We present evidence of complex balancing regulation of HTR1B transcription by common polymorphisms in its promoter. Computational analysis of the HTR1B gene predicted that a 5 0 segment, spanning common DNA sequence variations, TÀ261G, AÀ161T, and À182INS/ DELÀ181, contained a putative functional promoter. Using a secreted alkaline phosphatase (SEAP) reporter gene system, we found that the haplotype À261G_À182INSÀ181_AÀ161 enhanced transcriptional activity 2.3-fold compared with the haplotype TÀ261_À182INSÀ181_AÀ161. Conversely, À161T reversed this, and the net effect when À261G and À161T were in the same haplotype (À261G_À182INSÀ181_À161T) was equivalent to the major haplotype (TÀ261_À182INSÀ181_AÀ161). Electrophoretic mobility shift experiments showed that À261G and À161T modify the binding of transcription factors (TFs): À261G generates a new AP2 binding site, while alleles AÀ161 and À161T exhibit different binding characteristics to AP1. TÀ261G and AÀ161T were found to be in linkage disequilibrium (LD) with G861C in a European ancestry population. Interestingly, G861C has been reported to be associated with several psychiatric disorders. Our results indicate that HTR1B is the target of substantial transcriptional genetic regulation by common haplotypes, which are in LD with the HTR1B single-nucleotide polymorphism (SNP) most commonly used in association studies. Molecular Psychiatry (2003) 8, 901-910.
Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val 108/158 Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P ¼ 0.051) in ARVCF, and a stronger signal (global P ¼ 0.0019-0.0036) from three-marker haplotypes spanning the 3 0 portions of COMT and ARVCF, including Val 108/158 Met with Val 108/158 being the overtransmitted allele, consistent with previous studies. We also find Val 108/158 Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence. Molecular Psychiatry (2005) 10, 353-365.
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