Kouhsar Morteza, Weymouth Luke, Smith Adam R, Imm Jennifer, Bredemeyer Claudia, Wedatilake Yehani, Torkamani Ali, Bergh Sverre, Selbæk Geir, Mill Jonathan, Ballard Clive, Sweet Robert A, Kofler Julia, Creese Byron, Pishva Ehsan, Lunnon Katie
Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, Devon, UK.
Norwegian National Centre for Aging and Health, Vestfold Hospital Trust, Tønsberg, Norway.
Alzheimers Dement. 2025 Feb;21(2):e14501. doi: 10.1002/alz.14501.
The presence of psychosis in Alzheimer's disease (AD) is suggested to be associated with distinct molecular and neuropathological profiles in the brain.
We 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.
We 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.
This represents the largest epigenetic study of AD+P to date, identifying pleiotropic relationships between AD+P and related traits.
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.
阿尔茨海默病（AD）中精神病性症状的存在被认为与大脑中独特的分子和神经病理学特征有关。
我们使用EPIC芯片评估了患有精神病性症状的AD供体（AD+P）和无精神病性症状的AD供体（AD-P）的脑DNA甲基化情况。加权基因共表达网络分析在一个发现队列（匹兹堡AD研究中心：113例AD+P，40例AD-P）中确定了共甲基化基因模块，并在一个独立队列（BDR：79例AD+P，117例AD-P）中进行了验证，同时进行了基因本体论和细胞类型富集分析。整合遗传数据以识别甲基化数量性状位点（mQTL），并将其与相关性状的全基因组关联研究（GWAS）共定位。
我们重复验证了一个与AD+P相关的模块，该模块在突触通路以及兴奋性和抑制性神经元中富集。该模块中的mQTL与精神分裂症和受教育程度相关的变异共定位。
这是迄今为止关于AD+P的最大规模表观遗传学研究，确定了AD+P与相关性状之间的多效性关联。
对AD+P和AD-P受试者的前额叶皮质进行了DNA甲基化评估。加权基因共表达网络分析在一个发现队列中确定了六个与AD+P相关的共甲基化位点模块。其中一个模块在独立队列中得到了重复验证。该模块在突触基因以及兴奋性和抑制性神经元中富集。定位到该模块中基因的mQTL与精神分裂症和受教育程度的GWAS位点共定位。
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