Work

Combining Mendelian randomization and experimental approaches for the identification of miRNAs related to major depressive disorder

Year: 2026

Type: article

Abstract: BACKGROUND: A growing body of evidence links microRNAs (miRNAs) to major depressive disorder (MDD). However, the causal nature of these associations remains unclear. OBJECTIVES: This study aimed to investigate the potential causal association between miRNAs and MDD by combining Mendelian Randomization (MR) analyses and experimental validation. METHODS: Single-nucleotide polymorphisms (SNPs) significantly associated with the expression levels of miRNAs identified in the Framingham Heart Study (FHS) were used as instrumental variables serving as a proxy for miRNA exposure. The outcome was derived from the genome-wide association study (GWAS) of MDD (cases = 170,756, controls = 329,443). Two-sample MR was conducted to assess the association of miRNAs with MDD. The miRNAs identified from MR analyses were further validated in blood samples from individuals in the Women's Health in Lund Area (WHILA) cohort using qPCR. RESULTS: MR analysis identified six miRNAs significantly associated with MDD risk, including miR-133a-3p [Odds Ratio (OR) = 1.03, 95% Confidence interval (CI):1.00-1.05], miR-130a-3p (OR = 1.06, 95% CI:1.03-1.09), miR-138-5p (OR = 1.06, 95% CI:1.01-1.11), miR-629-5p (OR = 0.96, 95% CI:0.93-0.99), miR-132-3p (OR = 0.97, 95% CI:0.94-1.00) and miR-635-3p (OR = 0.97, 95% CI:0.95-0.99). Among them, miR-130a-3p (OR = 2.06, 95% CI:1.08-4.28, P = 0.04) and miR-132-3p (OR = 0.51, 95% CI:0.29-0.88, P = 0.02) were further confirmed to be associated with MDD by experimental validation. CONCLUSIONS: Combining genetic and experimental approaches, this study provides evidence supporting a potential causal role for specific circulating miRNAs in MDD. While the MR findings were limited by single-SNP instruments, precluding formal pleiotropy assessment, the experimental validation of miR-130a-3p and miR-132-3p strengthens the evidence. Further research with multi-SNP instruments and larger cohorts are needed to confirm causality and explore clinical relevance.

Source: Journal of Affective Disorders

DOI: 10.1016/j.jad.2026.121394