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Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing

Published online by Cambridge University Press:  12 September 2018

Naomi Sadeh ,
Jeffrey M. Spielberg ,
Mark W. Logue ,
Jasmeet P. Hayes ,
Erika J. Wolf ,
Regina E. McGlinchey ,
William P. Milberg ,
Steven A. Schichman ,
Annjanette Stone  and
Mark W. Miller
Naomi Sadeh*
Affiliation:
Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, USA National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA
Jeffrey M. Spielberg
Affiliation:
Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, USA Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA
Mark W. Logue
Affiliation:
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA Department of Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA
Jasmeet P. Hayes
Affiliation:
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA
Erika J. Wolf
Affiliation:
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA
Regina E. McGlinchey
Affiliation:
Translational Research Center for TBI and Stress Disorders and Geriatric Research, Educational and Clinical Center, VA Boston Healthcare System, Boston, MA, USA Department of Psychiatry, Harvard Medical School, Boston, MA, USA
William P. Milberg
Affiliation:
Translational Research Center for TBI and Stress Disorders and Geriatric Research, Educational and Clinical Center, VA Boston Healthcare System, Boston, MA, USA Department of Psychiatry, Harvard Medical School, Boston, MA, USA
Steven A. Schichman
Affiliation:
Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
Annjanette Stone
Affiliation:
Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
Mark W. Miller
Affiliation:
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA
*
Author for correspondence: Naomi Sadeh, E-mail: nsadeh@udel.edu
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Abstract

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.

Keywords

Alcohol usedisinhibitionneural circuitspolygenic risk scoresubstance use

Information

Type
Original Articles
Information
Psychological Medicine , Volume 49 , Issue 11 , August 2019 , pp. 1905 - 1913
Copyright
Copyright © Cambridge University Press 2018 

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