The Lingkage Disequilibrium Studies Of The Serotonin Transporter Gene In Affective Disorder

Background and Objective: Affective disorder is a complex mental disorder characterized by severe mood changes. The major affective disorder is usually divided into bipolar disorder (or manic-depression) and major depression. Twin, family and adoption studies provide strong support for genetic factors in the pathogenesis of both disorders. In addition, some of these factors may overlap in the two diseases, since first-degree relatives of bipolar probands appear to increase risks for both bipolar and major depression. Several lines of pharmacological, neurobehavioral and therapeutic evidence suggest that alterations in the function of the human serotonin may be implicated in the pathogenesis of affective disorders. The classical tricyclic antidepressants, especially, some of selective serotonin reuptak inhibitors (SSRIs), such as fluoxetine, paroxetine and sertraline, are generally understood to involve an increase in the extracellular serotonin concentrations in the synapse by blocking the reuptake of released serotonin. The curative effect of antidepressants have been extensively identified in the clinical treatment. Many studies have suggested that the serotonin transporter plays an important role hi the uptake of serotonin into neurons. Therefore, the 5-HTT gene is a good target in the 5-HT system. The gene encoding 5-HTT has been cloned and maps to chromosome 17q^11.1-12 Two common polymorphisms have been described in the gene: a deletion /insertion of 44bp in the promoter region and a Variable-Number-Tandem-Repeat (VNTR) located in intron 2 (5-HTT-VNTR). These two polymorphisms influence the susceptibility to affective disorder. Few reported that the Pstl restrction fragment length polymorphism (AG/TTAC) caused by a single nucleotide mutation in the 3' untranslated region is in relation tovulnerability to affective disorder. According to the former, we conducted the linkage disequilibrium studies on three polymorphisms in 5-HTT gene in order to explore deeply and entirely the association between affective disorder and 5-HTT gene in molecular genetics among Chinese Han nationality. Material and Methods: The study selected affective disorder parent-offspring trios as research objects and investigated with self-editing family questionnaire according to Diagnostic Investigation Genet Scale(DIGS) provided by Harvard University and adopting American diagnostic criterion DSM-IV(Disgnostic and Statistic Manual of Mental Disorder,4rd) and combining with some psychological rating tools to reach phenotypes consistency and reduce heterogeneity as possible. Genomic DNA was isolated from 65 core pedigrees, 4 affected sib-pair pedigrees and 3 high-density family members of Chinese Han nationality, sum to 247(including 90 affective disorders ). The genotype was carried out using polymerase chain reaction (PCR) and restriction enzyme digestion teques.The study for the conducted a family-based systemic linkage disequilibrium analysis on the molecular genetic association between the three polymorphism points (5-HTTLPR, VNTR and 3'UTRG/T) in 5-HTT gene and affective disorders. The major study included: (1) investigation to affective disorder parent-offspring trios combined with quantitative rating on phenotypes using standard review to the patients; (2) linkage disequilibrium research on the three polymorphism loci in 5-HTT gene by using GHRR and HHRR methods and Transmission Disequilibrium Test (TDT) methods and multi-marker haplotypes analysis to them, so as to avoid pseudo-positive results and population stratification phenomenon which ensures rationality of methodology and science of conclusion; (3) sequencing analysis to part polymorphism fragment.ResuIts:There are no significant differences between parent group and patient group from 70 integrity core pedigree members of Chinese Han nationalit (including 70 affective disorder probands,222 parents) hi genotype and allele gene frequency of the three polymorphism loci (5-HTTLPR , VNTR and 3'UTRG / T) in 5-HTT gene by case-parent control study .The GHRR, HHRR and...