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DNA Methylation Signatures of Depressive Symptoms in Middle-Aged and Elderly Persons: Meta-Analysis of Multiethnic Epigenome-Wide Studies


Story Jovanova, Olivera; Nedeljkovic, Ivana; Spieler, Derek; Walker, Rosie M.; Liu, Chunyu; Luciano, Michelle; Bressler, Jan; Brody, Jennifer A.; Drake, Amanda J.; & Evans, Kathryn L., et al. (2018). DNA Methylation Signatures of Depressive Symptoms in Middle-Aged and Elderly Persons: Meta-Analysis of Multiethnic Epigenome-Wide Studies. JAMA Psychiatry, 75(9), 949-959. PMCID: PMC6142917


Importance: Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers.
Objective: To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood.
Design, Setting, and Participants: To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts.
Main Outcomes and Measures: Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire.
Results: The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 x 10-08; n = 11256; CDC42BPB gene), cg12325605 (P = 5.24 x 10-09; n = 11256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 x 10-08; n = 11256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 x 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 x 10-04) was associated with major depression.
Conclusions and Relevance: This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.


Reference Type

Journal Article

Year Published


Journal Title

JAMA Psychiatry


Story Jovanova, Olivera
Nedeljkovic, Ivana
Spieler, Derek
Walker, Rosie M.
Liu, Chunyu
Luciano, Michelle
Bressler, Jan
Brody, Jennifer A.
Drake, Amanda J.
Evans, Kathryn L.
Gondalia, Rahul
Kunze, Sonja
Kuhnel, Brigitte
Lahti, Jari
Lemaitre, Rozenn N.
Marioni, Riccardo E.
Swenson, Brenton R.
Himali, Jayandra Jung
Wu, Hongsheng
Li, Yun
McRae, Allan F.
Russ, Tom C.
Stewart, James D.
Wang, Zhiying
Zhang, Guosheng
Ladwig, Karl-Heinz
Uitterlinden, Andre G.
Guo, Xiuqing
Peters, Annette
Raikkonen, Katri
Starr, John M.
Waldenberger, Melanie
Wray, Naomi R.
Whitsel, Eric A.
Sotoodehnia, Nona
Seshadri, Sudha
Porteous, David J.
van Meurs, Joyce B. J.
Mosley, Thomas H., Jr.
McIntosh, Andrew M.
Mendelson, Michael M.
Levy, Daniel
Hou, Lifang
Eriksson, Johan G.
Fornage, Myriam
Deary, Ian J.
Baccarelli, Andrea A.
Tiemeier, Henning
Amin, Najaf