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. 2013 Oct 2;8(10):e76815.
doi: 10.1371/journal.pone.0076815. eCollection 2013.

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

Free PMC article

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

Esther Walton et al. PLoS One. .
Free PMC article


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.

Conflict of interest statement

Competing Interests: Veit Roessner has received lecture fees from Eli Lilly, Janssen-Cilag, Medice, Novartis, and was member of advisory boards of Eli Lilly, Novartis. All other authors have declared that no competing interests exist. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.


Figure 1
Figure 1. Effect of NRGN risk variant on brain function.
Functional map illustrating increased neural activity in rs12541 TT homozygotes compared to C carriers. SSC, somatosensory cortex; CC, cingulate cortex. Results were cluster-corrected and z-values are represented according to the color code.
Figure 2
Figure 2. Effect of NRGN risk variant on cortical thickness and ACC volume.
a) Cortical statistical map illustrating reduced cortical thickness for rs12807809 C carriers compared to TT homozygotes. The -log(CWP-value) is represented according to the color code. b) Boxplot showing mean and two standard errors of the standardized residuals for the effects of NRGN rs12807809 genotype on left rostal ACC volume controlled for intracranial volume, age, gender, diagnosis and scanner field strength.

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