Identification of gene ontologies linked to prefrontal-hippocampal functional coupling in the human brain

Abstract

Functional interactions between the dorsolateral prefrontal cortex and hippocampus during working memory have been studied extensively as an intermediate phenotype for schizophrenia. Coupling abnormalities have been found in patients, their unaffected siblings, and carriers of common genetic variants associated with schizophrenia, but the global genetic architecture of this imaging phenotype is unclear. To achieve genome-wide hypothesis-free identification of genes and pathways associated with prefrontal-hippocampal interactions, we combined gene set enrichment analysis with whole-genome genotyping and functional magnetic resonance imaging data from 269 healthy German volunteers. We found significant enrichment of the synapse organization and biogenesis gene set. This gene set included known schizophrenia risk genes, such as neural cell adhesion molecule (NRCAM) and calcium channel, voltage-dependent, beta 2 subunit (CACNB2), as well as genes with well-defined roles in neurodevelopmental and plasticity processes that are dysfunctional in schizophrenia and have mechanistic links to prefrontal-hippocampal functional interactions. Our results demonstrate a readily generalizable approach that can be used to identify the neurogenetic basis of systems-level phenotypes. Moreover, our findings identify gene sets in which genetic variation may contribute to disease risk through altered prefrontal-hippocampal functional interactions and suggest a link to both ongoing and developmental synaptic plasticity.

Keywords: GSEA; endophenotype; functional connectivity; genetic risk variants.

Fig. 1.

(A) WM-related BOLD activation (2-back > 0-back contrast) in 269 healthy controls for the n-back task. Functional maps (thresholded at P < 0.001, t = 3.12, uncorrected) are projected on a rendered MNI template and shown from a lateral (Left) and top (Right) view for presentation purposes. Color bar represents t values. (B) Functional connectivity between right DLPFC seed and left HC during WM. Mean connectivity with right DLPFC seed for 269 healthy volunteers within left HC mask is shown in sagittal (Left) and axial (Right) sections, using an MNI structural template for presentation purposes. Color bar represents t values. Map coordinates refer to the standard space as defined by the MNI.