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.

KEYWORDS:

• Adolescent depression
• HGF/c-MET signalling
• DNA methylation
• epigenetics
• epigenome-wide analysis

Acknowledgments

Genotyping was performed by the SNP&SEQ Technology Platform in Uppsala. The platform is part of Science for Life Laboratory at Uppsala University and is supported as a national infrastructure by the Swedish Research Council. L.K was supported by a fellowship from the Margaretha af Ugglas Foundation.

Authors’ contributions

DMC and HBS conceived and designed the study. DMC analyzed and interpreted the data and wrote the manuscript. JM interpreted the data and helped writing the manuscript. SV helped in analyzing and interpreting the results and writing the manuscript. LK and MJ performed the pyrosequencing analyses and helped writing the manuscript. NW recruited participants, gathered data and help writing the manuscript. JJ helped at interpretation of the results. HBS helped at the data interpretation.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplemental material

Supplemental data for this article can be accessed here.

Additional information

Funding

The studies were supported by the Swedish Research Foundation, the Åhlens Foundation, the Novo Nordisk Foundation, and the Swedish Brain Research Foundation.