Endophenotype Potential of Nucleus Accumbens Functional Connectivity: Effects of Polygenic Risk for Schizophrenia Interacting with Childhood Adversity

Christopher Eberle ,Yorick Peterse ,Filip Jukic ,Bertram Müller-Myhsok ,Darina Czamara ,Jade Martins ,Vanessa Schmoll ,Michael Czisch ,Elisabeth B Binder ,Philipp G Sämann

doi:10.20900/jpbs.20190011

Abstract

Epidemiological and genetic studies suggest that schizophrenia (SCZ) is associated with both polygenic and environmental risk factors. Little is known if these factors project on common functional circuits relevant to the pathophysiology of SCZ. Here we focussed on resting state functional MRI (rsfMRI) as a biological measure to investigate if genetic and environmental factors for SCZ risk affect the same circuits in healthy controls as well as patients. For this, we compared the effects of a polygenic risk score for SCZ (PGRS), childhood adversity (CA) and their interaction on functional connectivity density (FCD) mapping and nucleus accumbens (NAcc) seed connectivity between 23 patients with SCZ or schizoaffective disorder and 253 healthy subjects. Patients demonstrated strong FCD increases compared with healthy controls mainly in subcortical nuclei including the NAcc, replicating previous reports. In healthy subjects, FCD of the NAcc was positively correlated with both the PGRS and the PGRS-CA-interaction. Both for high PGRS and PGRS-CA-interaction, fine-mapping revealed higher connectivity between the NAcc and visual association cortices. In conclusion, polygenic risk for SCZ shifted global and regionally specific connectivity of the NAcc in healthy subjects into the direction of the connectivity pattern observed in SCZ, and this shift was intensified by higher levels of CA.

Highlights

Schizophrenia (SCZ) is a devastating brain disorder and severe form of psychotic illness with a complex phenotype presentation including hallucinations, delusions, thought disorder and blunted or reduced affect [1]
In our second set of analyses, we found that higher polygenic risk for SCZ correlated positively with functional connectivity density (FCD) in the bilateral nucleus accumbens (NAcc) and with specific NAcc connections in the secondary visual association cortices, and that polygenic effects were stronger in subjects with higher levels of childhood adversity (CA)
Beyond the direct genetic effect, we found that CA as measured by self-reports interacted with polygenic risk into the same effect direction

Summary

Introduction

Schizophrenia (SCZ) is a devastating brain disorder and severe form of psychotic illness with a complex phenotype presentation including hallucinations, delusions, thought disorder and blunted or reduced affect [1]. According to the stress-vulnerability model, onset and course of SCZ result from multiple factors [2]: On the one hand, there is an inherited risk of developing the disease as demonstrated by twin [3] and family studies [4,5]. A range of environmental factors can influence the expression of psychotic symptoms. Sexual abuse as a child, disruption of attachment relations or chronic victimization has been associated with hallucinations and paranoid symptoms in adulthood [10,11,12]

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Conclusion