Genetic variation in the DAOA gene complex: impact on susceptibility for schizophrenia and on cognitive performance.
BACKGROUND
The genetic region coding for d-amino acid oxidase activator (DAOA) is considered an intriguing susceptibility locus for schizophrenia. However, association studies have often resulted in conflicting findings, and the risk-conferring variants and their biological impact remain elusive. Our aim in this study was to investigate the relationship between DAOA variation and schizophrenia, and the influence of DAOA on cognitive performance.


METHODS
We analyzed block structure and association patterns of an approximately 173 kb region on chromosome 13q33, applying genotype data of 55 SNPs derived from Caucasian North American sample (178 cases, 144 healthy controls). Haplotypes were assigned using the program PHASE and frequencies compared between cases and controls. We applied MANOVA to investigate the relationship between the identified risk haplotype on cognitive performance.


RESULTS
We identified multiple haplotypes within the region containing the DAOA gene. Of these, one was significantly associated with schizophrenia, being over-represented in schizophrenia versus healthy controls. This haplotype was also associated with one aspect of cognitive performance, semantic fluency. Carriers of the risk haplotype showed better semantic fluency than non-carriers.


CONCLUSIONS
We report a significant effect of DAOA variation on risk for schizophrenia. Moreover, we identified a relationship between DAOA genetic variation and specific aspects of neurocognitive function. As the identified DAOA risk haplotype was associated with better performance on a semantic fluency measure, further work is required to identify the mechanism of DAOA action on CNS function, including the possibility of a role for balanced selection at this locus.
Division of Psychiatry Research, The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, New York 11004, United States.
Carolin
C
Opgen-Rhein
Todd
T
Lencz
Katherine E
KE
Burdick
Andres H
AH
Neuhaus
Pamela
P
DeRosse
Terry E
TE
Goldberg
Anil K
AK
Malhotra
D000328:Adult; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011594:Psychometrics / Q000706:statistics & numerical data; D012016:Reference Values; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000235:genetics*; D012564:Schizophrenic Language; D012641:Selection, Genetic; D014888:Wechsler Scales / Q000706:statistics & numerical data