| 1. |
- Pisanu, Claudia, et al.
(författare)
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Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI
- 2019
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Ingår i: Translational Psychiatry. - : NATURE PUBLISHING GROUP. - 2158-3188. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Patients with bipolar disorder (BD) show higher frequency of obesity and type 2 diabetes (T2D), but the underlying genetic determinants and molecular pathways are not well studied. Using large publicly available datasets, we (1) conducted a gene-based analysis using MAGMA to identify genes associated with BD and body mass index (BMI) or T2D and investigated their functional enrichment; and (2) performed two meta-analyses between BD and BMI, as well as BD and T2D using Metasoft. Target druggability was assessed using the Drug Gene Interaction Database (DGIdb). We identified 518 and 390 genes significantly associated with BD and BMI or BD and T2D, respectively. A total of 52 and 12 genes, respectively, were significant after multiple testing correction. Pathway analyses conducted on nominally significant targets showed that genes associated with BD and BMI were enriched for the Neuronal cell body Gene Ontology (GO) term (p = 1.0E-04; false discovery rate (FDR) = 0.025) and different pathways, including the Signaling by Hedgehog pathway (p = 4.8E -05, FDR = 0.02), while genes associated with BD and T2D showed no specific enrichment. The meta-analysis between BD and BMI identified 64 relevant single nucleotide polymorphisms (SNPs). While the majority of these were located in intergenic regions or in a locus on chromosome 16 near and in the NPIPL1 and SH2B1 genes (best SNP: rs4788101, p = 2.1E-24), five were located in the ETV5 gene (best SNP: rs1516725, p= 1E-24), which was previously associated with both BD and obesity, and one in the RPGRIP1L gene (rs1477199, p = 5.7E-09), which was also included in the Signaling by Hedgehog pathway. The meta-analysis between BD and T2D identified six significant SNPs, three of which were located in ALAS1 (best SNP: rs352165, p = 3.4E-08). Thirteen SNPs associated with BD and BMI, and one with BD and T2D, were located in genes which are part of the druggable genome. Our results support the hypothesis of shared genetic determinants between BD and BMI and point to genes involved in Hedgehog signaling as promising targets.
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| 2. |
- Abu Hamdeh, Sami, et al.
(författare)
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Differential DNA methylation of the genes for amyloid precursor protein, tau, and neurofilaments in human traumatic brain injury
- 2021
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 38:12, s. 1662-1669
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration; for example, amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM), and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients with iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH, and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828,888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation, and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain, and may have implications for the neurodegenerative disorders associated with TBI.
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| 3. |
- Alsehli, Ahmed M., et al.
(författare)
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Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia
- 2021
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Ingår i: Frontiers in Bioscience-Landmark. - : Frontiers Media S.A.. - 2768-6701 .- 2768-6698. ; 26:12, s. 1453-1463
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Methods: A cross-sectional cohort study based on baseline data collected between 2006–2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. Results: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 × 10−4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01–1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). Conclusion: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.
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| 4. |
- Boström, Adrian, et al.
(författare)
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A MIR4646 associated methylation locus is hypomethylated in adolescent depression
- 2017
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Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327 .- 1573-2517. ; 220, s. 117-128
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Boström, Adrian, et al.
(författare)
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Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling : A DNA methylation analysis of miRNA genes
- 2020
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Ingår i: Epigenetics. - : Taylor & Francis. - 1559-2294 .- 1559-2308. ; 15:1-2, s. 145-160
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Tidskriftsartikel (refereegranskat)abstract
- Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification ‘Compulsive Sexual Behavior Disorder’ is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD – cg18222192 (MIR708)(p < 10E-05,pFDR = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, pFDR = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that 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 signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.
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| 6. |
- Chatzittofis, Andreas, et al.
(författare)
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HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation shifts in Hypothalamic–pituitary–adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level ≥ 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders.
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| 7. |
- Ciuculete, Diana-Maria, et al.
(författare)
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A genetic risk score is significantly associated with statin therapy response in the elderly population
- 2017
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 91:3, s. 379-385
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Tidskriftsartikel (refereegranskat)abstract
- The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population.
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| 8. |
- Ciuculete, Diana-Maria, et al.
(författare)
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A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score
- 2017
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Ingår i: Translational Psychiatry. - : NATURE PUBLISHING GROUP. - 2158-3188. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Ciuculete, Diana-Maria, et al.
