Abstract
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 neurogranin (NRGN), can be used to identify these mechanisms. In this study we examined the association of two common NRGN 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 NRGN SNPs (rs12807809 and rs12541) were tested for association with working memory-elicited dorsolateral prefrontal cortex (DLPFC) activity and surface-wide cortical thickness. NRGN 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. NRGN 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 NRGN gene on functional and structural brain-based intermediate phenotypes for schizophrenia. These results support recent GWAS findings and further implicate NRGN in the pathophysiology of schizophrenia by suggesting that genetic NRGN risk variants contribute to subtle changes in neural functioning and anatomy that can be quantified with neuroimaging methods.
Highlights
Twin and family studies suggest a high heritability for schizophrenia [1], but results of candidate gene studies have been inconsistent
We studied a total of 206 participants (92 schizophrenia patients and 114 healthy volunteers) who enrolled in the multisite Mind Clinical Imaging Consortium study [21,22], were between 18 and 60 years of age, and fluent in English and who had complete structural, functional magnetic resonance imaging (MRI) and genotype data
We found no increased neural activity in C carriers compared to to risk allele homozygotes (TT) homozygotes
Summary
Twin and family studies suggest a high heritability for schizophrenia [1], but results of candidate gene studies have been inconsistent. A recent study of more than 300,000 single nucleotide polymorphisms (SNPs) in 12,945 schizophrenia patients and 34,591 healthy controls reported associations at genome-wide significance with rs12807809 located near neurogranin (NRGN) [2]. Studying the effects of risk variants for psychiatric disorders on brain function and structure can provide insight into disease-associated changes and mechanisms on a neuroscience systems level, and helps to verify GWAS results. We studied the effects of NRGN risk variants on brain-based intermediate phenotypes for schizophrenia. Neuroimaging-based intermediate phenotypes are heritable, disease-associated and stable traits that may show a stronger association with risk genes than behavior or diagnosis due to their greater proximity to the underlying biology [8]. Inconsistent findings in case-control studies can partially be due to small effect sizes of single genes on complex entities such as diagnostic categories. Dorsolateral prefrontal cortex (DLPFC) dysfunction during working memory processing and widespread reduced cortical thickness have both been shown to be heritable markers closely related to schizophrenia [9]
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