Exploratory imaging–genetics associations between habenula connectivity and symptom severity in major depressive disorder

Abstract

Objective: The habenula is implicated in mood regulation and sleep–wake processes and has been increasingly studied in major depressive disorder (MDD). This exploratory imaging–genetics study examined the potential associations between candidate gene polymorphisms, habenula-centered brain connectivity, and clinical symptom severity in patients with MDD. Methods: Ten candidate genes related to mood and circadian regulation were genotyped in patients with MDD and in healthy controls. All participants underwent 3 T structural and resting-state functional MRI. Seed-based structural and functional connectivity analyses were conducted focusing on the habenula. Imaging–genetics associations were examined with corrections for multiple comparisons. Results: Sixty-nine patients with MDD and forty-one healthy controls of Korean ethnicity were included. In MDD, structural connectivity between the left habenula and the left inferior frontal gyrus was significantly associated with rs2304672, and connectivity between the left habenula and the right ventral anterior thalamic nucleus was associated with rs7123390. Across all participants, functional connectivity between the left habenula and right parahippocampal gyrus showed consistent significant associations with multiple symptom domains, includin depression and sleep disturbance. Conclusion: In this modest-sized sample, preliminary imaging–genetics associations involving habenula-centered circuits were observed. These findings should be considered exploratory and hypothesis generating. Larger, adequately powered studies are required to confirm whether genetic variations meaningfully contribute to individual differences in habenular connectivity and symptom expression in patients with MDD.