Morteza Kouhsar, Luke Weymouth, Adam R. Smith, Jennifer Imm, Claudia Bredemeyer, Yehani Wedatilake, Ali Torkamani, Sverre Bergh, Geir Selbæk, Jonathan Mill, Clive Ballard, Robert A. Sweet, Julia Kofler, Byron Creese, Ehsan Pishva, Katie Lunnon
{"title":"A brain DNA co-methylation network analysis of psychosis in Alzheimer's disease","authors":"Morteza Kouhsar, Luke Weymouth, Adam R. Smith, Jennifer Imm, Claudia Bredemeyer, Yehani Wedatilake, Ali Torkamani, Sverre Bergh, Geir Selbæk, Jonathan Mill, Clive Ballard, Robert A. Sweet, Julia Kofler, Byron Creese, Ehsan Pishva, Katie Lunnon","doi":"10.1002/alz.14501","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>The presence of psychosis in Alzheimer's disease (AD) is suggested to be associated with distinct molecular and neuropathological profiles in the brain.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>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: <i>N</i> = 113 AD+P, <i>N</i> = 40 AD−P), with validation in an independent cohort (BDR: <i>N</i> = 79 AD+P, <i>N</i> = 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.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>This represents the largest epigenetic study of AD+P to date, identifying pleiotropic relationships between AD+P and related traits.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>DNA methylation was assessed in the prefrontal cortex in subjects with AD+P and AD−P.</li>\n \n <li>WGCNA identified six modules of co-methylated loci associated with AD+P in a discovery cohort.</li>\n \n <li>One of the modules was replicated in an independent cohort.</li>\n \n <li>This module was enriched for synaptic genes and in excitatory and inhibitory neurons.</li>\n \n <li>mQTLs mapping to genes in the module co-localized with GWAS loci for schizophrenia and educational attainment.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14501","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's & Dementia","FirstCategoryId":"3","ListUrlMain":"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14501","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
INTRODUCTION
The presence of psychosis in Alzheimer's disease (AD) is suggested to be associated with distinct molecular and neuropathological profiles in the brain.
METHODS
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.
RESULTS
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.
DISCUSSION
This 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.
阿尔茨海默病（AD）中精神病的存在被认为与大脑中不同的分子和神经病理特征有关。方法：我们使用EPIC阵列评估伴有精神病（AD+P）和无精神病（AD−P）的AD供体脑DNA甲基化。加权基因相关网络分析在发现队列（PITT-ADRC: N = 113 AD+P, N = 40 AD−P）中鉴定了共甲基化基因模块，并在独立队列（BDR: N = 79 AD+P, N = 117 AD−P）中进行了验证，并进行了基因本体和细胞型富集分析。整合遗传数据，鉴定甲基化数量性状位点（mqtl），这些位点与相关性状的GWAS共定位。结果我们复制了一个AD+P相关模块，该模块在突触通路和兴奋性和抑制性神经元中富集。该模块中的mqtl与精神分裂症和教育程度相关的变异共定位。这是迄今为止最大的AD+P表观遗传学研究，确定了AD+P和相关性状之间的多效性关系。在AD+P和AD - P受试者的前额皮质中评估DNA甲基化。WGCNA在一项发现队列中鉴定出6个与AD+P相关的共甲基化位点模块。其中一个模块在一个独立的队列中被复制。该模块在突触基因和兴奋性和抑制性神经元中富集。与精神分裂症和受教育程度的GWAS基因共定位的模块中的mqtl。
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
