title: Novel gene-brain structure relationships in psychotic disorder revealed using parallel independent component analyses.
abstract: Schizophrenia, schizoaffective disorder, and psychotic bipolar disorder overlap with regard to symptoms, structural and functional brain abnormalities, and genetic risk factors. Neurobiological pathways connecting genes to clinical phenotypes across the spectrum from schizophrenia to psychotic bipolar disorder remain largely unknown.
  
  
  
  We examined the relationship between structural brain changes and risk alleles across the psychosis spectrum in the multi-site Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) cohort. Regional MRI brain volumes were examined in 389 subjects with a psychotic disorder (139 schizophrenia, 90 schizoaffective disorder, and 160 psychotic bipolar disorder) and 123 healthy controls. 451,701 single-nucleotide polymorphisms were screened and processed using parallel independent component analysis (para-ICA) to assess associations between genes and structural brain abnormalities in probands.
  
  
  
  482 subjects were included after quality control (364 individuals with psychotic disorder and 118 healthy controls). Para-ICA identified four genetic components including several risk genes already known to contribute to schizophrenia and bipolar disorder and revealed three structural components that showed overlapping relationships with the disease risk genes across the three psychotic disorders. Functional ontologies representing these gene clusters included physiological pathways involved in brain development, synaptic transmission, and ion channel activity.
  
  
  
  Heritable brain structural findings such as reduced cortical thickness and surface area in probands across the psychosis spectrum were associated with somewhat distinct genes related to putative disease pathways implicated in psychotic disorders. This suggests that brain structural alterations might represent discrete psychosis intermediate phenotypes along common neurobiological pathways underlying disease expression across the psychosis spectrum.
authors: Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Ctr, Boston, MA, USA; Baylor College of Medicine, Texas Medical Center, Houston, TX, USA. Electronic address: ntandon@bidmc.harvard.edu.
authors: Neeraj
authors: N
authors: Tandon
authors: Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Ctr, Boston, MA, USA; College of Physicians & Surgeons, Columbia University Medical Center, New York, NY, USA.
authors: Pranav
authors: P
authors: Nanda
authors: Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Ctr, Boston, MA, USA.
authors: Jaya L
authors: JL
authors: Padmanabhan
authors: Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Ctr, Boston, MA, USA.
authors: Ian T
authors: IT
authors: Mathew
authors: School of Social Work, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Shaun M
authors: SM
authors: Eack
authors: Olin Neuropsychiatry Research Center, Hartford, CT, USA; Department of Psychiatry and Neurobiology, Yale University, New Haven, CT, USA.
authors: Balaji
authors: B
authors: Narayanan
authors: Olin Neuropsychiatry Research Center, Hartford, CT, USA; Department of Psychiatry and Neurobiology, Yale University, New Haven, CT, USA.
authors: Shashwath A
authors: SA
authors: Meda
authors: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors: Sarah E
authors: SE
authors: Bergen
authors: Genomas, Inc, Hartford, CT, USA.
authors: Gualbert
authors: G
authors: Ruaño
authors: Genomas, Inc, Hartford, CT, USA.
authors: Andreas
authors: A
authors: Windemuth
authors: Genomas, Inc, Hartford, CT, USA.
authors: Mohan
authors: M
authors: Kocherla
authors: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors: Tracey L
authors: TL
authors: Petryshen
authors: Department of Psychology, Department of Neuroscience, Bio-Imaging Research Center, University of Georgia, Athens, GA, USA.
authors: Brett
authors: B
authors: Clementz
authors: Psychiatry, UT Southwestern, Dallas, TX, USA.
authors: John
authors: J
authors: Sweeney
authors: Psychiatry, UT Southwestern, Dallas, TX, USA.
authors: Carol
authors: C
authors: Tamminga
authors: Olin Neuropsychiatry Research Center, Hartford, CT, USA; Department of Psychiatry and Neurobiology, Yale University, New Haven, CT, USA.
authors: Godfrey
authors: G
authors: Pearlson
authors: Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Ctr, Boston, MA, USA.
authors: Matcheri S
authors: MS
authors: Keshavan
mesh_terms: D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D025341:Principal Component Analysis; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*
keywords: Bipolar disorder; Brain structure; Endophenotype; Genes; Intermediate phenotype; MRI; Nosology; Schizoaffective disorder; Schizophrenia