jackson G. Thorp - QIMR Berghofer Medical Research Institute
Brett N. Adey - King's College London
Jodie Lord - King's College London
Helena L. Davies - King's College London
Jessica Mundy - King's College London
Abigail R. ter Kuile - South London and Maudsley NHS Foundation Trust
Molly R. Davies - South London and Maudsley NHS Foundation Trust
Christopher Huebel - King's College London
Shannon Bristow - King's College London
Sang Hyuck Lee - Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London, England
Henry Rogers - King's College London
Charles Curtis - King's College London
Saakshi Kakar - King's College London
Chelsea M. Malouf - King's College London
Gursharan Kalsi - King's College London
Ryan Arathimos - King's College London
Anne Corbett - University of Exeter
Clive Ballard - University of Exeter
Helen Brooker - University of Exeter
Byron Creese - Brunel University of London
Dag Aarsland - King's College London
Adam Hampshire - King's College London
Latha Velayudhan - King's College London
Thalia C. Eley - King's College London
Gerome Breen - South London and Maudsley NHS Foundation Trust
Alfredo Iacoangeli - King's College London
Sulev Koks - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
Cathryn M. Lewis - King's College London
Petroula Proitsi - Queen Mary University of London
Publication Details: Nature mental health, Vol.3(2), pp.212-228
Publisher: Springer Nature
Number of pages: 20
Grant note: MNDA - NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London Spastic Paraplegia Foundation 18177 / NIHR Maudsley Biomedical Research Centre Translational Medicine in Exeter 2 (EXCITEME2) Perron Institute for Neurological and Translational Science - Alzheimer's Research UK King's College London DRIVE-Health Centre for Doctoral Training MND Scotland, Darby Rimmer MND Foundation Rosetrees Trust National Institute of Health and Care Research Exeter Biomedical Research Centre Alzheimer's Research UK; Alzheimer's Research UK (ARUK)
Identifiers: 991005743444507891
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

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