A brain DNA co-methylation network analysis of psychosis in Alzheimer's disease

被引：1

作者：

Kouhsar, Morteza ^{[1
]}

Weymouth, Luke ^{[1
]}

Smith, Adam R. ^{[1
]}

Imm, Jennifer ^{[1
]}

Bredemeyer, Claudia ^{[1
]}

Wedatilake, Yehani ^{[2
,3
]}

Torkamani, Ali ^{[4
]}

Bergh, Sverre ^{[2
,3
]}

Selbaek, Geir ^{[2
,5
]}

Mill, Jonathan ^{[1
]}

Ballard, Clive ^{[1
]}

Sweet, Robert A. ^{[6
]}

Kofler, Julia ^{[7
]}

Creese, Byron ^{[1
,8
]}

Pishva, Ehsan ^{[1
,9
]}

Lunnon, Katie ^{[1
]}

机构：

[1] Univ Exeter, Fac Hlth & Life Sci, Dept Clin & Biomed Sci, Exeter, Devon, England

[2] Vestfold Hosp Trust, Norwegian Natl Ctr Aging & Hlth, Tonsberg, Norway

[3] Innlandet Hosp Trust, Res Ctr Age Related Funct Decline & Dis, Ottestad, Norway

[4] Scripps Res Inst, La Jolla, CA USA

[5] Oslo Univ Hosp, Dept Geriatr Med, Oslo, Norway

[6] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA

[7] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA

[8] Brunel Univ London, Dept Life Sci, Div Psychol, Uxbridge, England

[9] Maastricht Univ, Fac Hlth Med & Life Sci FHML, Sch Mental Hlth & Neurosci MHeNs, Dept Psychiat & Neuropsychol, Maastricht, Netherlands

来源：

ALZHEIMERS & DEMENTIA | 2025年 / 21卷 / 02期

基金：

美国国家卫生研究院;

关键词：

Alzheimer's disease (AD); brain; DNA methylation; epigenetics; methylation quantitative trait loci (mQTLs); pathways; psychosis; schizophrenia; weighted gene correlation network analysis (WGCNA); GENOME-WIDE ASSOCIATION; NEUROPSYCHIATRIC SYMPTOMS; RISK-FACTORS; DEMENTIA; TAU; HALLUCINATIONS; SCHIZOPHRENIA; PIMAVANSERIN; DELUSIONS; GENOTYPE;

D O I：

10.1002/alz.14501

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

INTRODUCTIONThe presence of psychosis in Alzheimer's disease (AD) is suggested to be associated with distinct molecular and neuropathological profiles in the brain. METHODSWe assessed brain DNA methylation in AD donors with psychosis (AD+P) and without psychosis (AD-P) using the EPIC array. Weighted gene correlation network analysis identified modules of co-methylated genes in a discovery cohort (PITT-ADRC: N = 113 AD+P, N = 40 AD-P), with validation in an independent cohort (BDR: N = 79 AD+P, N = 117 AD-P), with Gene Ontology and cell-type enrichment analysis. Genetic data were integrated to identify methylation quantitative trait loci (mQTLs), which were co-localized with GWAS for related traits. RESULTSWe replicated one AD+P associated module, which was enriched for synaptic pathways and in excitatory and inhibitory neurons. mQTLs in this module co-localized with variants associated with schizophrenia and educational attainment. DISCUSSIONThis represents the largest epigenetic study of AD+P to date, identifying pleiotropic relationships between AD+P and related traits. Highlights DNA methylation was assessed in the prefrontal cortex in subjects with AD+P and AD-P. WGCNA identified six modules of co-methylated loci associated with AD+P in a discovery cohort. One of the modules was replicated in an independent cohort. This module was enriched for synaptic genes and in excitatory and inhibitory neurons. mQTLs mapping to genes in the module co-localized with GWAS loci for schizophrenia and educational attainment.

引用

页数：14

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