DNA methylation signatures of depressive symptoms in middle-aged and elderly persons: Meta-analysis of multiethnic epigenome-wide studies

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

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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 levelswere 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 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 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.

Original languageEnglish (US)
Pages (from-to)949-959
Number of pages11
JournalJAMA Psychiatry
Volume75
Issue number9
DOIs
StatePublished - Sep 2018

Fingerprint

DNA Methylation
Meta-Analysis
Depression
Epigenomics
Methylation
Biomarkers
Gene-Environment Interaction
Chromosomes, Human, Pair 11
Depressive Disorder
Basal Ganglia
Research
African Americans
Sample Size
Population
Genes
Epidemiology
Fibroblasts
Outcome Assessment (Health Care)
Gene Expression

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Jovanova, Olivera Story ; Nedeljkovic, Ivana ; Spieler, Derek ; Walker, Rosie M. ; Liu, Chunyu ; Luciano, Michelle ; Bressler, Jan ; Brody, Jennifer ; Drake, Amanda J. ; Evans, Kathryn L. ; Gondalia, Rahul ; Kunze, Sonja ; Kuhnel, Brigitte ; Lahti, Jari ; Lemaitre, Rozenn N. ; Marioni, Riccardo E. ; Swenson, Brenton ; Himali, Jayandra Jung ; Wu, Hongsheng ; Li, Yun ; McRae, Allan F. ; Russ, Tom C. ; Stewart, James ; Wang, Zhiying ; Zhang, Guosheng ; Ladwig, Karl Heinz ; Uitterlinden, Andre G. ; Guo, Xiuqing ; Peters, Annette ; Räikkönen, Katri ; Starr, John M. ; Waldenberger, Melanie ; Wray, Naomi R. ; Whitsel, Eric A. ; Sotoodehnia, Nona ; Seshadri, Sudha ; Porteous, David J. ; Van Meurs, Joyce ; Mosley, Thomas H. ; McIntosh, Andrew M. ; Mendelson, Michael M. ; Levy, Daniel ; Hou, Lifang ; Eriksson, Johan G. ; Fornage, Myriam ; Deary, Ian J. ; Baccarelli, Andrea ; Tiemeier, Henning ; Amin, Najaf. / DNA methylation signatures of depressive symptoms in middle-aged and elderly persons : Meta-analysis of multiethnic epigenome-wide studies. In: JAMA Psychiatry. 2018 ; Vol. 75, No. 9. pp. 949-959.
@article{1d1f276e10fd45eda7ff137a8d7a0c31,
title = "DNA methylation signatures of depressive symptoms in middle-aged and elderly persons: Meta-analysis of multiethnic epigenome-wide studies",
abstract = "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 levelswere 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 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 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.",
author = "Jovanova, {Olivera Story} and Ivana Nedeljkovic and Derek Spieler and Walker, {Rosie M.} and Chunyu Liu and Michelle Luciano and Jan Bressler and Jennifer Brody and Drake, {Amanda J.} and Evans, {Kathryn L.} and Rahul Gondalia and Sonja Kunze and Brigitte Kuhnel and Jari Lahti and Lemaitre, {Rozenn N.} and Marioni, {Riccardo E.} and Brenton Swenson and Himali, {Jayandra Jung} and Hongsheng Wu and Yun Li and McRae, {Allan F.} and Russ, {Tom C.} and James Stewart and Zhiying Wang and Guosheng Zhang and Ladwig, {Karl Heinz} and Uitterlinden, {Andre G.} and Xiuqing Guo and Annette Peters and Katri R{\"a}ikk{\"o}nen and Starr, {John M.} and Melanie Waldenberger and Wray, {Naomi R.} and Whitsel, {Eric A.} and Nona Sotoodehnia and Sudha Seshadri and Porteous, {David J.} and {Van Meurs}, Joyce and Mosley, {Thomas H.} and McIntosh, {Andrew M.} and Mendelson, {Michael M.} and Daniel Levy and Lifang Hou and Eriksson, {Johan G.} and Myriam Fornage and Deary, {Ian J.} and Andrea Baccarelli and Henning Tiemeier and Najaf Amin",
year = "2018",
month = "9",
doi = "10.1001/jamapsychiatry.2018.1725",
language = "English (US)",
volume = "75",
pages = "949--959",
journal = "JAMA Psychiatry",
issn = "2168-622X",
publisher = "American Medical Association",
number = "9",

