全基因组关联分析的多组学和途径分析表明，调节和免疫与言语陈述性记忆表现有关。

Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.

机构信息

Department of Data Science, John D. Bower School of Population Health, University of Mississippi Medical Center, Jackson, MS, USA.

Gertrude C. Ford Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson, MS, USA.

出版信息

Alzheimers Res Ther. 2024 Jan 20;16(1):14. doi: 10.1186/s13195-023-01376-6.

DOI:10.1186/s13195-023-01376-6

PMID:38245754

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10799499/

Abstract

BACKGROUND

Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS

We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS

The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS

VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

摘要

背景

揭示言语陈述性记忆（VDM）全基因组关联研究（GWAS）结果背后的功能相关性，可能有助于开发干预措施，以减少与年龄相关的记忆衰退和痴呆。

方法

我们对来自 29076 名无痴呆的欧洲血统老年人的段落（PAR-dr）和单词列表（WL-dr）延迟回忆 GWAS 进行了多组学和途径富集分析。我们评估了单变体关联与 44 种组织中的表达数量性状基因座（eQTLs）和海马体中的甲基化数量性状基因座（meQTLs）之间的关系。我们确定了基因关联与 53 种组织中的转录物水平、免疫基因注释以及转录因子（TFs）和 microRNAs 的调控之间的关系。为了确定显著的途径，在每个队列中测试了基因集富集，并在队列之间进行了荟萃分析。对脑组织中途径成分基因的差异表达进行了分析。

结果

VDM 的单变体关联与所有组织中的 eQTLs 以及海马体中的 meQTLs 显示出显著的连锁不平衡（LD）。更强的 WL-dr 基因关联与四个脑区（包括海马体）的表达减少相关。更强的 PAR-dr 和/或 WL-dr 基因关联与免疫密切相关，并受 31 个 TF 和 2 个 microRNAs 影响。包括 1 型糖尿病在内的六个途径与 PAR-dr 和 WL-dr 均显示出显著的关联。这些途径包括 15 个与 VDM 表现密切相关的 MHC 基因，在脑组织中根据认知状态显示出不同的表达模式。