| Title: | Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer's disease |
| Journal: | Nature Mental Health |
| Published: | 15 Jan 2025 |
| DOI: | https://doi.org/10.1038/s44220-024-00369-0 |
| URL: | https://kclpure.kcl.ac.uk/portal/en/publications/a800859d-995c-4fbd-9999-cbb73501c27b |
Publication 15121
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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.</p>
34 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
1 Application
| Application ID | Title |
|---|---|
| 18177 | Multi-trait GWAS analyses in the UK Biobank |
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