Investigating Irritability as a Potentially Causal Risk Pathway to Depression Using Two Genetically Informed Designs

Abstract

Background

Major depressive disorder (MDD) is heterogeneous, with diverse risk pathways leading to illness. Identifying causal routes to depression helps prioritize targets for early intervention and prevention strategies. Although irritability is associated with risk for later depression, this 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 from ages 15 to 25 years using the NPR. Second, we conducted bidirectional two-sample Mendelian randomization (MR) to examine relationships between genetic liability to self-reported irritability and depression, using published genome-wide association studies.

Results

In CATSS, associations were observed between irritability at age 15 (parent-reported odds ratio [OR] = 1.93 [1.61–2.34], p = 4.65 × 10⁻¹²; self-reported OR = 1.62 [1.36–1.93], p = 7.13 × 10⁻⁸) and NPR-recorded MDD diagnoses from 15 to 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 = .032). Results were inconclusive for parent-reported irritability (OR = 1.20 [0.73–1.96], p = .47). MR revealed a bidirectional relationship (irritability to depression inverse-variance weighted [IVW] OR = 3.31 [2.07–5.28], p = 5.5 × 10⁻⁷; depression to irritability IVW OR = 1.07 [1.05–1.10], p = 3.2 × 10⁻¹¹).

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.