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A MIR4646 associated methylation locus is hypomethylated in adolescent depression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Univ Zurich, Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland..
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2017 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 220, 117-128 p.Article in journal (Refereed) Published
Abstract [en]

Background: Studies of epigenetics and transcriptional activity in adolescents may provide knowledge about possible preventive strategies of depression. Methods: We present a methylome-wide association study (MWAS) and cohort validation analysis of depression in adolescents, in two separate cohorts: discovery (n = 93) and validation data set 1 (n = 78). The genome-wide methylation pattern was measured from whole blood using the Illumina 450K array. A second validation cohort, validation data set 2, consists of post-mortem brain biopsies from depressed adults (n = 58). We performed a MWAS by robust multiple linear regressions of methylation to a modified risk-score assessment of depression. Methylation levels of candidate CpG sites were correlated with expression levels of the associated gene in an independent cohort of 11 healthy volunteers. Results: The methylation state of two CpG sites reliably predicted ratings of depression in adolescents (cg13227623 and cg04102384) (p < 10E-06). Cohort validation analysis confirmed cg04102384 - located in the promoter region of microRNA 4646 (MIR4646) - to be hypomethylated in both validation data set 1 and validation data set 2 (p < 0.05). Cg04102384 was inversely correlated to expression levels of MIR4646-3p in healthy controls (p < 0.05). Limitations: MIR4646 was not differentially expressed in a subset of samples with adolescent depression measured by qRT-PCR measurements. Conclusion: We identify a specific MIR4646 associated epigenetic risk site to be associated with depression in adolescents. Cg04102384 putatively regulates gene expression of MIR4646-3p. Target gene prediction and gene set overrepresentation analysis revealed involvement of this miRNA in fatty acid elongation, a process related to omega-3 fatty acids, previously associated with depression.

Place, publisher, year, edition, pages
2017. Vol. 220, 117-128 p.
Keyword [en]
MIR4646, Methylome-wide association study, Adolescent depression, Omega-3, MicroRNA
National Category
Neurology Psychiatry
Identifiers
URN: urn:nbn:se:uu:diva-333057DOI: 10.1016/j.jad.2017.05.017ISI: 000406463700017PubMedID: 28618313OAI: oai:DiVA.org:uu-333057DiVA: diva2:1156137
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2017-11-10 Created: 2017-11-10 Last updated: 2017-11-10Bibliographically approved

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Boström, AdrianCiuculete, Diana-MariaAttwood, Misty M.Titova, Olga EMwinyi, JessicaSchiöth, Helgi B.

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