No abstract

Approximately 10% of Japanese alcoholics develop their disease despite having an inactive form of aldehyde dehydrogenase-2 (ALDH2), 1 known as a genetic deterrent of heavy drinking due to adverse reactions after drinking.2 Such alcoholics are considered to be advantageous in genetic research because they should show reduced heterogeneity and possess genetic factors conferring susceptibility to alcohol dependence. Examination of the −1438 A/G polymorphism of the serotonin 2A (5HT2A) receptor gene in 225 Japanese alcoholics with inactive ALDH2 revealed the presence of significantly more of the G allele than was found in 361 control subjects. The frequency of the G allele in 282 alcoholics with active ALDH2 fell between the G allele frequencies of controls and subjects with inactive ALDH2. These data suggest that although the effect is relatively small, genetic variability in the 5HT2A receptor is involved in the development of alcohol dependence.Genetic factors play pivotal roles in the development of alcohol dependence, as twin, adoption studies consistently show. These factors may involve genetic variation in neurotransmission. Recently, Collier and colleagues 3 reported a positive association between a biallelic polymorphism (−1438 G/A) in the promoter region of the serotonin 2A (5HT2A) receptor gene and anorexia nervosa. They reported that the frequency of an A allele was overrepresented in patients with anorexia nervosa compared with that in controls. However, evidence against these findings 4 makes them controversial.Because (1) several lines of evidence have shown that the function of the serotonergic system is closely related to the alterations in food and ethanol intake in both animals and humans, 5-7 and (2) eating disorders are often coincident with alcohol dependence, 8 we speculate that the 5HT2A receptor gene promoter polymorphism confers genetic susceptibility to alcohol dependence. To explore this hypothesis, we have investigated possible associations between 5HT2A receptor gene promoter polymorphism and alcohol dependence.The most likely model of inherited alcohol dependence involves the interaction of multiple genes that have minor effects and sociocultural factors in the environment, which leads to the development of the disease in genetically susceptible individuals. One of the major obstacles in identifying genes that produce minor effects is the heterogeneity of the disease to be examined. To overcome this problem, we studied alcoholics with inactive aldehyde dehydrogenase-2 (ALDH2), which is encoded by either heterozygous ALDH2*1/2*2 or homozygous ALDH2*2, a welldefined genetic risk factor that lowers the risk for alcohol dependence.2,9,10 The heterogeneity of the disease is considered to be relatively low in this genetically defined subgroup, compared with the entire alcoholic population.In addition, individuals who have become alcoholic despite their inactive ALDH2 probably have one or more factors that increase their susceptibility to alcohol dependence. If 5HT2A receptor gene polymorphis...

Several lines of evidence support possible serotonin transporter (5-HTT) involvement in modulating eating disorders (ED). The 5-HTT gene is a good candidate for genetic studies on the course of ED, despite controversy concerning the association between polymorphism in the 5-HTT gene promoter region (5-HTTLPR) and ED. Comparison of 5-HTTLPR distribution in 195 female Japanese ED patients and 290 age- and gender-matched control subjects facilitated examining the association between the course of the disease and 5-HTTLPR in 138 of 195 ED subjects. The 5-HTTLPR S allele frequency was significantly higher in subjects with anorexia nervosa (AN) than in control subjects. Among subjects observed > or =3 years, the S allele frequency was significantly higher in those diagnosed as AN at ED onset than in those diagnosed as AN in this study. The 5-HTTLPR S allele might play some role in the development of AN with persistent disease.

No abstract

Regulators of G-protein signaling are a family of proteins that negatively regulate the intracellular signaling of G protein-coupled receptors, such as the serotonin receptor. Recent studies have suggested that one of these proteins, the regulator of G-protein signaling 2 (RGS2), plays an important part in anxiety and/or aggressive behavior. To explore the involvement of the RGS2 gene in the vulnerability to suicide, we screened Japanese suicide victims for sequence variations in the RGS2 gene and carried out an association study of RGS2 gene polymorphisms with suicide victims. In the eight identified polymorphisms that were identified by mutation screening, we genotyped four common single-nucleotide polymorphisms (SNPs) in the RGS2 gene, and found significant differences in the distribution of the SNP3 (C + 2971G, rs4606) genotypes and alleles of the SNP2 (C-395G, rs2746072) and the SNP3 between completed suicides and the controls. The distribution of the haplotype was also significantly different between the two groups (global po0.0001). Furthermore, RGS2 immunoreactivity significantly increased in the amygdala and the prefrontal cortex (Brodmann area 9 (BA9)) of the postmortem brain of the suicide subjects. These findings suggest that RGS2 is genetically involved in the biological susceptibility to suicide in the Japanese population.