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Neuropsychopharmacology. 2015 Oct;40(11):2510-6. doi: 10.1038/npp.2015.86. Epub 2015 Mar 24.

NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression.

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Department of Psychiatry, University of Marburg, Marburg, Germany.
Department of Psychiatry, University of Münster, Münster, Germany.
Department of Clinical Radiology, University of Münster, Münster, Germany.
Department of Psychosomatic Medicine, University of Leipzig, Leipzig, Germany.
Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
Department of Psychiatry, University of Würzburg, Würzburg, Germany.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.


Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. In addition, whole-brain data from the combined sample were analyzed. Risk (A)-allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and regulation. The present data suggest that NCAN forms susceptibility to neurostructural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors.

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