Association between NRGN gene polymorphism and resting-state hippocampal functional connectivity in schizophrenia

Based on genome-wide association studies, a single-nucleotide polymorphism in the NRGN gene (rs12807809) is considered associated with schizophrenia (SZ). Moreover, hippocampal dysfunction is associated with rs12807809. In addition, converging evidence suggests that hippocampal dysfunction is involved in SZ pathophysiology. However, the association among rs12807809, hippocampal dysfunction and SZ pathophysiology is unknown. Therefore, this study investigated the association between rs12807809 and hippocampal functional connectivity at rest in SZ.

In total, 158 participants were studied, including a C-carrier group carrying the non-risk C allele (29 SZ patients and 46 healthy controls) and a TT homozygous group carrying the risk T allele (30 SZ patients and 53 healthy controls). All participants were scanned using resting-state functional magnetic resonance imaging. Hippocampal functional connectivity was computed and compared among the 4 groups.

Significant main effects of diagnosis were observed in the functional connectivity between the hippocampus and bilateral fusiform gyrus, bilateral lingual gyrus, left inferior temporal gyrus, left caudate nucleus, bilateral thalamus and bilateral anterior cingulate gyri. In contrast, no significant main effect of genotype was found. In addition, a significant genotype by diagnosis interaction in the functional connectivity between the hippocampus and left anterior cingulate gyrus, as well as bilateral middle cingulate gyri, was observed, with TT homozygotes with SZ showing less functional connectivity than C-carriers with SZ and healthy control TT homozygotes.

These findings are the first to suggest an association between rs12807809 and abnormal Papez circuit function in patients with SZ. This study also implicates NRGN variation and abnormal Papez circuit function in SZ pathophysiology.