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

Cao, Linlin LU ; Sundquist, Kristina LU ; Zhang, Yujie LU orcid ; Memon, Ashfaque A LU orcid ; Hedelius, Anna LU ; Li, Ning ; Ji, Jianguang LU orcid ; Sundquist, Jan LU ; Zheng, Deqiang LU and Wang, Xiao LU (2026) In Journal of Affective Disorders 403.
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Mendelian randomization, microRNA, Major depressive disorder
in
Journal of Affective Disorders
volume
403
article number
121394
pages
9 pages
publisher
Elsevier
external identifiers
  • pmid:41690636
ISSN
0165-0327
DOI
10.1016/j.jad.2026.121394
language
English
LU publication?
yes
additional info
Copyright © 2026 The Author(s). Published by Elsevier B.V. All rights reserved.
id
aea57521-f579-4323-9416-6b4ca36dc315
date added to LUP
2026-02-23 15:28:27
date last changed
2026-02-23 16:13:04
@article{aea57521-f579-4323-9416-6b4ca36dc315,
  abstract     = {{<p>BACKGROUND: A growing body of evidence links microRNAs (miRNAs) to major depressive disorder (MDD). However, the causal nature of these associations remains unclear.</p><p>OBJECTIVES: This study aimed to investigate the potential causal association between miRNAs and MDD by combining Mendelian Randomization (MR) analyses and experimental validation.</p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Cao, Linlin and Sundquist, Kristina and Zhang, Yujie and Memon, Ashfaque A and Hedelius, Anna and Li, Ning and Ji, Jianguang and Sundquist, Jan and Zheng, Deqiang and Wang, Xiao}},
  issn         = {{0165-0327}},
  keywords     = {{Mendelian randomization; microRNA; Major depressive disorder}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Affective Disorders}},
  title        = {{Combining Mendelian randomization and experimental approaches for the identification of miRNAs related to major depressive disorder}},
  url          = {{http://dx.doi.org/10.1016/j.jad.2026.121394}},
  doi          = {{10.1016/j.jad.2026.121394}},
  volume       = {{403}},
  year         = {{2026}},
}