Associations between polygenic risk, negative symptoms, and functional connectome topology during a working memory task in early-onset schizophrenia

Working memory (WM) deficit in schizophrenia is thought to arise from a widespread neural inefficiency. However, we do not know if this deficit results from the illness-related genetic risk and influence the symptom burden in various domains, especially in patients who have an early onset illness. We used graph theory to examine the topology of the functional connectome in 99 subjects (27 early-onset schizophrenia (EOS), 24 asymptomatic siblings, and 48 healthy subjects) during an n-back task, and calculated their polygenic risk score (PRS) for susceptibility to schizophrenia. Linear regression analysis was used to test associations of the PRS, clinical symptoms, altered connectomic properties, and WM accuracy in EOS. Indices of small-worldness and segregation were elevated in EOS during the WM task compared with the other two groups; these connectomic aberrations correlated with increased PRS and negative symptoms. In patients with higher polygenic risk, WM performance was lower only when both the connectomic aberrations and the burden of negative symptoms were higher. Negative symptoms had a stronger moderating role in this relationship. Our findings suggest that the aberrant connectomic topology is a feature of WM task performance in schizophrenia; this relates to higher polygenic risk score as well as higher burden of negative symptoms. The deleterious effects of polygenic risk on cognition are played out via its effects on the functional connectome, as well as negative symptoms.