Fig. 1

Study design and workflow diagram. Using whole blood of the discovery cohort comprising adolescents, meQTL analyses, together with associations between ncRNA levels and genotype and DNAm and depression scores were performed. The replication cohort comprised 219 adults and 64 previously identified meQTL-CpG pairs were validated in whole blood. The NICHD cohort containing 45 adult brain tissues was used to analyze the association between the MDD diagnosis and DNAm at the HACE1 gene. A positive relationship between DNAm degree and RNA expression levels of HACE1 was identified in CD14+ cells, in the MESA cohort. The EXPHIP cohort included 15 MDD-diagnosed and 15 matched controls and helped to identify lower HACE1 mRNA levels in depressed CA1 hippocampal region. The functional relevance of the findings was investigated using different bioinformatic or molecular biological software tools. DAWBA, Development and Well-Being Assessment; DNAm, DNA methylation; SNP, single-nucleotide polymorphism; ncRNA, non-coding RNA; meQTL, methylation quantitative trait locus; MDD, major depressive disorder