(författare)
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Challenges in Analyzing Functional Epigenetic Data in Perspective of Adolescent Psychiatric Health
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:10
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Forskningsöversikt (refereegranskat)abstract
- The formative period of adolescence plays a crucial role in the development of skills and abilities for adulthood. Adolescents who are affected by mental health conditions are at risk of suicide and social and academic impairments. Gene-environment complementary contributions to the molecular mechanisms involved in psychiatric disorders have emphasized the need to analyze epigenetic marks such as DNA methylation (DNAm) and non-coding RNAs. However, the large and diverse bioinformatic and statistical methods, referring to the confounders of the statistical models, application of multiple-testing adjustment methods, questions regarding the correlation of DNAm across tissues, and sex-dependent differences in results, have raised challenges regarding the interpretation of the results. Based on the example of generalized anxiety disorder (GAD) and depressive disorder (MDD), we shed light on the current knowledge and usage of methodological tools in analyzing epigenetics. Statistical robustness is an essential prerequisite for a better understanding and interpretation of epigenetic modifications and helps to find novel targets for personalized therapeutics in psychiatric diseases.
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| 10. |
- Ciuculete, Diana-Maria, et al.
(författare)
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Changes in methylation within the STK32B promoter are associated with an increased risk for generalized anxiety disorder in adolescents
- 2018
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Ingår i: Journal of Psychiatric Research. - : Elsevier BV. - 0022-3956 .- 1879-1379. ; 102, s. 44-51
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Tidskriftsartikel (refereegranskat)abstract
- Generalized anxiety disorder (GAD) is highly prevalent among adolescents. An early detection of individuals at risk may prevent later psychiatric condition. Genome-wide studies investigating single nucleotide polymorphisms (SNPs) concluded that a focus on epigenetic mechanisms, which mediate the impact of environmental factors, could more efficiently help the understanding of GAD pathogenesis. We investigated the relationship between epigenetic shifts in blood and the risk to develop GAD, evaluated by the Development and Well-Being Assessment (DAWBA) score, in 221 otherwise healthy adolescents. Our analysis focused specifically on methylation sites showing high inter-individual variation but low tissue-specific variation, in order to infer a potential correlation between results obtained in blood and brain. Two statistical methods were applied, 1) a linear model with limma and 2) a likelihood test followed by Bonferroni correction. Methylation findings were validated in a cohort of 160 adults applying logistic models against the outcome variable "anxiety treatment obtained in the past" and studied in a third cohort with regards to associated expression changes measured in monocytes. One CpG site showed 1% increased methylation in adolescents at high risk of GAD (cg16333992, P-adj. = 0.028, estimate = 3.22), as confirmed in the second cohort (p = 0.031, estimate = 1.32). The identified and validated CpG site is located within the STK32B promoter region and its methylation level was positively associated with gene expression. Gene ontology analysis revealed that STK32B is involved in stress response and defense response. Our results provide evidence that shifts in DNA methylation are associated with a modulated risk profile for GAD in adolescence.
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| 11. |
- Ciuculete, Diana Maria, et al.
(författare)
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Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression
- 2020
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 15:6-7, s. 646-663
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 12. |
- Ciuculete, Diana-Maria, et al.
(författare)
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meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes
- 2020
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Ingår i: Clinical Epigenetics. - : BMC. - 1868-7083 .- 1868-7075. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. Results We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (totaln= 435 healthy individuals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (p(adj.)< 0.05) with meQTL effect. Lower DNAm at cg02098413 located in theHACE1promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (p(raw)= 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated withHACE1mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lowerHACE1mRNA expression in CA1 hippocampus of MDD patients compared with healthy controls (p= 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 (SHANK2) (p(adj.)= 0.015, mRNA difference = 5.2%). Gene ontology analysis of the miRNA target genes highlighted implication in neuronal processes. Conclusions Collectively, our findings from a multi-tissue (blood and brain) and multi-layered (genetic, epigenetic, transcriptomic) approach suggest that genetic factors may influence depression by modulating DNAm and miRNA levels. Alterations atHACE1andSHANK2loci imply potential mechanisms, such as oxidative stress in the brain, underlying depression. Our results deepened the knowledge of molecular mechanisms in depression and suggest new epigenetic targets that should be further evaluated.
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| 13. |
- Ciuculete, Diana-Maria, et al.
(författare)
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Response to Leusink et al.
- 2017
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 92:5, s. 566-566
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 14. |
- Elbere, Ilze, et al.
