ZNF804A and cortical structure in schizophrenia: in vivo and postmortem studies.
Recent evidence indicated that the ZNF804A (rs1344706) risk allele A is associated with better cognitive performance in patients with schizophrenia. Moreover, it has been demonstrated that ZNF804A may also be related to relatively intact gray matter volume in patients. To further explore these putatively protective effects, the impact of ZNF804A on cortical thickness and folding was examined in this study. To elucidate potential molecular mechanisms, an allelic-specific gene expression study was also carried out. Magnetic resonance imaging cortical thickness and folding were computed in 55 genotyped patients with schizophrenia and 40 healthy controls. Homozygous risk allele carriers (AA) were compared with AC/CC carriers. ZNF804A gene expression was analyzed in a prefrontal region using postmortem tissue from another cohort of 35 patients. In patients, AA carriers exhibited significantly thicker cortex in prefrontal and temporal regions and less disturbed superior temporal cortical folding, whereas the opposite effect was observed in controls, ie, AA carrier status was associated with thinner cortex and more severe altered cortical folding. Along with this, our expression analysis revealed that the risk allele is associated with lower prefrontal ZNF804A expression in patients, whereas the opposite effect in controls has been observed by prior analyses. In conclusion, our analyses provide convergent support for the hypothesis that the schizophrenia-associated ZNF804A variant mediates protective effects on cortex structure in patients. In particular, the allele-specific expression profile in patients might constitute a molecular mechanism for the observed protective influence of ZNF804A on cortical thickness and folding and potentially other intermediate phenotypes.
*To whom correspondence should be addressed; Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07740 Jena, Germany; tel: +49-3641-9-35665, fax: +49-3641-9-35444, e-mail: christoph.schultz@med.uni-jena.de.
Carl Christoph
CC
Schultz
Igor
I
Nenadic
Brien
B
Riley
Vladimir I
VI
Vladimirov
Gerd
G
Wagner
Kathrin
K
Koch
Claudia
C
Schachtzabel
Thomas W
TW
Mühleisen
Buket
B
Basmanav
Markus M
MM
Nöthen
Thomas
T
Deufel
Michael
M
Kiehntopf
Marcella
M
Rietschel
Jürgen R
JR
Reichenbach
Sven
S
Cichon
Ralf G M
RG
Schlösser
Heinrich
H
Sauer
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D066128:Gray Matter / Q000378:metabolism / Q000473:pathology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology*; D065840:Protective Factors; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology*; D055815:Young Adult
D051741:Kruppel-Like Transcription Factors; C540527:ZNF804A protein, human
ZNF804A; cortical folding; cortical thickness; gene expression; psychosis; rs1344706; schizophrenia; susceptibility gene