Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing.
paper
Primary
Public
- Authors
- Sadeh, Naomi; Spielberg, Jeffrey M; Logue, Mark W; Hayes, Jasmeet P; Wolf, Erika J; McGlinchey, Regina E; Milberg, William P; Schichman, Steven A; Stone, Annjanette; Miller, Mark W
- Year
- 2019
- Journal
- Psychological medicine
- PMID
- 30207258
- DOI
- 10.1017/S0033291718002672
- PMCID
- PMC6414280
BACKGROUND: Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders. METHODS: One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes. RESULTS: A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs. CONCLUSIONS: Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.
Network Related to Externalizing Polygenic ScoreCircle/sphere color reflects module. Stick/ball figure created using Kamada-Kawai spring embedder algorithm (SONIA; Bender-deMoll and McFarland, 2006). R = right; L = left; ACC = anterior cingulate cortex; IFG = inferior frontal gyrus. Node color indicates different modules. The six 3d brain images show (clockwise from top left) an axial view from superior to the brain, a coronal view from anterior to the brain, a sagittal view from left of the brain, a sagittal view from right of the brain, a coronal view from posterior to the brain, and an axial view from inferior to the brain (created via BrainNet Viewer; Xia et al., 2013).
LLM interpretation
This figure consists of six 3D brain anatomical views (axial, coronal, and sagittal) and a corresponding network diagram illustrating the Externalizing Polygenic Score network. The network diagram uses a ball-and-stick model where nodes represent brain regions (e.g., L Thalamus, L Amygdala) and colors indicate different modules. The connections between nodes vary in thickness, representing the strength of the relationships between the labeled anatomical regions.
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| Name | Type |
|---|---|
| aberrant connectivity local | phenotype |
| ACC | anatomy |
| Acute suicide risk local | phenotype |
| Adults with alcohol dependence local | cohort |
| age | phenotype |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| alcohol/substance disorders local | phenotype |
| alcohol/substance use disorders local | phenotype |
| Alcohol Use Disorder | phenotype |
| amphetamines | drug |
| amygdala | anatomy |
| ancestry principal components | drug |
| Aneurysm clip local | phenotype |
| anterior cingulate cortex | anatomy |
| antisocial personality disorder | phenotype |
| behavioral disinhibition | phenotype |
| bipolar disorder | phenotype |
| brain | anatomy |
| brain circuits | anatomy |
| brain structure | anatomy |
| cannabis use | phenotype |
| caudate nucleus | anatomy |
| Cerebrovascular accident local | phenotype |
| cocaine | phenotype |
| Cognitive disorder due to general medical condition local | phenotype |
| conduct disorder | phenotype |
| Current employment local | phenotype |
| death | phenotype |
| Deployment-related blast exposure local | phenotype |
| Discovery externalizing disorders GWAS local | cohort |
| disinhibited behaviors | phenotype |
| dorsolateral prefrontal cortex | anatomy |
| emotional-salience system local | anatomy |
| environmental influences | phenotype |
| epilepsy | phenotype |
| externalizing behavior | phenotype |
| externalizing disorders | phenotype |
| Externalizing Phenotype local | phenotype |
| externalizing polygenic score local | variant |
| Externalizing polygenic score local | drug |
| Externalizing Polygenic Score local | variant |
| externalizing PS local | phenotype |
| externalizing PS local | variant |
| EXT PGS | phenotype |
| frontal pole | anatomy |
| Genetic effects local | phenotype |
| genetic risk for externalizing | phenotype |
| Handedness | phenotype |
| healthy controls | cohort |
| High polygenic externalizing local | phenotype |
| hippocampus | anatomy |
| identified network local | anatomy |
| IFG pars triangularis local | anatomy |
| impulsivity | phenotype |
| inferior frontal gyrus | anatomy |
| inferior frontal gyrus pars triangularis local | anatomy |
| inhibitory control | phenotype |
| inhibitory control tasks local | phenotype |
| Inhibitory control tasks local | phenotype |
| Iraqi Freedom local | cohort |
| latent externalizing dimension | phenotype |
| Latent Externalizing Spectrum local | phenotype |
| left IFG pars triangularis local | anatomy |
| Left rostral anterior cingulate cortex local | anatomy |
| Lifetime alcohol or substance use diagnosis local | phenotype |
| Lifetime alcohol/substance use local | phenotype |
| Little2015 local | cohort |
| Low polygenic externalizing local | phenotype |
| Mean connectivity local | phenotype |
| mental health outcomes | phenotype |
| Metal implant local | phenotype |
| Mild TBI local | phenotype |
| military veterans local | cohort |
| Military veterans local | cohort |
| Moderate traumatic brain injury local | phenotype |
| myocardial infarction | phenotype |
| Neural connectivity/integrity local | phenotype |
| Neural Network Connectivity local | phenotype |
| neural network parameters local | phenotype |
| Neural Phenotype local | phenotype |
| Neuroimaging-genetics sample local | cohort |
| Operations Enduring Freedom local | cohort |
| opioid | drug |
| other substances | phenotype |
| Pacemaker local | phenotype |
| Pagliaccio2015 local | cohort |
| pallidum | anatomy |
| Participation Coefficient local | phenotype |
| PFC | anatomy |
| polygenic risk score | cohort |
| Polygenic Variation local | phenotype |
| Polysubstance local | drug |
| Post-Traumatic Stress Disorder | phenotype |
| prefrontal cortex | anatomy |
| pregnancy | phenotype |
| psychiatric outcomes | phenotype |
| psychiatric populations local | cohort |
| psychosis | phenotype |
| putamen | anatomy |
| resting-state connectivity local | phenotype |
| resting-state functional connectivity local | phenotype |
| resting-state functional networks local | anatomy |
| reward system | anatomy |
| Right amygdala Participation Coefficient local | phenotype |
| rostral ACC | anatomy |
| Rostral cingulate cortex local | anatomy |
| Severe traumatic brain injury local | phenotype |
| sex | phenotype |
| Shrapnel local | phenotype |
| SNP | cohort |
| striatal areas local | anatomy |
| striatum | anatomy |
| subcortical regions | anatomy |
| substance use | phenotype |
| temporal pole | anatomy |
| total cholesterol | phenotype |
| Trait constraint local | phenotype |
| trait-like brain networks local | anatomy |
| Trauma-exposed veterans local | cohort |
| trauma exposure | phenotype |
| ventral striatum | anatomy |
| visual region | anatomy |
| White non-Hispanic individuals local | cohort |
| Within-Module Degree Z-Score local | phenotype |
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