Neural mechanisms of a genome-wide supported psychosis variant.
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.
Esslinger
Christine
C
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, J5, 68159 Mannheim, Germany.
Walter
Henrik
H
Kirsch
Peter
P
Erk
Susanne
S
Schnell
Knut
K
Arnold
Claudia
C
Haddad
Leila
L
Mier
Daniela
D
Opitz von Boberfeld
Carola
C
Raab
Kyeon
K
Witt
Stephanie H
SH
Rietschel
Marcella
M
Cichon
Sven
S
Meyer-Lindenberg
Andreas
A
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
D051741:Kruppel-Like Transcription Factors; C540527:ZNF804A protein, human