Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients

Abstract

Depression is common among late-onset Alzheimer’s Disease (LOAD) patients. Only a few studies investigated the genetic variability underlying the comorbidity of depression in LOAD. Moreover, the epigenetic and transcriptomic factors that may contribute to comorbid depression in LOAD have yet to be studied. Using transcriptomic and DNA-methylomic datasets from the ROSMAP cohorts, we investigated differential gene expression and DNA-methylation in LOAD patients with and without comorbid depression. Differential expression analysis did not reveal significant association between differences in gene expression and the risk of depression in LOAD. Upon sex-stratification, we identified 25 differential expressed genes (DEG) in males, of which CHI3L2 showed the strongest upregulation, and only 3 DEGs in females. Additionally, testing differences in DNA-methylation found significant hypomethylation of CpG (cg20442550) on chromosome 17 (log2FC = −0.500, p = 0.004). Sex-stratified differential DNA-methylation analysis did not identify any significant CpG probes. Integrating the transcriptomic and DNA-methylomic datasets did not discover relationships underlying the comorbidity of depression and LOAD. Overall, our study is the first multi-omics genome-wide exploration of the role of gene expression and epigenome alterations in the risk of comorbid depression in LOAD patients. Furthermore, we discovered sex-specific differences in gene expression underlying the risk of depression symptoms in LOAD.

Exploring the Genetic Landscape of Mild Behavioral Impairment as an Early Marker of Cognitive Decline: An Updated Review Focusing on Alzheimer’s Disease

“…DNA methylation biomarkers possibly affecting the risk for AD have been recently developed via the integration of blood and genome methylome data [ 128 ]. Sex-specific differences have been identified in the DNA methylation patterns affecting the risk of depression among patients with late-onset AD [ 129 ]. The relationship between DNA methylation biomarkers with affective dysregulation or other MBI domains could shed more light on the epigenetic mechanisms underlying MBI.…”

Sex differences in the relationship between depression and Alzheimer’s disease—mechanisms, genetics, and therapeutic opportunities

“…Furthermore, the first multi-omics investigation on a genomewide scale delved into the role of epigenome alterations and gene expression in the risk of comorbid depression in patients with late-onset AD and elucidated sex-specific disparities in the expression of gene that contribute to the manifestation of depressive symptoms in late-onset AD (Upadhya et al, 2022). Specifically, there were 25 differentially expressed genes associated with depression in AD men, and CHI3L2, involved in multiple inflammatory reactions of depression in late-onset AD, was the most upregulated gene, while only three differentially expressed genes were associated with depression in AD women (Upadhya et al, 2022). (Santos et al, 2016) and constitutes a well-established pathological hallmark in the brains of AD patients (Long and Holtzman, 2019) while exerting a significant influence on the regulation of depressive disorders (Jia et al, 2021).…”

“…The study uncovered a favorable genetic correlation between depressive symptoms and psychosis of AD ( DeMichele-Sweet et al, 2021 ). Furthermore, the first multi-omics investigation on a genome-wide scale delved into the role of epigenome alterations and gene expression in the risk of comorbid depression in patients with late-onset AD and elucidated sex-specific disparities in the expression of gene that contribute to the manifestation of depressive symptoms in late-onset AD ( Upadhya et al, 2022 ). Specifically, there were 25 differentially expressed genes associated with depression in AD men, and CHI3L2 , involved in multiple inflammatory reactions of depression in late-onset AD, was the most upregulated gene, while only three differentially expressed genes were associated with depression in AD women ( Upadhya et al, 2022 ).…”