A methylation study of long-term depression risk

Abstract

Recurrent and chronic Major Depressive Disorder (MDD) accounts for a substantial part of the disease burden because this course is most prevalent and typically requires long-term treatment. We associated blood DNA methylation profiles from 581 MDD patients at baseline with MDD status 6 years later. A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P=2.0×10 −16). Top MWAS results were enriched specific pathways, overlapped with genes found in GWAS of MDD disease status, autoimmune disease and inflammation, and co-localized with eQTLS and (genic enhancers of) of transcription sites in brain and blood. Many of these findings remained significant after correction for multiple testing. The major themes emerging were cellular responses to stress and signaling mechanisms linked to immune cell migration and inflammation. This suggests that an immune signature of treatment-resistant depression is already present at baseline. We also created a methylation risk score (MRS) to predict MDD status 6 years later. The AUC of our MRS was 0.724 and higher than risk scores created using a set of five putative MDD biomarkers, genomewide SNP data, and 27 clinical, demographic and lifestyle variables. Although further studies are needed to examine the generalizability to different patient populations, these results suggest that methylation profiles in blood may present a promising avenue to support clinical decision making by providing empirical information about the likelihood MDD is chronic or will recur in the future. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Epigenetic prediction of major depressive disorder

“…A recent study of 581 individuals with depressive symptoms used machine learning methods to train a predictor of MDD using DNAm data. They found that MRS could discriminate future MDD disease status with an area under the curve (AUC) of 0.72 [13]. Notably, this study did not use an independent sample to test their MRS and they discriminated between transient and chronic MDD over a 6year period.…”

Association between DNA Methylation Levels in Brain Tissue and Late-Life Depression in Community-Based Participants

“…Recent epigenome-wide association studies (EWAS) showed an association of wholeblood DNA methylation levels with depressive symptoms 7,8 as well as MDD [9][10][11] , but little is known about brain epigenetic markers of depression or MDD. The EWAS of depressive symptoms were both conducted in late middle-aged and elderly people from the general population (mean age 70 years 8 and 65 years 7 ), an age group with an increased risk of developing dementia 12 .…”

“…On the other hand, recent EWAS of MDD were performed in younger participants (mean age 42 years) [9][10][11] and it is unclear if their findings can be generalized across age groups.…”

“…Furthermore, most previous EWAS on depression were limited due to measuring DNA methylation changes in blood [7][8][9][10] . Two recent studies conducted EWAS of MDD in 206 postmortem brain samples, but the MDD diagnosis was based on information obtained from a family member and there was no information on dementia 9,11 .…”

Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system

“…Recent studies have also shown the potential of a DNAm-based risk score to predict MDD and its associated lifestyle and environmental factors, including antidepressant use (14,15). Barbu et al (2020) (15) trained a DNAm predictor of MDD in 3,047 individuals using a penalised regression model and showed that it was significantly associated with self-reported antidepressant use in an independent cohort.…”