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Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.ORCID iD: 0000-0001-6377-0270
Victoria Univ, Inst Hlth & Sport iHeS, Footscray, Vic, Australia.ORCID iD: 0000-0002-4074-7083
Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
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2020 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 15, no 6-7, p. 646-663Article in journal (Refereed) Published
Abstract [en]

Unrecognized depression during adolescence can result in adult suicidal behaviour. The aim of this study was to identify, replicate and characterize DNA methylation (DNAm) shifts in depression aetiology, using a longitudinal, multi-tissue (blood and brain) and multi-layered (genetics, epigenetics, transcriptomics) approach. We measured genome-wide blood DNAm data at baseline and one-year follow-up, and imputed genetic variants, in 59 healthy adolescents comprising the discovery cohort. Depression and suicidal symptoms were determined using the Development and Well-Being Assessment (DAWBA) depression band, Montgomery-Åsberg Depression Rating Scale-Self (MADRS-S) and SUicide Assessment Scale (SUAS). DNAm levels at follow-up were regressed against depression scores, adjusting for sex, age and the DNAm residuals at baseline. Higher methylation levels of 5% and 13% at cg24627299 within the MET gene were associated with higher depression scores (praw<1e-4) and susceptibility for suicidal symptoms (padj.<0.005). The nearby rs39748 was discovered to be a methylation and expression quantitative trait locus in blood cells. mRNA levels of hepatocyte growth factor (HGF) expression, known to strongly interact with MET, were inversely associated with methylation levels at cg24627299, in an independent cohort of 1180 CD14+ samples. In an open-access dataset of brain tissue, lower methylation at cg24627299 was found in 45 adults diagnosed with major depressive disorder compared with matched controls (padj.<0.05). Furthermore, lower MET expression was identified in the hippocampus of depressed individuals compared with controls in a fourth, independent cohort. Our findings reveal methylation changes at MET in the pathology of depression, possibly involved in downregulation of HGF/c-MET signalling the hippocampal region.

Place, publisher, year, edition, pages
Informa UK Limited , 2020. Vol. 15, no 6-7, p. 646-663
Keywords [en]
Adolescent depression, DNA methylation, HGF/c-MET signalling, epigenetics, epigenome-wide analysis
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-401871DOI: 10.1080/15592294.2019.1700628ISI: 000503306700001PubMedID: 31852353OAI: oai:DiVA.org:uu-401871DiVA, id: diva2:1384282
Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2022-03-22Bibliographically approved
In thesis
1. Functional epigenetic analyses in the context of psychiatric health in adolescence
Open this publication in new window or tab >>Functional epigenetic analyses in the context of psychiatric health in adolescence
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adolescence is a unique and formative period for learning and developing skills and abilities for adulthood. The prevalence of mental health problems in adolescents is estimated to 10-20%, being a major risk for suicide, social and academic impairments. Suicide is the third leading cause of death in older adolescents (15-19 years). Genetic studies suggest that gene-environment interaction contributes to molecular mechanisms of the differential risks for psychiatric disorders and epigenetic marks such as DNA methylation (DNAm) and non-coding RNA (ncRNA) are likely involved. In this doctoral thesis, we investigated how the environmentally modifiable factors are associated with genetic variation, anxiety disorders, depression and suicidal behavior. Using well described bioinformatic and statistical methods, e.g. DNAm preprocessing techniques, gene ontology enrichment, chromatin state inference, correlation of DNAm in blood and brain tissues and eQTL effect, we uncovered functional differential DNAm, meQTL and eQTL associations in the context of depression, generalized anxiety and suicidal thoughts in multiple datasets. First, in an epigenome-wide study, we identified associations between psychiatric-related SNPs and DNAm at CpG sites located within enhancer regions in hippocampus. Then, using a targeted approach by including CpG sites with cross tissue relevance, we found and replicated an association between differentially DNAm at one genomic locus and risk for generalized anxiety disorder. The functional role of the CpG site was supported by the observed association between DNAm shifts and mRNA expression in blood, together with its location within regulatory chromatin state in brain. In a longitudinal epigenome-wide study, we identified changes in DNAm levels at the gene promoter for risk for depression. Moreover, in blood, DNAm at one CpG site was associated with suicidal behavior and mRNA expression, which may be genetically controlled. These findings could be translated in the brain as differentially DNAm and mRNA expression levels at the same locus were observed for major depression in post-mortem tissue brain. Lastly, we identified meQTL and micro-RNA (miRNA) eQTL involved in depression in whole blood and brain. Gene ontology terms of the predicted target genes for one miRNA involved behavioral fear and defense response, presynaptic signal transductions, and presynaptic active zone organization. Overall, this thesis investigated and demonstrated a complementary influence of genetic and epigenetic factors underlying pathogenesis of psychiatric disorders.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2022. p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1828
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-469236 (URN)978-91-513-1459-4 (ISBN)
Public defence
2022-05-19, Hall IX, Universitetshuset, Biskopsgatan 3, Uppsala, 09:00 (English)
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Available from: 2022-04-26 Created: 2022-03-22 Last updated: 2022-06-14

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