Bipolar disorder (BD) is a highly heterogeneous and heritable psychiatric illness. Age at onset has been shown to be a powerful tool for dissecting both the phenotypic and genetic complexity of BD. In this article, we present findings from an association study between the DRD2 TaqIA polymorphism and age at onset, showing that both alleles and genotypes at this locus associate with early onset BD.

Anorexia Nervosa (AN) is a young-onset psychiatric illness, for which the etiology remains unknown and presents a high heritability. Thus, the genetic component is estimated to be 70%. To identify the vulnerability genes to AN, different approaches of molecular genetic are performed, including linkage analysis, the candidate gene association study and, the Genome-Wide Association Study (GWAS). Some polymorphisms of candidate genes, such as the BDNF gene that encodes for the brain-derived neurotrophic factor, were found associated with AN in several studies. In addition to the DNA polymorphisms, there are several other changes around the DNA information, like methylation or the histone modifications, named epigenetic, that modulate the transcription of genes. Thus, first descendents after the Dutch famine in the Second World War have showed a higher risk of impaired glucose tolerance in adulthood. And women exposed to famine in utero presented DNA methylation differences but without link of cause or consequence between famine event and epigenetic changes. To date, only few events of methylation in specific candidate genes have been investigated in AN. Thus, an hypermethylation of the DRD2 gene's promoter was found associated with a downregulation of this gene expression in AN compared to healthy control women (HCW), using leucocytes. While a hypermethylation of the DAT1 promoter was observed correlated with an upregulation of this gene expression. Another study has showed no difference of the methylation level of the Proopiomelanocortin (POMC) promoter between the goups of HCW, underweight AN (acAN) and weight-recovered AN (recAN). But, the expression of POMC was significantly higher in acAN compared to recAN and HCW, and correlated with the leptin levels. These studies suggest that both the etiology and the pathologic consequences of AN could be derived by epigenetic factors, such as the methylation.

Alleles of the D2 dopamine receptor (DRD2) and the alcohol dehydrogenase 2 (ADH2) genes were determined in 69 French Polynesian alcoholic patients and 57 controls matched for racial origin. Three racial groups were studied: pure Polynesians (PP), Polynesians mixed with Caucasian (PCA) ancestry and Polynesians mixed with Chinese (PCH) ancestry. DRD2 A1 allele frequencies in the alcoholics compared to their controls in these groups were: PP,.26 vs .32 (P = .69); PCA, .44 vs .35 (P = .46); PCH, .40 vs 0.39 (P = .88). ADH2 1 allele frequencies in alcoholics compared to their controls groups were: PP, .56 vs .62 (P = .66); PCA, .75 vs .56 (P = .09); PCH, .78 vs .32 (P = .009). In the PCA group, the combination of the DRD2 A1 genotypes and the ADH2 1 homozygotes was strongly associated with alcoholism (P = .0027). This preliminary study shows the importance of ascertaining racial ancestry in molecular genetic association studies. Moreover, it suggests that a combination of genes are involved in susceptibility to the development of alcoholism.

The presence of comorbid anxiety disorders (AD) and bipolar II disorders (BP-II) compounds disability complicates treatment, worsens prognosis, and has been understudied. The genes involved in metabolizing dopamine and encoding dopamine receptors, such as aldehyde dehydrogenase 2 (ALDH2) and dopamine D2 receptor (DRD2) genes, may be important to the pathogenesis of BP-II comorbid with AD. We aimed to clarify ALDH2 and DRD2 genes for predisposition to BP-II comorbid with and without AD. The sample consisted of 335 subjects BP-II without AD, 127 subjects BP-II with AD and 348 healthy subjects as normal control. The genotypes of the ALDH2 and DRD2 Taq-IA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a statistically significant association between DRD2 Taq-I A1/A2 genotype and BP-II with AD (OR = 2.231, P = 0.021). Moreover, a significant interaction of the DRD2 Taq-I A1/A1 and the ALDH2*1*1 genotypes in BP-II without AD was revealed (OR = 5.623, P = 0.001) compared with normal control. Our findings support the hypothesis that a unique genetic distinction between BP-II with and without AD, and suggest a novel association between DRD2 Taq-I A1/A2 genotype and BP-II with AD. Our study also provides further evidence that the ALDH2 and DRD2 genes interact in BP-II, particularly BP-II without AD.

Tardive dyskinesia (TD) is a side-effect of chronic antipsychotic medication. Abnormalities in dopaminergic activity in the nigrostriatal system have been most often suggested to be involved because the agents which cause TD share in common potent antagonism of dopamine D2 receptors (DRD2), that notably is not balanced by effects such as more potent serotonin (5-HT)2A antagonism. Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD. The most consistent findings have been found with the Ser9Gly polymorphism of the DRD3 gene. Although DRD2 has long been hypothesized to be the main target for antipsychotics, only a few polymorphisms in DRD2 have been investigated for their potential involvement in the aetiology of TD. In the present study, we investigated 12 polymorphisms spanning the DRD2 gene and their association with TD in our European Caucasian (n=202) and African–American (n=30) samples. Genotype frequencies for a functional polymorphism, C957T (Duan et al., 2003; Hirvonen et al., 2004), and the adjacent C939T polymorphism were found to be significantly associated with TD (p=0.013 and p=0.022 respectively). DRD2 genotypes were not significantly associated with TD severity as measured by AIMS (Abnormal Involuntary Movement Scale) with the exception of a trend for C939T (p=0.071). Both TD and total AIMS scores were found to be significantly associated with two-marker haplotypes containing C939T and C957T (p=0.021 and p=0.0087 respectively). Preliminary results indicated that C957T was also associated with TD in our African–American sample (p=0.047). Taken together, the present study suggests that DRD2 may be involved in TD in the Caucasian population, although further studies are warranted.

Se determinaron los alelos de los genes del receptor D2 de dopamina (DRD2) y del alcohol deshidrogenasa 2 (ADH2) en 69 pacientes alcohólicos de la Polinesia francesa y 57 controles empa- rejados en cuanto a su origen racial. Se estudiaron tres grupos raciales: polinesios puros (PP), polinesios mezclados con ascendencia caucasiana (PACauc) y polinesios mezclados con ascendencia china (PACh). En estos grupos, las frecuencias del alelo Al del DRD2 en los alcohólicos en comparación con sus controles fueron: PP: 0,26 frente a 0,32 (P = 0,69); PACauc: 0,44 frente a 0,35 (P = 0,46); PACh: 0,40 frente a 0,39 (P = 0,88). Las frecuencias del alelo 1 de la ADH2 en alcohólicos en comparación con sus grupos de control fueron: PP: 0,56 frente a 0,62 (P = 0,66); PACauc: 0,75 frente a 0,56 (P = 0,09); PACh: 0,78 frente a 0,32 (P = 0,009). En el grupo de PACauc, la combinación de los geno- tipos Al del DRD2 y los homocigotos 1 de la ADH2 estaba fuertemente asociada con el alcoholismo (P = 0,0027). Este estudio preliminar muestra la importancia de comprobar la ascendencia racial en los estudios de asociación de genética molecular. Además, indica que en la susceptibilidad al desarrollo del alcoholismo está implicada una combinación de genes.