Abbas Parsian

Human chromosomes 11p15 and 4p12 and alcohol dependence: Possible association with the GABRB1 gene

To determine the role of genes in the chromosomal regions 11p15 and 4p12 in the development of alcohol dependence, a sample of alcoholics (n = 133) and normal controls (n = 89) were screened using polymorphisms in the dopamine D4 receptor (DRD4), tyrosine hydroxylase (TH), and GABA receptor beta1 (GABRbeta1) genes. Comparison of total alcoholics with normal controls for GABRbeta1 gene was highly significant (p = 0.004). The difference between type II alcoholics and normal controls for the same allele frequencies was also significant (p = 0.029). The allele distributions of the polymorphisms in the DRD4 and TH genes in alcoholics and normal controls were similar and their differences were not significant. Our association studies indicate that the GABRbeta1 gene may play a role in the development of alcoholism. Therefore, it is important to screen a sample of well-characterized alcoholics with functional polymorphisms in all of the GABAalpha receptor subunit genes and determine their relationship with alcoholism phenotypes. Results with TH and DRD4 genes indicate that these two genes may not play major roles in the development of alcoholism.

Genetic association between monoamine oxidase and manic‐depressive illness: Comparison of relative risk and haplotype relative risk data

There have been several conflicting reports of association of monoamine oxidase (MAO) A gene polymorphisms and bipolar affective disorder. In order to determine the possible role of the MAO region in susceptibility to affective disorders in an independent sample, we have genotyped 83 probands of bipolar affective disorder families, 56 sets of parents of bipolar probands, and 84 normal controls for intronic simple sequence repeat polymorphisms of the MAO-A and MAO-B genes. For MAO-A there were no significant differences in allele frequencies between bipolar and normal control groups for both genders. However, for MAO-B there were significant differences between groups for both genders. In contrast, allele-wise haplotype relative risk analysis for the 56 bipolar proband-parent trios found no significant differences between transmitted and non-transmitted allele frequencies for MAO-A or B. These data do not support the association of MAO-A or B with bipolar affective disorder but do demonstrate that undetected population stratification can be an important source of bias in case-control studies.

No Association Between Polymorphisms in the Human Dopamine D3 and D4 Receptors Genes and Alcoholism

The human dopamine D2 receptor gene (DRD2) has received considerable attention for the past several years as a potential candidate that may affect susceptibility to alcoholism. The association studies that compared the frequencies of alleles of DRD2 gene between alcoholics and control groups have produced equivocal results. Dopamine D3 and D4 receptor genes (DRD3 and DRD4) are in the same class as DRD2 but with different pharmacological properties. We have used relative risk and haplotype relative risk approaches to test associations between alleles of DRD3 and DRD4 genes and alcoholism. For relative risk studies 162 probands from multiple incidence alcoholic families have been compared to 89 psychiatrically normal controls. Haplotype relative risk approaches have used 29 alcoholic probands in which both parents were available for genotyping. The Bal I restriction enzyme site in DRD3 and tandem repeat (VNTR) in DRD4 genes polymorphisms were used to genotype the above samples. The results of relative risk approaches for both DRD3 and DRD4 genes were negative for comparisons of alcoholics and subtypes of alcoholics with normal controls. Haplotype relative risk approaches also were negative for both genes. These results suggest that any role played by these receptors may account for only part of the variation in susceptibility to alcoholism.

Human dopamine transporter gene polymorphism (VNTR) and alcoholism

The dopamine transporter (DAT1) is responsible for taking released dopamine back up into presynaptic terminals and terminating dopaminergic activity. It has been shown that cocaine binds to the dopamine transporter and blocks dopamine reuptake in a fashion that correlates with cocaine reward and reinforcement. To determine the role of this gene in the development of alcoholism, we have used two approaches, relative risk and haplotype relative risk. The relative risk approach involved 162 alcoholic probands who were categorized into type I and type II, and 89 unrelated normal controls. In the haplotype relative risk approach, 29 trios (father, mother, and proband) were genotyped with dopamine transporter gene polymorphism. Comparison of allele frequencies between total alcoholics, subtypes of alcoholics, and normal controls were negative. The results of haplotype relative risk, differences between alleles transmitted and nontransmitted, were also negative. However, both approaches produced similar results. Therefore, we concluded that the VNTR polymorphism in DAT1 gene is not associated with alcoholism susceptibility genes in our samples.

Genomic Clone OS-2 (D10S20) Detects Different Restriction Fragment Length Polymorphisms in Caucasians and Orientals for Both HindIII and TaqI

Restriction fragment length polymorphisms (RFLPs) for the anonymous DNA probe OS-2 were studied in a Caucasian population. In a sample of 15 two- and three-generation families and 31 unrelated individuals, the restriction endonuclease TaqI revealed an RFLP not seen in a Japanese sample. A similar situation has been observed for this probe with the restriction endonuclease HindIII.