Adriana Díaz-Anzaldúa

Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population.

Tourette syndrome (TS) is a genetically complex disorder for which no causative genes have been unequivocally identified. Nevertheless, a number of molecular genetic studies have investigated several candidate genes, particularly those implicated in dopamine modulation. The results of these studies were inconclusive, which may be due, at least in part, to the variable ethnicity of the patients included in different studies and the chosen research design. In this study, we used a family-based association approach to investigate the implication of dopamine-related candidate genes, which had been previously reported as possibly associated with TS [genes that encode for the dopamine receptors DRD2, DRD3 and DRD4, the dopamine transporter 1 (SLC6A3) and the monoamine oxidase-A (MAO-A). The studied group was composed of 110 TS patients. These patients were selected from the French Canadian population, which displays a founder effect. Excess transmission of the 7-repeat allele of the DRD4 exon-3 VNTR polymorphism (χ2 TDT =4.93, 1 df, P=0.026) and the putative ‘high-activity’ alleles of the MAO-A promoter VNTR polymorphism (χ2 TDT =7.124, 1 df P=0.0076) were observed. These results were confirmed in a subgroup of patients with no attention deficit/hyperactivity or obsessive compulsive comorbid disorders. Haplotype analysis using one or two supplemental polymorphism in each of these genes confirmed these associations and allowed one to identify risk haplotypes. No associations were found for DRD2, DRD3 or SLC6A3. These data support the notion that DRD4 and MOA-A genes may confer an increased risk for developing TS in the French Canadian population.

Association between 7q31 markers and tourette syndrome

Tourette syndrome (TS) is a complex neuropychiatric disorder with a strong genetic basis. Although no specific susceptibility genes have been identified for TS, cytogenetic studies in selected cases suggest the existence of a predisposing gene located in the 7q31 chromosomal region. In order to test the hypothesis of a possible relationship between this region and TS at the population level, we undertook a family based association study in a sample of French Canadian patients from Quebec. For this purpose, markers D7S522, D7S523, and D7S1516 were tested using the extended transmission disequilibrium test (e‐TDT). Marker D7S522 showed a biased transmission of alleles from heterozygote parents to their TS offsprings (allele‐wise TDT χ2 = 12.61, 4 df, P = 0.013, genotype‐wise TDT χ2 = 15.49, 7 df, P = 0.030). When the analysis was restricted to patients without ADHD or OCD comorbidity, similar results were observed both allele and genotype‐wise (χ2 = 10.68, 4 df, P = 0.03 and χ2 = 12.55, 5 df, P = 0.028, respectively). In addition, marker D7S523 was also associated (allele‐wise TDT χ2 = 18.37, 7 df, P = 0.01 and genotype‐wise TDT χ2 = 46.26, 17 df, P = 0.00016), and showed a tendency for association in the comorbidity‐free subgroup (genotype‐wise TDT χ2 = 18.7, 10 df, P = 0.044). Finally, marker D7S1516, contained in the inner mitochondrial membrane peptidase 2 like (IMMP2L) gene, also showed a tendency for association (genotype‐wise TDT χ2 = 32.87, 21 df, P = 0.048). These results may reflect the proximity of markers D7S522, D7S523, and possibly D7S1516 to a gene or regulatory region relevant to TS predisposition.

Chromosome 11‐q24 region in Tourette syndrome: Association and linkage disequilibrium study in the French Canadian population

Previous studies have found association and linkage between Tourette syndrome (TS) and markers at the 11q24 region, mainly with markers D11S1377 and D11S933. In order to determine if these positive findings could be replicated in our sample, we undertook a family‐based association study in 199 French Canadian TS nuclear families. We genotyped 572 individuals from 174 complete and 25 incomplete TS trios. TDT analysis failed to detect an association between TS and six markers from 11q24. Furthermore, no haplotype combining alleles from D11S1377, D11S933, or any of the other four markers was associated with the disorder. Linkage disequilibrium analysis showed evidence of historical recombination between every contiguous pair of markers, indicating that these genetic variants are probably in equilibrium in the French Canadian population. Further analysis in additional families, with different methodologies (linkage and association) will be required in order to determine if the 11q24 region harbors a susceptibility locus for TS. If it does, this defect may not be frequent in the French Canadian population due to locus heterogeneity.

Endophenotypes and biomarkers: an approach to molecular genetic studies of mental disorders - Endofenotipos y biomarcadores: un enfoque hacia el estudio genético molecular de los trastornos mentales

Aun se desconocen diversos aspectos de la etiologia y fisiopatologia de los trastornos mentales. La susceptibilidad a estos depende en parte de la variabilidad en la secuencia genomica en las personas. El genotipo, un ambiente dado, un perfil epigenetico especifico y factores estocasticos afectan el fenotipo, el cual incluye estructuras corporales, procesos fisiologicos y conducta. Los fenotipos psiquiatricos generalmente se limitan al funcionamiento y a los sintomas clinicos, debido a que el acceso al Sistema Nervioso Central es complicado y en la mayoria de los casos no hay pruebas biologicas que necesariamente contribuyan al diagnostico. Por esta razon, en la actualidad se buscan alternativas para facilitar la identificacion de factores de riesgo de tipo genetico. La identificacion de marcadores biologicos, cognitivos o conductuales medibles, fenotipos intermedios o endofenotipos podria ser una de estas nuevas opciones. Estos marcadores podrian ser mas simples que el diagnostico psiquiatrico general, y de manera ideal tendrian un significado biologico preciso y una accion mas directa en los genes. El empleo de endofenotipos ha sido util en otras ramas de la medicina. Hasta ahora se han propuesto diversos criterios y especificaciones para los endofenotipos. En esta revision se describiran posibles tipos de endofenotipos o biomarcadores, asi como fenotipos relacionados con la respuesta farmacologica en algunos trastornos psiquiatricos.