title: Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes.
abstract: Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates <0.05); and (3) contain 62 genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P = 0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4.56, P = 5.00 × 10(-4); odds ratio 2.60, P = 0.049).The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author.
authors.affiliation: Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA, Medical and Population Genetics Program and The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, København Ø 2100, Denmark, Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen, Denmark.
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, København Ø 2100, Denmark, Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen, Denmark.
authors.forename: Pascal
authors.initials: P
authors.lastname: Timshel
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02142, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: Samantha
authors.initials: S
authors.lastname: Lent
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-17177, Sweden, Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA, Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599-7160, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine and National Centre for Mental Health, Cardiff University, Cardiff CF24 4HQ, UK.
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen 9711, The Netherlands and.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA, Medical and Population Genetics Program and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA joelh@broadinstitute.org.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
mesh_terms: D002874:Chromosome Mapping; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D007473:Ion Channels