(författare)
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Significantly altered peripheral blood cell DNA methylation profile as a result of immediate effect of metformin use in healthy individuals
- 2018
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Metformin is a widely prescribed antihyperglycemic agent that has been also associated with multiple therapeutic effects in various diseases, including several types of malignancies. There is growing evidence regarding the contribution of the epigenetic mechanisms in reaching metformin's therapeutic goals; however, the effect of metformin on human cells in vivo is not comprehensively studied. The aim of our study was to examine metformin-induced alterations of DNA methylation profiles in white blood cells of healthy volunteers, employing a longitudinal study design.Results: Twelve healthy metformin-naive individuals where enrolled in the study. Genome-wide DNA methylation pattern was estimated at baseline, 10h and 7days after the start of metformin administration. The whole-genome DNA methylation analysis in total revealed 125 differentially methylated CpGs, of which 11 CpGs and their associated genes with the most consistent changes in the DNA methylation profile were selected: POFUT2, CAMKK1, EML3, KIAA1614, UPF1, MUC4, LOC727982, SIX3, ADAM8, SNORD12B, VPS8, and several differentially methylated regions as novel potential epigenetic targets of metformin. The main functions of the majority of top-ranked differentially methylated loci and their representative cell signaling pathways were linked to the well-known metformin therapy targets: regulatory processes of energy homeostasis, inflammatory responses, tumorigenesis, and neurodegenerative diseases.Conclusions: Here we demonstrate for the first time the immediate effect of short-term metformin administration at therapeutic doses on epigenetic regulation in human white blood cells. These findings suggest the DNA methylation process as one of the mechanisms involved in the action of metformin, thereby revealing novel targets and directions of the molecular mechanisms underlying the various beneficial effects of metformin.Trial registrationEU Clinical Trials Register, 2016-001092-74. Registered 23 March 2017, https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001092-74/LV.
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| 15. |
- Fredriksson, Robert, et al.
(författare)
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The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain.
- 2019
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- SLC18B1 is a sister gene to the vesicular monoamine and acetylcholine transporters, and the only known polyamine transporter, with unknown physiological role. We reveal that Slc18b1 knock out mice has significantly reduced polyamine content in the brain providing the first evidence that Slc18b1 is functionally required for regulating polyamine levels. We found that this mouse has impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms. We also show that Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions and that expression of components of GABA and glutamate signalling are changed. We further observe a partial resistance to diazepam, manifested as significantly lowered reduction in locomotion after diazepam treatment. We suggest that removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to long-term reduction in glutamatergic signalling.
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| 16. |
- Jokinen, Jussi, et al.
(författare)
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Epigenetic changes in the CRH gene are related to severity of suicide attempt and a general psychiatric risk score in adolescents
- 2018
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 27, s. 123-133
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study, comprising 88 suicide attempters, was to identify hypothalamic-pituitary-adrenal (HPA) -axis coupled CpG-sites showing methylation shifts linked to severity of the suicide attempt. Candidate methylation loci were further investigated as risk loci for a general psychiatric risk score in two cohorts of adolescents (cohort 1 and 2). The genome-wide methylation pattern was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip. Subjects were stratified into high-risk and low-risk groups based on the severity of the suicidal behavior. We included CpG sites located within 2000 basepairs away from transcriptional start site of the following HPA-axis coupled genes: corticotropin releasing hormone (CRH), corticotropin releasing hormone binding protein (CRHBP), corticotropin releasing hormone receptor 1 (CRHR1), corticotropin releasing hormone receptor 2 (CRHR2), FK506-binding protein 51 (FKBP5) and the glucocorticoid receptor (NR3C1). Themethylation state of two corticotropin releasing hormone (CRH)-associated CpG siteswere significantly hypomethylated in the high-risk group of suicide attempters (n=31) (cg19035496 and cg23409074) (p < 0.001). Adolescent cohort 1 and 2 consisted of 129 and 93 subjects, respectively, and were stratified by the in silico generated DAWBA measurements of a general psychiatric risk score into high-risk group (>similar to 50% risk) or controls. In adolescent cohort 2, cg19035496 was hypermethylated in subjects with a high general psychiatric risk score. Our results show epigenetic changes in the CRH gene related to severity of suicide attempt in adults and a general psychiatric risk score in adolescents.
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| 17. |
- Jokinen, Jussi, et al.