}

Jovanova, OS, Nedeljkovic, I, Spieler, D, Walker, RM, Liu, C, Luciano, M, Bressler, J, Brody, J, Drake, AJ, Evans, KL, Gondalia, R, Kunze, S, Kuhnel, B, Lahti, J, Lemaitre, RN, Marioni, RE, Swenson, B, Himali, JJ, Wu, H, Li, Y, McRae, AF, Russ, TC, Stewart, J, Wang, Z, Zhang, G, Ladwig, KH, Uitterlinden, AG, Guo, X, Peters, A, Räikkönen, K, Starr, JM, Waldenberger, M, Wray, NR, Whitsel, EA, Sotoodehnia, N, Seshadri, S, Porteous, DJ, Van Meurs, J, Mosley, TH, McIntosh, AM, Mendelson, MM, Levy, D, Hou, L, Eriksson, JG, Fornage, M, Deary, IJ, Baccarelli, A, Tiemeier, H & Amin, N 2018, 'DNA methylation signatures of depressive symptoms in middle-aged and elderly persons: Meta-analysis of multiethnic epigenome-wide studies', JAMA Psychiatry, vol. 75, no. 9, pp. 949-959. https://doi.org/10.1001/jamapsychiatry.2018.1725

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

In: JAMA Psychiatry, Vol. 75, No. 9, 09.2018, p. 949-959.

Research output: Contribution to journalArticle

TY - JOUR

T1 - DNA methylation signatures of depressive symptoms in middle-aged and elderly persons

T2 - Meta-analysis of multiethnic epigenome-wide studies

AU - Jovanova, Olivera Story

AU - Nedeljkovic, Ivana

AU - Spieler, Derek

AU - Walker, Rosie M.

AU - Liu, Chunyu

AU - Luciano, Michelle

AU - Bressler, Jan

AU - Brody, Jennifer

AU - Drake, Amanda J.

AU - Evans, Kathryn L.

AU - Gondalia, Rahul

AU - Kunze, Sonja

AU - Kuhnel, Brigitte

AU - Lahti, Jari

AU - Lemaitre, Rozenn N.

AU - Marioni, Riccardo E.

AU - Swenson, Brenton

AU - Himali, Jayandra Jung

AU - Wu, Hongsheng

AU - Li, Yun

AU - McRae, Allan F.

AU - Russ, Tom C.

AU - Stewart, James

AU - Wang, Zhiying

AU - Zhang, Guosheng

AU - Ladwig, Karl Heinz

AU - Uitterlinden, Andre G.

AU - Guo, Xiuqing

AU - Peters, Annette

AU - Räikkönen, Katri

AU - Starr, John M.

AU - Waldenberger, Melanie

AU - Wray, Naomi R.

AU - Whitsel, Eric A.

AU - Sotoodehnia, Nona

AU - Seshadri, Sudha

AU - Porteous, David J.

AU - Van Meurs, Joyce

AU - Mosley, Thomas H.

AU - McIntosh, Andrew M.

AU - Mendelson, Michael M.

AU - Levy, Daniel

AU - Hou, Lifang

AU - Eriksson, Johan G.

AU - Fornage, Myriam

AU - Deary, Ian J.

AU - Baccarelli, Andrea

AU - Tiemeier, Henning

AU - Amin, Najaf

PY - 2018/9

Y1 - 2018/9

N2 - 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 levelswere 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 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 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.

AB - 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 levelswere 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 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 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.

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