Extensive linkage disequilibrium mapping at HTR2A and DRD3 for schizophrenia susceptibility genes in the Galician population.
The serotonin and dopamine neurotransmitter systems are candidate pathways in the development of schizophrenia because of the assumed causal relationship with the observed symptoms as well as effective targeting of the corresponding receptors by antipsychotic drugs. However, genetic association studies have systematically focused on a limited set of genes and single nucleotide polymorphisms (SNPs), including T102C at HTR2A and Ser9Gly at DRD3. Meta-analyses of the associations between these two markers and schizophrenia revealed a true increase in risk, the magnitude of the effect being very low. In the present study we analyzed 260 schizophrenic patients and 354 control subjects from a homogeneous population, the Galician population, using an extensive linkage disequilibrium (LD) mapping approach, genotyping a total of 47 SNPs to test for the existence of additional variants that confer higher risk. We detected nominal significant association with schizophrenia for several haplotype tag SNPs (htSNPs) at HTR2A, although the significance was lost after multiple test corrections. In addition, haplotype analyses involving a sliding window approach, with window size 2 to 4 SNPs, revealed significant differences in frequencies of the DRD3 haplotypes at the 3' half of the gene region. This difference, which remains clearly significant after multiple test corrections (p=0.002, 0.0001, and 0.0025, for window sizes 2, 3, and 4, respectively), was mainly due to over-representation of several rare haplotypes in patients, at the expense of a single common haplotype; this represents interesting evidence of rare haplotypes for susceptibility detected using common htSNPs due to their strong effect.
Domínguez
Eduardo
E
Applied Pharmacology to Membrane Biology and Signal Transduction Mechanisms Research Group (BIOFARMA), School of Pharmacy, University of Santiago de Compostela, E-15782, Santiago de Compostela, Spain. edardo7@usc.es
Loza
María Isabel
MI
Padín
Fernando
F
Gesteira
Alejandro
A
Paz
Eduardo
E
Páramo
Mario
M
Brenlla
Julio
J
Pumar
Estefanía
E
Iglesias
Fernanda
F
Cibeira
Alcira
A
Castro
Marián
M
Caruncho
Héctor
H
Carracedo
Angel
A
Costas
Javier
J
D024509:3' Flanking Region / Q000235:genetics; D024506:5' Flanking Region / Q000235:genetics; D000328:Adult; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006360:Heat-Shock Proteins; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D018832:Molecular Chaperones; D020641:Polymorphism, Single Nucleotide; D050637:Receptors, Dopamine D3 / Q000235:genetics; D012306:Risk; D012559:Schizophrenia / Q000208:ethnology / Q000235:genetics*; D013030:Spain
C485782:DNAJC7 protein, human; D005819:Genetic Markers; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D050637:Receptors, Dopamine D3