Investigating irritability as a potentially causal risk pathway into depression using two genetically informed designs

Shakeshaft, Amy ORCID: https://orcid.org/0000-0003-1412-5413, Oginni, Olakunle, Martin, Joanna ORCID: https://orcid.org/0000-0002-8911-3479, Dennison, Charlotte A. ORCID: https://orcid.org/0000-0002-7493-2041, Eyre, Olga, Leibenluft, Ellen, Lundström, Sebastian, Stergiakouli, Evie, Larsson, Henrik, Lichtenstein, Paul, Stringaris, Argyris, Riglin, Lucy, Taylor, Mark J. and Thapar, Anita ORCID: https://orcid.org/0000-0002-3689-737X 2025. Investigating irritability as a potentially causal risk pathway into depression using two genetically informed designs. Biological Society Global Open Science , 100566. 10.1016/j.bpsgos.2025.100566

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Abstract

Background Major Depressive Disorder (MDD) is heterogenous with diverse risk pathways leading to illness. Identifying causal routes into depression helps prioritize targets for early intervention and prevention strategies. Although irritability is associated with risk for later depression, association could be explained by confounders, including genetic confounders. Methods We used two genetically informed designs to examine whether irritability is causally linked to depression. First, using data from the Child and Adolescent Twin Study in Sweden (CATSS, N=16,495), and linked Swedish National Patient Register (NPR), we assessed the relationship between irritability and MDD using the monozygotic twin differences design, which controls for genetic influences. Irritability was assessed at age 15 using the Strengths and Difficulties Questionnaire. MDD diagnoses were identified between ages 15-25 years using NPR. Second, we conducted bidirectional two-sample Mendelian randomization (MR) to examine relationships between genetic liability to self-reported irritability and depression, using published GWAS. Results In CATSS, associations were observed between irritability at age 15 (parent-reported OR=1.93 [1.61, 2.34], p=4.65x10-12; self-reported OR=1.62 [1.36, 1.93], p=7.13x10-8) and NPR recorded MDD diagnoses between 15-25 years. Monozygotic twin analysis revealed an association between self-reported twin differences in irritability and MDD discordance (OR=1.57 [1.04, 2.36], p=0.032). Results were inconclusive for parent-reported irritability (OR=1.20 [0.73,1.96], p=0.47). MR revealed a bidirectional relationship (irritability to depression IVW=3.31 [2.07, 5.28], p=5.5x10-7; depression to irritability IVW=1.07 [1.05, 1.10], p=3.2x10-11). Conclusions These results indicate that self-reported irritability may represent a causal risk pathway to MDD and thus could serve as a potential target for MDD prevention or early intervention.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine Research Institutes & Centres > Wolfson Centre for Young People's Mental Health (WCYPMH)
Publisher:	Elsevier
ISSN:	2667-1743
Date of First Compliant Deposit:	15 July 2025
Date of Acceptance:	1 July 2025
Last Modified:	15 Jul 2025 13:00
URI:	https://orca.cardiff.ac.uk/id/eprint/179793

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