title: Genetic variation in CACNA1C affects neural processing in major depression.
abstract: Genetic studies found the A allele of the single nucleotide polymorphism rs1006737 in the CACNA1C gene, which encodes for the alpha 1C subunit of the voltage-dependent, L-type calcium ion channel Cav1.2, to be overrepresented in patients with major depressive disorder (MDD). Altered prefrontal brain functioning and impaired semantic verbal fluency (SVF) are robust findings in these patients. A recent functional magnetic resonance imaging (fMRI) study found the A allele to be associated with poorer performance and increased left inferior frontal gyrus (IFG) activation during SVF tasks in healthy subjects. In the present study, we investigated the effects of rs1006737 on neural processing during SVF in MDD. In response to semantic category cues, 40 patients with MDD and 40 matched controls overtly generated words while brain activity was measured with fMRI. As revealed by whole brain analyses, genotype significantly affected brain activity in patients. Compared to patients with GG genotype, patients with A allele demonstrated increased task-related activation in the left middle/inferior frontal gyrus and the bilateral cerebellum. Patients with A allele also showed enhanced functional coupling between left middle/inferior and right superior/middle frontal gyri. No differential effects of genotype on SVF performance or brain activation were found between diagnostic groups. The current data provide further evidence for an impact of rs1006737 on the left IFG and demonstrate that genetic variation in CACNA1C modulates neural responses in patients with MDD. The observed functional alterations in prefrontal and cerebellar areas might represent a mechanism by which rs1006737 influences susceptibility to MDD.
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany. Electronic address: heidelore.backes@med.uni-marburg.de.
authors.forename: Heidelore
authors.initials: H
authors.lastname: Backes
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dietsche
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Nagels
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Konrad
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J 5, 68159 Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J 5, 68159 Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
authors.forename: Tilo
authors.initials: T
authors.lastname: Kircher
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Krug
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001921:Brain / Q000098:blood supply / Q000473:pathology*; D001931:Brain Mapping; D020746:Calcium Channels, L-Type / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D003865:Major Depressive Disorder / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005838:Genotype; D005858:Germany; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007859:Learning Disabilities / Q000209:etiology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010100:Oxygen; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012660:Semantics; D014706:Verbal Learning / Q000502:physiology; D055815:Young Adult
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D010100:Oxygen
keywords: CACNA1C; Cerebellum; Left inferior frontal gyrus; Major depression; Verbal fluency; fMRI