(författare)
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Methylation of HPA axis related genes in men with hypersexual disorder
- 2017
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Ingår i: Psychoneuroendocrinology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0306-4530 .- 1873-3360. ; 80, s. 67-73
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Tidskriftsartikel (refereegranskat)abstract
- Hypersexual Disorder (HD) defined as non-paraphilic sexual desire disorder with components of compulsivity, impulsivity and behavioral addiction, and proposed as a diagnosis in the DSM 5, shares some overlapping features with substance use disorder including common neurotransmitter systems and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function. In this study, comprising 67 HD male patients and 39 male healthy volunteers, we aimed to identify HPA-axis coupled CpG-sites, in which modifications of the epigenetic profile are associated with hypersexuality. The genome-wide methylation pattern was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip, measuring the methylation state of over 850 K CpG sites. Prior to analysis, the global DNA methylation pattern was pre-processed according to standard protocols and adjusted for white blood cell type heterogeneity. We included CpG sites located within 2000 bp of the transcriptional start site of the following HPA-axis coupled genes: Corticotropin releasing hormone (CRH), corticotropin releasing hormone binding protein (CRHBP), corticotropin releasing hormone receptor I (CRHR1), corticotropin releasing hormone receptor 2 (CRHR2), FKBP5 and the glucocorticoid receptor (NR3C1). We performed multiple linear regression models of methylation M-values to a categorical variable of hypersexuality, adjusting for depression, dexamethasone non-suppression status, Childhood Trauma Questionnaire total score and plasma levels of TNF-alpha and IL-6. Of 76 tested individual CpG sites, four were nominally significant (p<0.05), associated with the genes CRH, CRHR2 and NR3C1. Cg23409074-located 48 bp upstream of the transcription start site of the CRH gene - was significantly hypomethylated in hypersexual patients after corrections for multiple testing using the FDR-method. Methylation levels of cg23409074 were positively correlated with gene expression of the CRH gene in an independent cohort of 11 healthy male subjects. The methylation levels at the identified CRH site, cg23409074, were significantly correlated between blood and four different brain regions. CRH is an important integrator of neuroendocrine stress responses in the brain, with a key role in the addiction processes. Our results show epigenetic changes in the CRH gene related to hypersexual disorder in men.
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| 18. |
- Miguet, Maud, et al.
(författare)
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Perceived stress is related to lower blood pressure in a Swedish cohort
- 2023
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Ingår i: Scandinavian Journal of Public Health. - : Sage Publications. - 1403-4948 .- 1651-1905. ; 51:4, s. 611-618
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Tidskriftsartikel (refereegranskat)abstract
- Aims: General psychosocial stress and job strain have been related to blood pressure (BP) with conflicting results. This study sought to explore the contribution of several lifestyle factors in the relation between general psychosocial stress, job strain and BP.Methods: This cross-sectional study investigated the association of general stress and job strain with systolic BP (SBP) and diastolic BP in a sample of 9441 employed individuals from the EpiHealth cohort. General stress was measured by the Perceived Stress Scale. Job strain was assessed with the Job Content Questionnaire, assessing two dimensions of job strain: psychological job demand and decision latitude. Linear regression and sensitivity analysis were performed.Results: At the uncorrected model, general stress, job demand and decision latitude were all inversely associated with SBP. After further adjustment for lifestyle and health parameters, only general stress was associated with SPB (β coefficient: -0.103; 95% confidence interval -0.182 to 0.023).Cconclusions: General stress is associated with lower SBP independently of lifestyle in middle-aged adults. Our findings point towards a major contribution for job-unrelated stressors in determining SBP and support the pivotal role of lifestyle behaviours and health status in modulating the effect of stress on BP, calling for a careful selection of confounders.
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| 19. |
- Rasmusson, Annica J., et al.
(författare)
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Toll-like receptor 4 methylation grade is linked to depressive symptom severity
- 2021
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Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- This study explores potential associations between the methylation of promoter-associated CpG sites of the toll-like receptor (TLR)-family, plasma levels of pro-inflammatory proteins and depressive symptoms in young female psychiatric patients. Ratings of depressive symptoms and blood samples were obtained from 92 young women seeking psychiatric care. Methylation of 32 promoter-associated CpG sites in TLR1 to TLR10 was analysed using the Illumina Infinium Methylation EPIC BeadChip. Expression levels of 91 inflammatory proteins were determined by proximity extension assay. Statistical correlations between depressive state, TLR1-10 methylation and inflammatory proteins were investigated. Four additional cohorts were studied to evaluate the generalizability of the findings. In the discovery cohort, methylation grade of cg05429895 (TLR4) in blood was inversely correlated with depressive symptoms score in young adults. After correction for multiple testing, plasma levels of macrophage inflammatory protein 1 beta (MIP-1 beta/CCL4) were associated with both TLR4 methylation and depressive symptom severity. A similar inverse association between TLR4 methylation in blood and affective symptoms score was also found in a cohort of 148 both males and females (<40 years of age) from the Danish Twin Registry. These findings were not, however, replicated in three other external cohorts; which differed from the first two cohorts by a higher age and mixed ethnicities, thus limiting the generalizability of our findings. However, TLR4 methylation inversely correlated with TLR4 mRNA expression in the Danish Twin Study indicating a functional significance of methylation at this particular CpG. Higher depression scores in young Scandinavian adults was associated with decreased methylation of TLR4 in blood.
