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

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 (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.

The molecular pathophysiology of mood disorders: From the analysis of single molecular layers to multi-omic integration

“…The cismeQTL analysis (SNP-CpG regression) showed a significant genetic-epigenetic interaction in 13 out of the 18 differentially methylated CpG sites. Ciuculete et al (2020) considered a step-by-step approach with regressions using blood and brain DNAme data. In their discovery cohort of 59 adolescents, they first identified an increase in blood DNAme at the cg24627299 site that was associated with higher depression scores and suicidal ideation during a 1-year follow-up.…”

meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes

“…All 786 were genotyped using the Infinium Global Screening Array at the SNP&SEQ SciLife Platform at Uppsala University, interrogating 700,078 genetic variants. SNPs were imputed as previously described [59], and all 102 selected SNPs had imputation scores > 0.8. Blood DNAm profiles of the 221 adolescents were assessed with the Illumina 450 K methylation Beadchip.…”

A Glimpse Into the Sexual Dimorphisms in Major Depressive Disorder Through Epigenetic Studies

“…MDD may arise in part from the differential expressions and actions of the same gene across brain regions. Ciuculete et al (2020) discovered higher methylation levels within the hepatocyte growth factor receptor ( MET ) gene associated with higher depression scores and susceptibility for suicidal symptoms, along with an inverse relationship to mRNA levels of both hepatocyte growth factor (HGF) expression and MET expression in the hippocampus ( Ciuculete et al, 2020 ). Misztak et al (2020) discovered significant decreases in H3K9/14ac expression, BDNF protein levels and p-S421-MeCP2/MeCP2 protein ratio in both the frontal cortex (FCx) and hippocampus, along with significant increases in HDAC3 protein levels and H3K27me2 expression in both the FCx and hippocampus, as well as increases in Sin3a in the hippocampus in suicide victims ( Misztak et al, 2020 ).…”