No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics

AR Sanders, J Duan, DF Levinson… - American Journal of …, 2008 - Am Psychiatric Assoc
AR Sanders, J Duan, DF Levinson, J Shi, D He, C Hou, GJ Burrell, JP Rice, DA Nertney…
American Journal of Psychiatry, 2008Am Psychiatric Assoc
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. Method: The sample included 1,870 cases …
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.
Method
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.
American Journal of Psychiatry