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

被引：0

作者：

Gilchrist, Lachlan ^{[1
,2
]}

Spargo, Thomas P. ^{[3
,4
,5
,6
]}

Green, Rebecca E. ^{[7
]}

Coleman, Jonathan R. I. ^{[1
,5
,6
]}

Howard, David M. ^{[1
]}

Thorp, Jackson G. ^{[8
]}

Adey, Brett N. ^{[1
]}

Lord, Jodie ^{[3
]}

Davies, Helena L. ^{[1
,9
,10
]}

Mundy, Jessica ^{[1
]}

ter Kuile, Abigail R. ^{[1
,5
,6
]}

Davies, Molly R. ^{[1
,5
,6
]}

Huebel, Christopher ^{[1
,11
,12
]}

Bristow, Shannon ^{[1
,5
,6
]}

Lee, Sang Hyuck ^{[1
,5
,6
]}

Rogers, Henry ^{[1
,5
,6
]}

Curtis, Charles ^{[1
,5
,6
]}

Kakar, Saakshi ^{[1
,5
,6
]}

Malouf, Chelsea M. ^{[1
,5
,6
]}

Kalsi, Gursharan ^{[1
,5
,6
]}

Arathimos, Ryan ^{[1
]}

Corbett, Anne ^{[13
]}

Ballard, Clive ^{[13
]}

Brooker, Helen ^{[13
]}

Creese, Byron ^{[14
]}

Aarsland, Dag ^{[15
]}

Hampshire, Adam ^{[16
]}

Velayudhan, Latha ^{[15
]}

Eley, Thalia C. ^{[1
,5
,6
]}

Breen, Gerome ^{[1
,5
,6
]}

Iacoangeli, Alfredo ^{[2
,3
,4
,5
,6
]}

Koks, Sulev ^{[2
,17
]}

Lewis, Cathryn M. ^{[1
,5
,6
,18
]}

Proitsi, Petroula ^{[3
,19
]}

机构：

[1] Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London, England

[2] Perron Inst Neurol & Translat Sci, Perth, WA, Australia

[3] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Basic & Clin Neurosci, London, England

[4] Kings Coll London, Inst Psychiat Psychol & Neurosci, Inst Psychiat Psychol & Neurosci, London, England

[5] Kings Coll London, South London & Maudsley NHS Fdn Trust, NIHR Maudsley Biomed Res Ctr, London, England

[6] Kings Coll London, London, England

[7] Univ Coll London Med Sch, UCL, MRC Unit Lifelong Hlth Ageing, London OX3 7FD, England

[8] QIMR Berghofer Med Res Inst, Translat Neurogenom Lab, Brisbane, Qld, Australia

[9] Copenhagen Univ Hosp, Ctr Eating & Feeding Disorders Res, Mental Hlth Ctr Ballerup, Mental Hlth Serv CPH, Copenhagen, Denmark

[10] Mental Hlth Ctr Sct Hans, Inst Biol Psychiat, Mental Hlth Serv Copenhagen, Roskilde, Denmark

[11] Aarhus Univ, Natl Ctr Register Based Res, Aarhus BSS, Aarhus, Denmark

[12] Charite, Dept Radiooncol, Berlin, Germany

[13] Univ Exeter, Coll Med & Hlth, Exeter, England

[14] Brunel Univ London, Dept Life Sci, London, England

[15] Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Hlth Brain Ageing, Dept Psychol Med, London, England

[16] Kings Coll London, Inst Psychiat Psychol & Neurosci, Inst Psychiat Psychol & Neurosci, London, England

[17] Murdoch Univ, Ctr Mol Med & Innovat Therapeut, Perth, WA, Australia

[18] Kings Coll London, Dept Med & Mol Genet, London, England

[19] Queen Mary Univ London, Wolfson Inst Populat Hlth, Ctr Prevent Neurol, London, England

来源：

NATURE MENTAL HEALTH | 2025年 / 3卷 / 02期

基金：

美国国家卫生研究院; 英国经济与社会研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; MENDELIAN RANDOMIZATION; RISK-FACTOR; DEMENTIA; EXPRESSION; TRANSCRIPTOME; INSTRUMENTS; LOCI; ARCHITECTURE; METAANALYSIS;

D O I：

10.1038/s44220-024-00369-0

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

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.

引用

页码：212 / 228

页数：20

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