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 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

doi:10.1038/s44220-024-00369-0

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 Hübel, Shannon Bristow, Sang Hyuck Lee, Henry Rogers, Charles Curtis, Saakshi Kakar, Chelsea M. Malouf, Gursharan KalsiRyan 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	160
Pages (from-to)	212-228
Number of pages	17
Journal	Nature Mental Health
Volume	3
Issue number	2
DOIs	https://doi.org/10.1038/s44220-024-00369-0
Publication status	Published - Feb 2025

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Gilchrist, L., Spargo, T. P., Green, R. E., Coleman, J. R. I., Howard, D. M., Thorp, J. G., Adey, B. N., Lord, J., Davies, H. L., Mundy, J., ter Kuile, A. R., Davies, M. R., Hübel, C., Bristow, S., Lee, S. H., Rogers, H., Curtis, C., Kakar, S., Malouf, C. M., ... Proitsi, P. (2025). Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer’s disease. Nature Mental Health , 3(2), 212-228. Article 160. https://doi.org/10.1038/s44220-024-00369-0

@article{a800859d995c4fbd9999cbb73501c27b,

title = "Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer{\textquoteright}s disease",

abstract = "Depression is a risk factor for the later development of Alzheimer{\textquoteright}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.",

author = "Lachlan Gilchrist and Spargo, {Thomas P.} and Green, {Rebecca E.} and Coleman, {Jonathan R.I.} and Howard, {David M.} and Thorp, {Jackson G.} and Adey, {Brett N.} and Jodie Lord and Davies, {Helena L.} and Jessica Mundy and {ter Kuile}, {Abigail R.} and Davies, {Molly R.} and Christopher H{\"u}bel and Shannon Bristow and Lee, {Sang Hyuck} and Henry Rogers and Charles Curtis and Saakshi Kakar and Malouf, {Chelsea M.} and Gursharan Kalsi and Ryan Arathimos and Anne Corbett and Clive Ballard and Helen Brooker and Byron Creese and Dag Aarsland and Adam Hampshire and Latha Velayudhan and Eley, {Thalia C.} and Gerome Breen and Alfredo Iacoangeli and Sulev K{\~o}ks and Lewis, {Cathryn M.} and Petroula Proitsi",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = feb,

doi = "10.1038/s44220-024-00369-0",

language = "English",

volume = "3",

pages = "212--228",

journal = "Nature Mental Health ",

issn = "2731-6076",

publisher = "Nature Research",

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Gilchrist, L, Spargo, TP, Green, RE, Coleman, JRI, Howard, DM, Thorp, JG, Adey, BN, Lord, J, Davies, HL, Mundy, J, ter Kuile, AR, Davies, MR, Hübel, C, Bristow, S, Lee, SH , Rogers, H , Curtis, C , Kakar, S, Malouf, CM, Kalsi, G, Arathimos, R, Corbett, A , Ballard, C, Brooker, H, Creese, B, Aarsland, D , Hampshire, A , Velayudhan, L , Eley, TC , Breen, G , Iacoangeli, A, Kõks, S, Lewis, CM & Proitsi, P 2025, 'Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer’s disease', Nature Mental Health , vol. 3, no. 2, 160, pp. 212-228. https://doi.org/10.1038/s44220-024-00369-0

TY - JOUR

T1 - Depression symptom-specific genetic associations in clinically diagnosed and proxy case Alzheimer’s disease

AU - Gilchrist, Lachlan

AU - Spargo, Thomas P.

AU - Green, Rebecca E.

AU - Coleman, Jonathan R.I.

AU - Howard, David M.

AU - Thorp, Jackson G.

AU - Adey, Brett N.

AU - Lord, Jodie

AU - Davies, Helena L.

AU - Mundy, Jessica

AU - ter Kuile, Abigail R.

AU - Davies, Molly R.

AU - Hübel, Christopher

AU - Bristow, Shannon

AU - Lee, Sang Hyuck

AU - Rogers, Henry

AU - Curtis, Charles

AU - Kakar, Saakshi

AU - Malouf, Chelsea M.

AU - Kalsi, Gursharan

AU - Arathimos, Ryan

AU - Corbett, Anne

AU - Ballard, Clive

AU - Brooker, Helen

AU - Creese, Byron

AU - Aarsland, Dag

AU - Hampshire, Adam

AU - Velayudhan, Latha

AU - Eley, Thalia C.

AU - Breen, Gerome

AU - Iacoangeli, Alfredo

AU - Kõks, Sulev

AU - Lewis, Cathryn M.

AU - Proitsi, Petroula

PY - 2025/2

Y1 - 2025/2

N2 - 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.

AB - 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.

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U2 - 10.1038/s44220-024-00369-0

DO - 10.1038/s44220-024-00369-0

M3 - Article

AN - SCOPUS:85217160269

SN - 2731-6076

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SP - 212

EP - 228

JO - Nature Mental Health

JF - Nature Mental Health

IS - 2

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ER -

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

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