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

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.

Where the genome meets the connectome: understanding how genes shape human brain connectivity

“…For instance, insular connectivity networks have been correlated with cross-disorder PGS, as well as PGSs for bipolar disorder, autism, and schizophrenia, but not major depression or ADHD (Wang et al, 2017). Stronger global and regionally specific connectivity of the nucleus accumbens, which is known to be altered in schizophrenia (Eberle et al, 2019;Lee et al, 2018), has been associated with increased PGS for this disorder in healthy subjects (Eberle et al, 2019). It is important to note, however, that the limited predictive accuracy of polygenic scores may partly reflect the fact that PGSs do not consider rare variants, which tend to have larger phenotypic effects (Bomba et al, 2017).…”