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| 20. |
- Rukh, Gull, et al.
(författare)
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Personality, lifestyle and job satisfaction : causal association between neuroticism and job satisfaction using Mendelian randomisation in the UK biobank cohort
- 2020
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Ingår i: Translational Psychiatry. - : NATURE PUBLISHING GROUP. - 2158-3188. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Job-related stress has been associated with poor health outcomes but little is known about the causal nature of these findings. We employed Mendelian randomisation (MR) approach to investigate the causal effect of neuroticism, education, and physical activity on job satisfaction. Trait-specific genetic risk score (GRS) based on recent genome wide association studies were used as instrumental variables (IV) using the UK Biobank cohort (N = 315,536). Both single variable and multivariable MR analyses were used to determine the effect of each trait on job satisfaction. We observed a clear evidence of a causal association between neuroticism and job satisfaction. In single variable MR, one standard deviation (1 SD) higher genetically determined neuroticism score (4.07 units) was associated with -0.31 units lower job satisfaction (95% confidence interval (CI): -0.38 to -0.24; P = 9.5 x 10(-20)). The causal associations remained significant after performing sensitivity analyses by excluding invalid genetic variants from GRS(Neuroticism) (beta(95%CI): -0.28(-0.35 to -0.21); P = 3.4 x 10(-15)). Education (0.02; -0.08 to 0.12; 0.67) and physical activity (0.08; -0.34 to 0.50; 0.70) did not show any evidence for causal association with job satisfaction. When genetic instruments for neuroticism, education and physical activity were included together, the association of neuroticism score with job satisfaction was reduced by only -0.01 units, suggesting an independent inverse causal association between neuroticism score (P = 2.7 x 10(-17)) and job satisfaction. Our findings show an independent causal association between neuroticism score and job satisfaction. Physically active lifestyle may help to increase job satisfaction despite presence of high neuroticism scores. Our study highlights the importance of considering the confounding effect of negative personality traits for studies on job satisfaction.
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| 21. |
- Tan, Xiao, et al.
(författare)
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Associations between chronotype, MTNR1B genotype and risk of type 2 diabetes in UK Biobank
- 2020
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 287:2, s. 189-196
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo examine the association between the MTNR1B G risk allele, type 2 diabetes (T2D) and chronotype in the UK Biobank.MethodsData from the baseline investigation of the UK Biobank were utilized (n = 337 083 White British; mean age: 56.9 years; 54% women). MTNR1B rs10830963 was directly genotyped [CC (reference group), CG and GG]. Chronotype was divided into four categories: definitely morning (reference group); more morning than evening; more evening than morning; and definitely evening. Logistic regression analyses were performed to estimate odds ratios and 95% confidence intervals (CIs) for T2D, controlling for age, sex and other confounders.ResultsCarriers of the rs10830963 risk allele had a higher risk of T2D [CG vs. CC: OR (95% CI) 1.10 (1.07, 1.15); GG vs. CC: 1.21 (1.14, 1.29)]. Compared with definitely morning chronotype, participants with definitely evening chronotype exhibited the highest risk of T2D [1.25 (1.17, 1.33)]. Despite a nonsignificant interaction between chronotype and the risk allele [0.98 (0.94, 1.01), P = 0.176 for interaction term], we found that definitely evening chronotype (vs. definitely morning) was linked with a higher risk of T2D amongst CC and CG but not GG carriers. Additionally, we saw that the GG genotype (vs. CC) was associated with a higher risk of T2D across all chronotype categories, except for definitely evening.ConclusionOur findings suggest that the MTNR1B G risk allele and late chronotype increase the risk of T2D. The association between late chronotype and higher risk of T2D appears to vary across MTNR1B rs10830963 genotypes.
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