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.
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.
| Original language | English |
|---|---|
| Article number | 100566 |
| Journal | Biological Psychiatry Global Open Science |
| Volume | 5 |
| Issue number | 6 |
| Early online date | 7 Jul 2025 |
| DOIs | |
| Publication status | E-pub ahead of print - 7 Jul 2025 |
Bibliographical note
Publisher Copyright:© 2025 The Authors
Research Groups and Themes
- Bristol Population Health Science Institute