title: Candidate gene associations with mood disorder, cognitive vulnerability, and fronto-limbic volumes.
abstract: BACKGROUND
  Four of the most consistently replicated variants associated with mood disorder occur in genes important for synaptic function: ANK3 (rs10994336), BDNF (rs6265), CACNA1C (rs1006737), and DGKH (rs1170191).
  
  
  OBJECTIVE
  The present study examined associations between these candidates, mood disorder diagnoses, cognition, and fronto-limbic regions implicated in affect regulation.
  
  
  METHODS
  Participants included 128 individuals with bipolar disorder (33% male, Mean age = 38.5), 48 with major depressive disorder (29% male, Mean age = 40.4), and 149 healthy controls (35% male, Mean age = 36.5). Genotypes were determined by 5'-fluorogenic exonuclease assays (TaqMan®). Fronto-limbic volumes were obtained from high resolution brain images using Freesurfer. Chi-square analyses, bivariate correlations, and mediational models examined relationships between genetic variants, mood diagnoses, cognitive measures, and brain volumes.
  
  
  RESULTS
  Carriers of the minor BDNF and ANK3 alleles showed nonsignificant trends toward protective association in controls relative to mood disorder patients (P = 0.047). CACNA1C minor allele carriers had larger bilateral caudate, insula, globus pallidus, frontal pole, and nucleus accumbens volumes (smallest r = 0.13, P = 0.043), and increased IQ (r = 0.18, P < 0.001). CACNA1C associations with brain volumes and IQ were independent; larger fronto-limbic volumes did not mediate increased IQ. Other candidate variants were not significantly associated with diagnoses, cognition, or fronto-limbic volumes.
  
  
  CONCLUSIONS
  CACNA1C may be associated with biological systems altered in mood disorder. Increases in fronto-limbic volumes and cognitive ability associated with CACNA1C minor allele genotypes are congruent with findings in healthy samples and may be a marker for increased risk for neuropsychiatric phenotypes. Even larger multimodal studies are needed to quantify the magnitude and specificity of genetic-imaging-cognition-symptom relationships.
authors.affiliation: Centers for Autism and Pediatric Behavioral Health, Cleveland Clinic Cleveland, Ohio.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Frazier
authors.affiliation: Departments of Psychology and Psychiatry, University of North Carolina at Chapel Hill Chapel Hill, North Carolina.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Youngstrom
authors.affiliation: Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey VA Medical Center Houston, Texas.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Frankel
authors.affiliation: Department of Psychiatry and Behavioral Sciences, UT Center of Excellence on Mood Disorders, University of Texas Medical School at Houston Houston, Texas.
authors.forename: Giovana B
authors.initials: GB
authors.lastname: Zunta-Soares
authors.affiliation: Department of Psychiatry and Behavioral Sciences, UT Center of Excellence on Mood Disorders, University of Texas Medical School at Houston Houston, Texas.
authors.forename: Marsal
authors.initials: M
authors.lastname: Sanches
authors.affiliation: Center of Excellence in Neurosciences, Texas Tech University Health Science Center El Paso, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Escamilla
authors.affiliation: Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey VA Medical Center Houston, Texas.
authors.forename: David A
authors.initials: DA
authors.lastname: Nielsen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, UT Center of Excellence on Mood Disorders, University of Texas Medical School at Houston Houston, Texas.
authors.forename: Jair C
authors.initials: JC
authors.lastname: Soares
mesh_terms: D000328:Adult; D000483:Alleles; D017487:Ankyrins / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000235:genetics; D003071:Cognition / Q000502:physiology*; D003865:Major Depressive Disorder / Q000235:genetics* / Q000473:pathology; D019852:Diacylglycerol Kinase / Q000235:genetics; D005260:Female; D005625:Frontal Lobe / Q000473:pathology*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008032:Limbic System / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D009929:Organ Size / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins; D019208:Brain-Derived Neurotrophic Factor; C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D019852:Diacylglycerol Kinase
keywords: ANK3; BDNF; CACNA1C; DGKH; bipolar disorder; candidate gene; major depression; mediation; mood disorder; structural neuroimaging