title: Neural mechanisms of a genome-wide supported psychosis variant.
abstract: Schizophrenia is a devastating, highly heritable brain disorder of unknown etiology. Recently, the first common genetic variant associated on a genome-wide level with schizophrenia and possibly bipolar disorder was discovered in ZNF804A (rs1344706). We show, by using an imaging genetics approach, that healthy carriers of rs1344706 risk genotypes exhibit no changes in regional activity but pronounced gene dosage-dependent alterations in functional coupling (correlated activity) of dorsolateral prefrontal cortex (DLPFC) across hemispheres and with hippocampus, mirroring findings in patients, and abnormal coupling of amygdala. Our findings establish disturbed connectivity as a neurogenetic risk mechanism for psychosis supported by genome-wide association, show that rs1344706 or variation in linkage disequilibrium is functional in human brain, and validate the intermediate phenotype strategy in psychiatry.
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, J5, 68159 Mannheim, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Esslinger
authors.forename: Henrik
authors.initials: H
authors.lastname: Walter
authors.forename: Peter
authors.initials: P
authors.lastname: Kirsch
authors.forename: Susanne
authors.initials: S
authors.lastname: Erk
authors.forename: Knut
authors.initials: K
authors.lastname: Schnell
authors.forename: Claudia
authors.initials: C
authors.lastname: Arnold
authors.forename: Leila
authors.initials: L
authors.lastname: Haddad
authors.forename: Daniela
authors.initials: D
authors.lastname: Mier
authors.forename: Carola
authors.initials: C
authors.lastname: Opitz von Boberfeld
authors.forename: Kyeon
authors.initials: K
authors.lastname: Raab
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
mesh_terms: D000328:Adult; D000342:Affective Symptoms / Q000235:genetics / Q000503:physiopathology; D001714:Bipolar Disorder / Q000235:genetics / Q000503:physiopathology; D001931:Brain Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008606:Mental Processes; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology
chemical_list: D051741:Kruppel-Like Transcription Factors; C540527:ZNF804A protein, human