Genetic association studies provide considerable evidence that the 10-repeat allele of a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'-UTR) of the dopamine transporter gene (DAT1) is associated with a range of psychiatric phenotypes, most notably, attention deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study, we measured DAT1 messenger RNA levels in cerebellum, temporal lobe, and lymphocytes using quantitative real-time reverse-transcription polymerase chain reaction. Relative to a set of four control housekeeping genes (beta-actin, GAPD, ribosomal 18S, and beta2-microglobulin) we observed that increased levels of DAT1 expression were associated with the number of 10-repeat alleles. These data provide direct evidence that the VNTR, or another polymorphism in linkage disequilibrium with the VNTR, is involved in regulating expression of this gene.

Several studies have shown an association between schizophrenia and the C allele of a T-C polymorphism at nucleotide 102 and the 5HT2A receptor gene. In the present study we observed this association in a sample of 63 parent/offspring trios where the proband received a diagnosis of DSM-III-R schizophrenia using TDT analysis ( 2 = 6.26, P = 0.006, 2 = 9.00, P = 0.001 when one affected offspring was selected at random from each family, suggesting that the results are due to association rather than linkage). There was no significant difference between the transmission of C102 from heterozygous fathers and mothers, which fails to support a role for genomic imprinting in this effect. T102C does not result in an alteration of the amino acid sequence of the protein. We therefore screened the promoter of 5HT2A for polymorphisms using single-strand confirmation polymorphism analysis. An A-G polymorphism at −1438 that creates an HpaII restriction site was identified. This was found to be in complete linkage disequilibrium with T102C and is hence a candidate for the pathogenic variant in schizophrenia. Functional analysis of A-1438G using luciferase assay demonstrated significant basal promoter activity in 5HT2A expressing HeLa cells by both the A and G variants. However, comparison of the A and G variants showed no significant differences in basal activity nor when promoter activity was induced by cAMP and protein kinase C-dependent mechanisms.Keywords: schizophrenia; 5HT2A; serotonin receptor; 5HT2A receptor; genetics; allelic association Introduction genetic associations can lead to both false positive and false negative findings if there is population stratifiSeveral studies have shown an association between cation. Although attempts were made in most of the schizophrenia and allele 2 (C) of a T-C polymorphism previous studies to match for ethnicity, it is still possat nucleotide 102 in the 5HT2A receptor gene. [1][2][3] ible that stratification effects occurred. Family-based Although the odds ratios are small (1.7 for possession association designs overcome problems of stratifiof one or more copies of allele 2 2 ), the attributable fraccation. 11 Accordingly, we obtained DNA from parents tion is relatively high (0.35), because allele 2 is comof our original sample where available 2 and from mon in the general population. This association is additional parent/affected-offspring trios. In addition, therefore potentially of considerable therapeutic this approach has also allowed us to test for parentimportance. Some studies have failed to replicate these of-origin effects, a possibility highlighted by a recent findings, but they have all been small and lack of demonstration of genomic inprinting at this locus. 12 power 4-9 is one explanation for their failure to demonThe T102C polymorphism does not result in alterstrate a significant association. Indeed the results of a ation of the amino-acid sequence of the protein. It is recent meta-analysis including all published studies therefore likely that this polymorphism is no...

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