A MIR4646 associated methylation locus is hypomethylated in adolescent depression

Boström, Adrian; Ciuculete, Diana‐Maria; Attwood, Misty M.; Krattinger, Regina; Nikontovic, Lamia; Titova, Olga E.; Kullak‐Ublick, Gerd A.; Mwinyi, Jessica; Schiöth, Helgi B.

doi:10.1016/j.jad.2017.05.017

Cited by 21 publications

(13 citation statements)

References 74 publications

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“…On the other hand, miR-4646-5p (located on chr6) was the most differentially expressed miRNA in placenta between boys and girls, with higher expression in boys. Based on genome-wide DNA methylation, miR-4646-3p was associated with depression in adolescence [41]. In another study, miR-4646-3p was identified to be upregulated in peripheral blood from schizophrenic patients (n = 55) compared to healthy controls (n = 28) [42].…”

Section: Discussionmentioning

confidence: 97%

Genome-wide microRNA expression analysis in human placenta reveals sex-specific patterns: an ENVIRONAGE birth cohort study

et al. 2020

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There is an increasing interest in microRNAs (miRNAs) as they are of utmost importance in gene regulation at the posttranscriptional level. Sex-related susceptibility for non-communicable diseases later in life could originate in early life. Until now, no data on sex-specific miRNA expression are available for the placenta. Therefore, we investigated the difference by sex of newborn's miRNA expression in human placental tissue. Within the ENVIRONAGE birth cohort, miRNA and mRNA expression profiling was performed in 60 placentae (50% boys) using Agilent (8 × 60 K) microarrays. The distribution of chromosome locations was studied and pathway analysis of the identified sex-specific miRNAs in the placenta was carried out. Of the total 2558 miRNAs on the array, 597 miRNAs were expressed in over 70% of the samples and were included for further analyses. A total of 142 miRNAs were significantly (FDR<0.05) associated with the newborn's sex. In newborn girls, 76 miRNAs had higher expression (hsa-miR-361-5p as most significant) and 66 miRNAs had lower expression (hsa-miR-4646-5p as most significant) than in newborn boys. In the same study population, placental differentially expressed genes by sex were also identified using a whole genome approach. The placental gene expression revealed 27 differentially expressed genes by comparing girls to boys. Ultimately, we studied the miRNA-RNA interactome and identified 14 miRNA-mRNA interactions as sex-specific. Sex differences in placental m(i)RNA expression may reveal sex-specific patterns already present during pregnancy, which may influence physiological conditions in early or later life. These molecular processes might play a role in sex-specific disease susceptibility in later life.

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Section: Discussionmentioning

confidence: 97%

Genome-wide microRNA expression analysis in human placenta reveals sex-specific patterns: an ENVIRONAGE birth cohort study

et al. 2020

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“…Researchers have taken diverse approaches in examining patterns of DNAm that are associated with major depression; perhaps, not surprisingly, a wide range of findings have been reported. Most studies have found that the the CpG sites (using candidate and epigenome-wide approaches) associated with concurrent depressive symptoms or diagnosis [43][44][45][46][47] were characterized by lower levels of methylation (c.f., ref. 58 ).…”

Section: Discussionmentioning

confidence: 99%

“…We assessed and followed the girls prospectively into adulthood, or until they experienced their first depressive episode. Although some recent research has found no methylation sites that survived correction in relation to MDD 42 , several prior studies reported concurrent depressive symptoms and diagnoses were associated with DNAm using various approaches [43][44][45][46][47] . Given the biological relevance of HPA-axis function to risk for MDD, and that epigenetic variation may reflect combined genetic and environmental risks, we hypothesized that DNAm in CpG sites in HPA-axis genes assessed in early adolescence would predict the onset of MDD.…”

Section: Introductionmentioning

confidence: 96%

DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis

et al. 2019

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The stress response system is disrupted in individuals with major depressive disorder (MDD) as well as in those at elevated risk for developing MDD. We examined whether DNA methylation (DNAm) levels of CpG sites within HPAaxis genes predict the onset of MDD. Seventy-seven girls, approximately half (n = 37) of whom were at familial risk for MDD, were followed longitudinally. Saliva samples were taken in adolescence (M age = 13.06 years [SD = 1.52]) when participants had no current or past MDD diagnosis. Diagnostic interviews were administered approximately every 18 months until the first onset of MDD or early adulthood (M age of last follow-up = 19.23 years [SD = 2.69]). We quantified DNAm in saliva samples using the Illumina EPIC chip and examined CpG sites within six key HPA-axis genes (NR3C1, NR3C2, CRH, CRHR1, CRHR2, FKBP5) alongside 59 genotypes for tagging SNPs capturing cis genetic variability. DNAm levels within CpG sites in NR3C1, CRH, CRHR1, and CRHR2 were associated with risk for MDD across adolescence and young adulthood. To rule out the possibility that findings were merely due to the contribution of genetic variability, we re-analyzed the data controlling for cis genetic variation within these candidate genes. Importantly, methylation levels in these CpG sites continued to significantly predict the onset of MDD, suggesting that variation in the epigenome, independent of proximal genetic variants, prospectively predicts the onset of MDD. These findings suggest that variation in the HPA axis at the level of the methylome may predict the development of MDD.

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“…We measured body weight at the clinic and calculated for body mass index (BMI). Methylation analysis at baseline was available for 221 non-related adolescents, analysed in two batches [ 29 , 32 ]. Out of 130 adolescents analysed in the first batch, a subset of 61 came at the follow-up and therefore had extracted DNA available.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, analysing DNA signatures at early stages reduces the noise created by stochastic DNAm changes that happen with advancing age [ 28 ]. Only two studies reported methylome-wide findings associated with depression in adolescents [ 29 , 30 ]. One study that identified inverse association between methylation at MIR4646 and gene expression was underpowered (n = 11 adults).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression

et al. 2019

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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 (p raw <1e-4) and susceptibility for suicidal symptoms (p adj. <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 (p adj. <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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A MIR4646 associated methylation locus is hypomethylated in adolescent depression

Cited by 21 publications

References 74 publications

Genome-wide microRNA expression analysis in human placenta reveals sex-specific patterns: an ENVIRONAGE birth cohort study

Genome-wide microRNA expression analysis in human placenta reveals sex-specific patterns: an ENVIRONAGE birth cohort study

DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis

Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression

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