Abstract
Obesity is a clinically relevant and highly prevalent somatic comorbidity of major depression (MDD). Genetic predisposition and history of childhood trauma have both independently been demonstrated to act as risk factors for obesity and to be associated with alterations in reward related brain structure and function. We therefore aimed to investigate the influence of childhood maltreatment and genetic risk for obesity on structural and functional imaging correlates associated with reward processing in MDD. 161 MDD patients underwent structural and functional MRI during a frequently used card guessing paradigm. Main and interaction effects of a polygenic risk score for obesity (PRS) and childhood maltreatment experiences as assessed using the Childhood Trauma Questionnaire (CTQ) were investigated. We found that maltreatment experiences and polygenic risk for obesity significantly interacted on a) body mass index b) gray matter volume of the orbitofrontal cortex as well as on c) BOLD response in the right insula during reward processing. While polygenic risk for obesity was associated with elevated BMI as well as with decreased OFC gray matter and increased insular BOLD response in non-maltreated patients, these associations were absent in patients with a history of childhood trauma. No significant main effect of PRS or maltreatment on gray matter or BOLD response could be detected at the applied thresholds. The present study suggests that childhood maltreatment moderates the influence of genetic load for obesity on BMI as well as on altered brain structure and function in reward related brain circuits in MDD.
Highlights
Traits that were found to be significantly associated with depression-PRS at a minimum of four PRS variant p thresholds were selected for re-analysis in the independent replication sample
To further illustrate overlapping genetic architecture, we reported results for linkage disequilibrium (LD) score regression based on the summary statistics above
We have provided results for genetic correlation using Linkage Disequilibrium Score Regression v1.0.056 in the main text and phenotypic association between depressive symptoms and other variables in Supplementary Table 4 and Supplementary Figs. 12–14 for completeness
Summary
A significant and potentially causal effect of depression was found on lower microstructural integrity in four white matter microstructural measures and lower resting-state fluctuation amplitude in the Salience Network (Node 14) For these phenotypes, the effect from depression were shown using at least two MR methods after FDR correction An additional test was conducted to see whether there was a substantial reduction in effect sizes after controlling for depressive symptoms (assessed online by CIDI short form and PHQ-9, and PHQ-4 for current symptoms along with the imaging assessment), and all three white matter microstructural measures were found significant in the MR analysis as the causal consequences of depression showed large reductions in effect sizes (reduced by 20.5–30.9%), resting-state fluctuation amplitude in Salience Network did not show such a reduction We found no evidence of interactions between depression-PRS and adulthood trauma, recent stressful life events and household income (pFDR for linear regression >0.086)
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