MOLECULAR ANALYSIS OF THE DOPAMINE TRANSPORTER IN ADHD

点击翻译按钮获取中文摘要

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder of presumably heterogeneous etiology whose symptoms often persist beyond childhood. Both the familiality of ADHD and the moderate heritability of ADHD symptoms have been well established, suggesting that genetic transmission may represent an etiological factor for many individuals with this disorder. The dopamine transporter (DAT1=SLC 6A3) is a candidate susceptibility gene for ADHD because drugs which inhibit the dopamine transporter are efficacious in the short-term treatment of some symptoms of ADHD. We have previously found linkage disequilibrium between a variable number tandem repeat (VNTR) allele with 10 Copies at the dopamine transporter locus and ADHD. In an independent sample, we propose to replicate the family-based association between a dopamine transporter genetic marker and ADHD in 125 trios consisting of an a proband with ADHD and both parents. Diagnosis of ADHD will be based upon the Kiddie-SADS-Lifetime Version (K-SADS- PL). In order to advance our understanding of the genetics of this disorder, probands will be selected after undergoing a comprehensive diagnostic evaluation to rule out potentially confounding effects. In particular, children will be excluded whose ADHD may be the result of other co-morbid psychiatric disorders (e.g. lifetime diagnosis of Bipolar Disorder), suspected phenocopies of ADHD, or where there is diagnostic uncertainty. Transmission of the 10 copy allele at the dopamine transporter locus will be analyzed by the transmission/disequilibrium test, with the specific hypothesis that heterozygous parents with the 10 copy allele and any other copy allele at this locus will preferentially transmit the 10 copy allele to probands with DSM- III-R diagnosed ADHD. If linkage disequilibrium is replicated with DSM-rn-R diagnosis, linkage disequilibrium in DSM-IV subtypes of ADHD will be tested. If the previous family-based association is replicated, continued screening of the dopamine transporter gene for susceptibility mutations, including molecular biological study of the VNTR itself will be supported. Identification of a modifying allele at the dopamine transporter locus would be useful in the development of improved pharmacological agents for treatment of ADHD and may assist in design and implementation of early prevention/intervention strategies for children with genetic susceptibility to ADHD.