No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics.
OBJECTIVE
The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene.


METHODS
The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes.


RESULTS
Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association.


CONCLUSIONS
It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out.
Sanders
Alan R
AR
Department of Psychiatry and Behavioural Sciences, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201-3137, USA.
Duan
Jubao
J
Levinson
Douglas F
DF
Shi
Jianxin
J
He
Deli
D
Hou
Cuiping
C
Burrell
Gregory J
GJ
Rice
John P
JP
Nertney
Deborah A
DA
Olincy
Ann
A
Rozic
Pablo
P
Vinogradov
Sophia
S
Buccola
Nancy G
NG
Mowry
Bryan J
BJ
Freedman
Robert
R
Amin
Farooq
F
Black
Donald W
DW
Silverman
Jeremy M
JM
Byerley
William F
WF
Crowe
Raymond R
RR
Cloninger
C Robert
CR
Martinez
Maria
M
Gejman
Pablo V
PV
D000293:Adolescent; D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping / Q000706:statistics & numerical data; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics / Q000378:metabolism; D011786:Quality Control; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics*
D002394:Catechol O-Methyltransferase