title: Pathway analyses implicate glial cells in schizophrenia.
abstract: BACKGROUND
  The quest to understand the neurobiology of schizophrenia and bipolar disorder is ongoing with multiple lines of evidence indicating abnormalities of glia, mitochondria, and glutamate in both disorders. Despite high heritability estimates of 81% for schizophrenia and 75% for bipolar disorder, compelling links between findings from neurobiological studies, and findings from large-scale genetic analyses, are only beginning to emerge.
  
  
  METHODS
  Ten publically available gene sets (pathways) related to glia, mitochondria, and glutamate were tested for association to schizophrenia and bipolar disorder using MAGENTA as the primary analysis method. To determine the robustness of associations, secondary analyses were performed with: ALIGATOR, INRICH, and Set Screen. Data from the Psychiatric Genomics Consortium (PGC) were used for all analyses. There were 1,068,286 SNP-level p-values for schizophrenia (9,394 cases/12,462 controls), and 2,088,878 SNP-level p-values for bipolar disorder (7,481 cases/9,250 controls).
  
  
  RESULTS
  The Glia-Oligodendrocyte pathway was associated with schizophrenia, after correction for multiple tests, according to primary analysis (MAGENTA p = 0.0005, 75% requirement for individual gene significance) and also achieved nominal levels of significance with INRICH (p = 0.0057) and ALIGATOR (p = 0.022). For bipolar disorder, Set Screen yielded nominally and method-wide significant associations to all three glial pathways, with strongest association to the Glia-Astrocyte pathway (p = 0.002).
  
  
  CONCLUSIONS
  Consistent with findings of white matter abnormalities in schizophrenia by other methods of study, the Glia-Oligodendrocyte pathway was associated with schizophrenia in our genomic study. These findings suggest that the abnormalities of myelination observed in schizophrenia are at least in part due to inherited factors, contrasted with the alternative of purely environmental causes (e.g. medication effects or lifestyle). While not the primary purpose of our study, our results also highlight the consequential nature of alternative choices regarding pathway analysis, in that results varied somewhat across methods, despite application to identical datasets and pathways.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America ; Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America ; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Laramie E
authors.initials: LE
authors.lastname: Duncan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Holmans
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America ; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America ; Analytic and Translational Genetics Unit (ATGU), Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Phil H
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Colm T
authors.initials: CT
authors.lastname: O'Dushlaine
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Kirby
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Smoller
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America ; Schizophrenia and Bipolar Disorder Program, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Dost
authors.initials: D
authors.lastname: Öngür
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America ; Shervert Frazier Research Institute, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cohen
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D018698:Glutamic Acid