The Impact of Genome-Wide Supported Schizophrenia Risk Variants in the Neurogranin Gene on Brain Structure and Function

<div><p>The neural mechanisms underlying genetic risk for schizophrenia, a highly heritable psychiatric condition, are still under investigation. New schizophrenia risk genes discovered through genome-wide association studies (GWAS), such as <i>neurogranin</i> (<i>NRGN</i>), can be used to identify these mechanisms. In this study we examined the association of two common <i>NRGN</i> risk single nucleotide polymorphisms (SNPs) with functional and structural brain-based intermediate phenotypes for schizophrenia. We obtained structural, functional MRI and genotype data of 92 schizophrenia patients and 114 healthy volunteers from the multisite Mind Clinical Imaging Consortium study. Two schizophrenia-associated <i>NRGN</i> SNPs (rs12807809 and rs12541) were tested for association with working memory-elicited dorsolateral prefrontal cortex (DLPFC) activity and surface-wide cortical thickness. <i>NRGN</i> rs12541 risk allele homozygotes (TT) displayed increased working memory-related activity in several brain regions, including the left DLPFC, left insula, left somatosensory cortex and the cingulate cortex, when compared to non-risk allele carriers. <i>NRGN</i> rs12807809 non-risk allele (C) carriers showed reduced cortical gray matter thickness compared to risk allele homozygotes (TT) in an area comprising the right pericalcarine gyrus, the right cuneus, and the right lingual gyrus. Our study highlights the effects of schizophrenia risk variants in the <i>NRGN</i> gene on functional and structural brain-based intermediate phenotypes for schizophrenia. These results support recent GWAS findings and further implicate <i>NRGN</i> in the pathophysiology of schizophrenia by suggesting that genetic <i>NRGN</i> risk variants contribute to subtle changes in neural functioning and anatomy that can be quantified with neuroimaging methods.</p>