Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. Because the GABAA neurotransmitter receptor is an important mediator for several behavioral effects of alcohol, genes encoding GABA-related proteins are functional candidates to influence risk of alcohol dependence. Two genome-wide scans showed linkage of alcohol dependence to a region on chromosome 4p, which contains a cluster of genes encoding GABAA receptor subunits. A recent effort to fine map that region showed a haplotypic association of alcohol dependence to the gene encoding the GABAA receptor alpha-2 subunit (GABRA2). We examined 10 single nucleotide polymorphisms (SNPs) spanning the coding region of this gene in samples of European American subjects with alcohol dependence (n = 446), and controls (n = 334) screened to exclude substance use disorders. There was evidence of association to alcohol dependence for seven adjacent markers spanning 98,000 bp in the middle and 3'-portion of the GABRA2 gene (range of P-values = 0.008-0.03). When the subset of the alcohol-dependent subjects excluding those with a diagnosis of cocaine or opioid dependence or major depressive episode (n = 198) was examined, the strength of the association was increased across these 7 SNPs (range of P-values = 0.002-0.007). Two common haplotypes in this region accounted for 90.8% of chromosomes. The more common haplotype was present in 55.6% of control group chromosomes versus 48.2% of alcohol-dependent subjects (P = 0.007) and 45.8% of subjects with alcohol dependence but no co-morbid drug dependence or depression (P = 0.003). These findings replicate and extend recently reported findings, which together underscore the potential contribution of polymorphic variation at the GABRA2 locus to the risk for alcohol dependence.

The neurotransmitter serotonin (5-HT) has been shown to regulate alcohol consumption in both animals and humans. Since activity of the 5-HT transporter protein (5-HTT) regulates 5-HT levels, the gene encoding this protein may contribute to the risk of alcohol dependence (AD). Studies of the association to AD of a functional insertion-deletion polymorphism in the 5-HTT-linked promoter region (5-HTTLPR) have yielded inconsistent results. We conducted a meta-analysis of data from 17 published studies (including 3,489 alcoholics and 2,325 controls) investigating the association between 5-HTTLPR alleles and AD. The frequency of the short (S) allele at 5-HTTLPR was significantly associated with AD [odds ratio (OR) = 1.18, 95% CI = 1.03-1.33). Moreover, a greater association with the S allele was seen among individuals with AD complicated by either a co-morbid psychiatric condition or an early-onset or more severe AD subtype [OR = 1.34 (95% CI = 1.11-1.63)]. Allelic variation at 5-HTTLPR contributes to risk for AD, with the greatest effect observed among individuals with a co-occurring clinical feature.

GABA A receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABA A receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABA A receptor a-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-a steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n ¼ 7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n ¼ 20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.

Paget disease of bone, or "osteitis deformans," is a bone disorder characterized by rapid bone remodeling resulting in abnormal bone formation. It is the second most common metabolic bone disease after osteoporosis, affecting 3%-5% of subjects aged >40 years. Recent evidence suggests that predisposition to Paget disease may have a genetic component. Genetic linkage analysis of families with multigenerational Paget disease shows linkage to a region of chromosome 18q near the polymorphic locus D18S42. Approximately 1% of Paget patients develop osteosarcoma, which represents an increase in risk that is several thousandfold over that of the general population. Osteosarcoma in Paget patients is the underlying basis for a significant fraction of osteosarcomas occurring after age 60 years. Our analysis of tumor-specific loss of constitutional heterozygosity (LOH) in 96 sporadic osteosarcomas has identified a putative tumor-suppressor locus that maps to chromosome 18q. We have localized this tumor-suppressor locus between D18S60 and D18S42, a region tightly linked to familial Paget disease. Analysis of osteosarcomas from patients with Paget disease revealed that these tumors also undergo LOH in this region. These findings suggest that the association between Paget disease and osteosarcoma is the result of a single gene or two tightly linked genes on chromosome 18.

Variable findings in the literature in relation to the association of 5'-HTTLPR alleles to alcohol dependence seem to be due to factors other than the composition of study samples in terms of univariate typologies based on sex, comorbid drug dependence, or age of onset of alcohol dependence.