Cognitive state and connectivity effects of the genome-wide significant psychosis variant in ZNF804A.
Alterations of connectivity are central to the systems-level pathophysiology of schizophrenia. One of the best-established genome-wide significant risk variants for this highly heritable disorder, the rs1344706 single nucleotide polymorphism in ZNF804A, was recently shown to modulate connectivity in healthy carriers during working memory (WM) in a pattern mirroring that which was found in overt disease. However, it was unclear whether this finding is specific to WM or if it is present regardless of cognitive state. Therefore, we examined genotype effects on connectivity in healthy carriers during rest and an emotion processing task without WM component. 111 healthy German subjects performed a battery of functional imaging tasks. Functional connectivity with the right dorsolateral prefrontal cortex during rest and an implicit emotion recognition task was determined using the seed voxel method and compared to results during WM. During rest and during the emotional task, a pattern of reduced interhemispheric prefrontal connectivity with increasing number of rs1344706 risk alleles could be seen that was close to identical to that during WM, suggesting a state-independent influence of the genetic variant on interhemispheric processing, possibly through structural effects. By contrast, the abnormal prefronto-hippocampal connectivity was only seen during the WM task, indicating a degree of task specificity in agreement with prior results in patients with schizophrenia. Our findings confirm a key role for disturbed functional connectivity in the genetic risk architecture of schizophrenia and identify cognitive state-dependent and independent components with regard to WM function.
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany. christine.esslinger@zi-mannheim.de
Christine
C
Esslinger
Peter
P
Kirsch
Leila
L
Haddad
Daniela
D
Mier
Carina
C
Sauer
Susanne
S
Erk
Knut
K
Schnell
Claudia
C
Arnold
Stephanie H
SH
Witt
Marcella
M
Rietschel
Sven
S
Cichon
Henrik
H
Walter
Andreas
A
Meyer-Lindenberg
D003071:Cognition / Q000502:physiology*; D004247:DNA / Q000235:genetics; D004644:Emotions / Q000502:physiology; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany; D006579:Heterozygote; D007091:Image Processing, Computer-Assisted; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008570:Memory, Short-Term / Q000502:physiology; D009434:Neural Pathways / Q000502:physiology*; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000502:physiology; D011618:Psychotic Disorders / Q000235:genetics* / Q000523:psychology*; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology; D012938:Social Perception
D051741:Kruppel-Like Transcription Factors; C540527:ZNF804A protein, human; D004247:DNA; D010100:Oxygen