title: Bipolar disorder risk geneFOXO6modulates negative symptoms in schizophrenia: a neuroimaging genetics study.
abstract: Despite being diagnostically associated uniquely with schizophrenia, negative symptoms are also observed in bipolar disorder (BD). Genome-wide association studies (GWAS) have uncovered a number of shared risk genes between schizophrenia and BD. The objectives of this study were to examine whether previously identified risk genes for BD are associated with negative symptom severity within a first-episode schizophrenia (FES) cohort and to examine whether such genes influence brain morphology.
  
  
  
  Patients experiencing FES were genotyped for 21 previously identified BD risk genes; a series of univariate analyses of covariance examined the association between negative symptom severity, as measured using the Scale for the Assessment of Negative Symptoms (SANS), and genotype. A subset of participants underwent a structural 1.5 T MRIT1scan, analyzed for surface area and cortical thickness changes via the CIVET pipeline and LPBA40 atlas.
  
  
  
  We included 133 patients with FES in our analysis; 61 of them underwent structural MRI. We observed a significant association between negative symptom severity and the BD risk geneFOXO6(rs4660531). Individuals with the CC genotype presented significantly higher negative symptoms (Cohend= 0.46,F= 5.854,p= 0.017) and significantly smaller surface area within the right middle orbitofrontal gyrus (Cohend= 0.69,F= 7.289,p= 0.009) than carriers of allele A.
  
  
  
  Limitations of this study include its modest sample size and lack of a control sample.
  
  
  
  Lacking theFOXO6risk allele was associated with an increase in negative symptoms and surface area reduction in the right orbitofrontal gyrus - an area previously associated with negative symptoms - suggesting that presence of theFOXO6risk allele confers resistance against negative symptoms and associated neuroanatomical changes in individuals with FES.
authors.affiliation: From the Douglas Mental Health University Institute, Montreal, Que., Canada (Shenker, Sengupta, Joober, Malla, Chakravarty, Lepage); the Integrated Program in Neuroscience, McGill University, Montreal, Que., Canada (Shenker, Lepage); the Department of Psychiatry, McGill University, Montreal, Que., Canada (Sengupta, Joober, Malla, Chakravarty, Lepage); and the Department of Biomedical Engineering, McGill University, Montreal, Que., Canada (Chakravarty).
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Shenker
authors.affiliation: From the Douglas Mental Health University Institute, Montreal, Que., Canada (Shenker, Sengupta, Joober, Malla, Chakravarty, Lepage); the Integrated Program in Neuroscience, McGill University, Montreal, Que., Canada (Shenker, Lepage); the Department of Psychiatry, McGill University, Montreal, Que., Canada (Sengupta, Joober, Malla, Chakravarty, Lepage); and the Department of Biomedical Engineering, McGill University, Montreal, Que., Canada (Chakravarty).
authors.forename: Sarojini M
authors.initials: SM
authors.lastname: Sengupta
authors.affiliation: From the Douglas Mental Health University Institute, Montreal, Que., Canada (Shenker, Sengupta, Joober, Malla, Chakravarty, Lepage); the Integrated Program in Neuroscience, McGill University, Montreal, Que., Canada (Shenker, Lepage); the Department of Psychiatry, McGill University, Montreal, Que., Canada (Sengupta, Joober, Malla, Chakravarty, Lepage); and the Department of Biomedical Engineering, McGill University, Montreal, Que., Canada (Chakravarty).
authors.forename: Ridha
authors.initials: R
authors.lastname: Joober
authors.affiliation: From the Douglas Mental Health University Institute, Montreal, Que., Canada (Shenker, Sengupta, Joober, Malla, Chakravarty, Lepage); the Integrated Program in Neuroscience, McGill University, Montreal, Que., Canada (Shenker, Lepage); the Department of Psychiatry, McGill University, Montreal, Que., Canada (Sengupta, Joober, Malla, Chakravarty, Lepage); and the Department of Biomedical Engineering, McGill University, Montreal, Que., Canada (Chakravarty).
authors.forename: Ashok
authors.initials: A
authors.lastname: Malla
authors.affiliation: From the Douglas Mental Health University Institute, Montreal, Que., Canada (Shenker, Sengupta, Joober, Malla, Chakravarty, Lepage); the Integrated Program in Neuroscience, McGill University, Montreal, Que., Canada (Shenker, Lepage); the Department of Psychiatry, McGill University, Montreal, Que., Canada (Sengupta, Joober, Malla, Chakravarty, Lepage); and the Department of Biomedical Engineering, McGill University, Montreal, Que., Canada (Chakravarty).
authors.forename: M Mallar
authors.initials: MM
authors.lastname: Chakravarty
authors.affiliation: From the Douglas Mental Health University Institute, Montreal, Que., Canada (Shenker, Sengupta, Joober, Malla, Chakravarty, Lepage); the Integrated Program in Neuroscience, McGill University, Montreal, Que., Canada (Shenker, Lepage); the Department of Psychiatry, McGill University, Montreal, Que., Canada (Sengupta, Joober, Malla, Chakravarty, Lepage); and the Department of Biomedical Engineering, McGill University, Montreal, Que., Canada (Chakravarty).
authors.forename: Martin
authors.initials: M
authors.lastname: Lepage
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics; D001921:Brain / Q000000981:diagnostic imaging*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D015999:Multivariate Analysis; D009483:Neuropsychological Tests; D009929:Organ Size; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000000981:diagnostic imaging* / Q000235:genetics*; D055815:Young Adult
chemical_list: C478770:FOXO6 protein, human; D051858:Forkhead Transcription Factors