title: NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression.
abstract: 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.
authors: Department of Psychiatry, University of Marburg, Marburg, Germany.|Department of Psychiatry, University of Münster, Münster, Germany.
authors: Udo
authors: U
authors: Dannlowski
authors: Department of Clinical Radiology, University of Münster, Münster, Germany.
authors: Harald
authors: H
authors: Kugel
authors: Department of Psychiatry, University of Münster, Münster, Germany.
authors: Dominik
authors: D
authors: Grotegerd
authors: Department of Psychiatry, University of Münster, Münster, Germany.
authors: Ronny
authors: R
authors: Redlich
authors: Department of Psychiatry, University of Münster, Münster, Germany.
authors: Janina
authors: J
authors: Suchy
authors: Department of Psychiatry, University of Münster, Münster, Germany.
authors: Nils
authors: N
authors: Opel
authors: Department of Psychosomatic Medicine, University of Leipzig, Leipzig, Germany.
authors: Thomas
authors: T
authors: Suslow
authors: Department of Psychiatry, University of Marburg, Marburg, Germany.
authors: Carsten
authors: C
authors: Konrad
authors: Department of Psychiatry, University of Münster, Münster, Germany.
authors: Patricia
authors: P
authors: Ohrmann
authors: Department of Psychiatry, University of Münster, Münster, Germany.
authors: Jochen
authors: J
authors: Bauer
authors: Department of Psychiatry, University of Marburg, Marburg, Germany.
authors: Tilo
authors: T
authors: Kircher
authors: Department of Psychiatry, University of Marburg, Marburg, Germany.
authors: Axel
authors: A
authors: Krug
authors: Department of Psychiatry, University of Marburg, Marburg, Germany.
authors: Andreas
authors: A
authors: Jansen
authors: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors: Bernhard T
authors: BT
authors: Baune
authors: Department of Clinical Radiology, University of Münster, Münster, Germany.
authors: Walter
authors: W
authors: Heindel
authors: Department of Psychiatry, University of Würzburg, Würzburg, Germany.
authors: Katharina
authors: K
authors: Domschke
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors: Andreas J
authors: AJ
authors: Forstner
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors: Markus M
authors: MM
authors: Nöthen
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors: Jens
authors: J
authors: Treutlein
authors: Department of Psychiatry, University of Münster, Münster, Germany.
authors: Volker
authors: V
authors: Arolt
authors: Department of Psychiatry, University of Münster, Münster, Germany.
authors: Christa
authors: C
authors: Hohoff
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors: Marcella
authors: M
authors: Rietschel
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors: Stephanie H
authors: SH
authors: Witt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000235:genetics*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D015331:Cohort Studies; D003865:Major Depressive Disorder / Q000235:genetics* / Q000473:pathology*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D060005:Genotyping Techniques; D066128:Gray Matter / Q000473:pathology*; D006801:Humans; D007297:Inpatients; D037181:Lectins, C-Type / Q000235:genetics*; D008032:Limbic System / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D058580:Neurocan; D009929:Organ Size; D055815:Young Adult
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D037181:Lectins, C-Type; D009419:Nerve Tissue Proteins; D058580:Neurocan; C076817:NCAN protein, human