Digitala Vetenskapliga Arkivet

Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Show others and affiliations
2017 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, article id e1002Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies have identified a number of single-nucleotide polymorphisms (SNPs) that are associated with psychiatric diseases. Increasing body of evidence suggests a complex connection of SNPs and the transcriptional and epigenetic regulation of gene expression, which is poorly understood. In the current study, we investigated the interplay between genetic risk variants, shifts in methylation and mRNA levels in whole blood from 223 adolescents distinguished by a risk for developing psychiatric disorders. We analyzed 37 SNPs previously associated with psychiatric diseases in relation to genome-wide DNA methylation levels using linear models, with Bonferroni correction and adjusting for cell-type composition. Associations between DNA methylation, mRNA levels and psychiatric disease risk evaluated by the Development and Well-Being Assessment (DAWBA) score were identified by robust linear models, Pearson's correlations and binary regression models. We detected five SNPs (in HCRTR1, GAD1, HADC3 and FKBP5) that were associated with eight CpG sites, validating five of these SNP-CpG pairs. Three of these CpG sites, that is, cg01089319 (GAD1), cg01089249 (GAD1) and cg24137543 (DIAPH1), manifest in significant gene expression changes and overlap with active regulatory regions in chromatin states of brain tissues. Importantly, methylation levels at cg01089319 were associated with the DAWBA score in the discovery group. These results show how distinct SNPs linked with psychiatric diseases are associated with epigenetic shifts with relevance for gene expression. Our findings give a novel insight on how genetic variants may modulate risks for the development of psychiatric diseases.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 7, article id e1002
National Category
Psychiatry Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-319660DOI: 10.1038/tp.2016.275ISI: 000396451500002PubMedID: 28094813OAI: oai:DiVA.org:uu-319660DiVA, id: diva2:1087493
Funder
Swedish Research CouncilNovo NordiskThe Swedish Brain FoundationAvailable from: 2017-04-07 Created: 2017-04-07 Last updated: 2024-01-17Bibliographically approved
In thesis
1. Epigenetic dysregulation in relation to psychiatric traits in adolescence and adulthood
Open this publication in new window or tab >>Epigenetic dysregulation in relation to psychiatric traits in adolescence and adulthood
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Epigenetics has evolved into a key research focus in the field of psychiatry. DNA methylation is the most researched epigenetic mechanism. In paper I-III, 130 and 93 adolescents were randomly recruited at two separate intervals. Subjects were evaluated by web-based diagnostic interviews using the Development and Well-Being Assessment (DAWBA), providing computer generated diagnostic predictions of probability of diagnosis, covering several psychiatric disorders. For Paper I-II, the genome-wide DNA methylation pattern was measured from whole blood using the Illumina 450K array, and for paper IV by the Illumina EPIC BeadChip. In paper I, a methylome-wide association study (MWAS) was conducted (n=93) followed by a validation analysis (n=78), contrasting methylation levels in groups stratified by DAWBA depression risk scores. A microRNA4646 (MIR4646) associated methylation locus was differentially methylated in the MWAS (pbonf<0.05) and results were replicated in the validation cohort (p<0.05). Methylation levels at the identified locus correlated inversely with gene expression levels of MIR4456 (p<0.05). In silico analysis suggests MIR4646 may influence synthesis of omega-3 fatty acids, previously implicated in major depressive disorder. In paper II, 37 single nucleotide polymorphisms (SNP:s) previously associated with psychiatric disease were evaluated in relation to genome-wide DNA methylation levels in 130 adolescents in a methylome-wide (mQTL) analysis. Five SNP-CpG pairs were identified (pbonf<0.05) and replicated (p<0.05). Methylation of three of these were shown to be significantly correlated with gene expression levels of the associated genes (p<0.05). One identified GAD1-coupled methylation site was differentially methylated to a general psychiatric risk score in adolescents (p<0.05). In Paper III, hypothalamic-pituitary-adrenal (HPA)-axis coupled DNA methylation loci were investigated in 88 suicide attempters to identify associations to severity of suicide attempt. One corticotropin releasing hormone (CRH)-associated CpG-site was significantly hypomethylated in the high-risk group of suicide-attempters (n=31)(cg19035496, p<0.001) and exhibited hypermethylation in an external study group of adolescents in dependency of a general psychiatric risk score (p<0.05). In paper IV, 8,852 microRNA (miRNA) associated CpG-sites were investigated for an association with hypersexual disorder (HD). A microRNA-4456 (MIR4456) associated CpG-site (cg01299774) was borderline significant in HD (pFDR=5.81E-02) and differentially methylated in alcohol dependence (p<0.05) in an independent study group. Methylation levels at cg01299774 correlated inversely with expression levels of MIR4456 (p<0.01) and MIR4456 was lower expressed in HD (p<0.05). In-silico analyses suggests MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signaling pathway.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2021. p. 93
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1705
Keywords
methylome-wide, DNA methylation, hypersexual disorder, microRNA, oxytocin signaling, psychiatry, hsa-miR-4456, microRNA-4456, MIR4456, epigenetic dysregulation, microRNA expression, gene target prediction, epigenetics, suicide, suicide attempt, HPA axis, CRH gene, Epigenetics, Methylation, Adolescent depression, MIR4646, methylome-wide association study, Omega-3, mQTL analysis, GAD1, HDAC3, DAWBA
National Category
Psychiatry Medical Genetics
Identifiers
urn:nbn:se:uu:diva-426237 (URN)978-91-513-1079-4 (ISBN)
Public defence
2021-01-22, Room A2:208, BMC, Husaregatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2020-12-22 Created: 2020-11-26 Last updated: 2021-01-25
2. 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)
Opponent
Supervisors
Available from: 2022-04-26 Created: 2022-03-22 Last updated: 2022-06-14

Open Access in DiVA

fulltext(1487 kB)374 downloads
File information
File name FULLTEXT01.pdfFile size 1487 kBChecksum SHA-512
0107488a3830ca9b2cff2ea945bb860d1bbfa574765caf37056be36d0c43606017003f7c60711a26f097a4817268aa25cf2031eabe74bcf6d725abf4695f7579
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Ciuculete, Diana-MariaBoström, Adrian E.Voisin, SarahTitova, Olga E.Bandstein, MarcusWilliams, Michael J.Mwinyi, JessicaSchiöth, Helgi B.
By organisation
Functional Pharmacology
In the same journal
Translational Psychiatry
PsychiatryPharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 374 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 771 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf