Novel, replicated associations between dopamine D3 receptor gene polymorphisms and schizophrenia in two independent samples.
BACKGROUND
Meta-analyses have suggested an association between schizophrenia (SZ) and a coding polymorphism (rs6280/Ser9Gly) at the dopamine D3 receptor gene (DRD3), but results have been inconsistent. Because most studies have evaluated only rs6280, the inconsistencies might reflect associations with other variants.


METHODS
We analyzed polymorphisms spanning 109kb in two independent samples (United States: 13 single nucleotide polymorphisms (SNPs), 331 cases, 151 trios, 274 control subjects; India: 11 SNPs, 141 trios).


RESULTS
In the U.S. samples, significant associations were detected with eight SNPs, including rs6280 (p = .001, odds ratio: 1.5). Consistent associations in the case-control and family-based analyses were detected with a common haplotype spanning intron 1 to the 3' region of the gene (rs324029-rs7625282-rs324030-rs2134655-rs10934254; case-control, p = .002; transmission disequilibrium test [TDT], p = .0009; global p-values = .002 and .007, respectively). In the Indian sample, one SNP was associated (rs10934254, p = .03). Moreover, over-transmission of the same common haplotype as the U.S. sample was observed in this cohort (TDT, p = .005; global test, p = .009). Ser9Gly (rs6280) was associated with SZ against this haplotype background but not other haplotypes.


CONCLUSIONS
These data suggest previous inconsistencies might have resulted from associations with other DRD3 variants. A liability locus might be in linkage disequilibrium (LD) with or carried against, an associated haplotype 3' to rs6280. Comprehensive SNP evaluation in larger samples is needed.
Talkowski
Michael E
ME
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15213, USA.
Mansour
Hader
H
Chowdari
Kodavali V
KV
Wood
Joel
J
Butler
Allison
A
Varma
Panchami G
PG
Prasad
Suman
S
Semwal
Prachi
P
Bhatia
Triptish
T
Deshpande
Smita
S
Devlin
Bernie
B
Thelma
B K
BK
Nimgaonkar
Vishwajit L
VL
D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
D050637:Receptors, Dopamine D3