A network of dopaminergic gene variations implicated as risk factors for schizophrenia.
We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia (SZ). In stage I, we screened 18 dopamine-related genes in two independent US Caucasian samples: 150 trios and 328 cases/501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT and SLC18A2 (alias VMAT2). In stage II, we comprehensively evaluated these four genes by genotyping 68 SNPs in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < or = 0.05). We sought epistasis between pairs of SNPs providing evidence of a main effect and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. In stage III, we confirmed our findings by genotyping 65 SNPs among 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were overtransmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (p(joint) < 0.05). We tested 29 putative interactions from stage II and detected replication between seven locus pairs (p < or = 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). In stage IV we evaluated rs464049 and rs3756450 for functional effects and found significant allele-specific differences at rs3756450 using electrophoretic mobility shift assays and dual-luciferase promoter assays. Our data suggest that a network of dopaminergic polymorphisms increase risk for SZ.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Michael E
ME
Talkowski
George
G
Kirov
Mikhil
M
Bamne
Lyudmila
L
Georgieva
Gonzalo
G
Torres
Hader
H
Mansour
Kodavali V
KV
Chowdari
Vihra
V
Milanova
Joel
J
Wood
Lora
L
McClain
Konasale
K
Prasad
Brian
B
Shirts
Jianping
J
Zhang
Michael C
MC
O'Donovan
Michael J
MJ
Owen
Bernie
B
Devlin
Vishwajit L
VL
Nimgaonkar
D000483:Alleles; D002031:Bulgaria; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D015331:Cohort Studies; D003627:Data Interpretation, Statistical; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D049410:Luciferases, Renilla / Q000378:metabolism; D016017:Odds Ratio; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D012737:Sex Factors; D014481:United States; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics*
C493593:DRD3 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D050637:Receptors, Dopamine D3; C493452:SLC18A2 protein, human; C493214:SLC6A3 protein, human; D050493:Vesicular Monoamine Transport Proteins; D049410:Luciferases, Renilla; D002394:Catechol O-Methyltransferase