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Background: GABRG1 and GABRA2, genes that encode the γ1 and α2 subunits, respectively, of the GABA-A receptor, are located in a cluster on chromosome 4p. Association of alcohol dependence (AD) with markers located at the 3′ region of GABRA2 has been replicated in several studies, but recent studies suggested the possibility that the signal may be attributable to the adjacent gene, GABRG1, located 90 kb distant in the 3′ direction. Owing to strong linkage disequilibrium (LD) in European Americans (EAs), the origin, or origins, of the association signal is very difficult to discern, but our previous population-based study suggested that decreased LD across the GABRG1- GABRA2 region in African Americans (AAs) may be useful for fine mapping and resolution of the association signal in that population. Methods: To examine these associations in greater detail, we genotyped 13 single nucleotide polymorphisms (SNPs) spanning GABRG1 and GABRA2 in 380 AAs with AD and in 253 AA controls. Results: Although there was no association between any individual SNP and AD, a highly significant difference was shown between AD subjects and controls in the frequency of a 3-SNP GABRA2 haplotype (global p = 0.00029). A similar level of significance was obtained in 6-SNP haplotypes that combined tagging SNPs from both genes (global p = 0.00994). High statistical significance was also shown with a 6-SNP haplotype (T-G-C-G-T-A), p = 0.0033. The T-G-C-G-T-A haplotype contains the most significant GABRA2 3-SNP haplotype ( p = 0.00019), G-T-A. Conclusions: These findings reflect the interrelationship between these 2 genes and the likelihood that risk loci exist in each of them. Study of an AA population allowed evaluation of these associations at higher genomic resolution than is possible in a EA population, owing to the much lower LD across these loci in AAs. [ABSTRACT FROM AUTHOR]

To identify and validate homogeneous subtypes of opioid use and related behaviors. Family-based and case-control genetic studies of opioid and/or cocaine dependence. Clinical and general community samples from Connecticut, Massachusetts, Pennsylvania and South Carolina. A total of 4061 individuals (2003 individuals from 835 families and 2058 unrelated individuals) recruited to participate in genetic studies. The computer-assisted Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) was used to assess participants' demographics, medical history, substance use behaviors and disorders and other psychiatric disorders. Five homogeneous subtypes were identified, which differed on opioid-related measures, demographics and prevalence rates of substance use and psychiatric disorders. Heritability estimates for the two most severely affected subtypes exceeded 0.60. An empirical approach based on opioid use and related behaviors can yield homogeneous subtypes that could be of value in gene finding for opioid dependence. [ABSTRACT FROM AUTHOR]

Background: A number of demographic factors, psychiatric disorders, and childhood risk factors have been associated with cocaine dependence (CD) and opioid dependence (OD), but little is known about their relevance to the rate at which dependence develops. Identification of the subpopulations at elevated risk for rapid development of dependence and the risk factors that accelerate the course of dependence is an important public health goal., Methods: Data were derived from cocaine dependent (n=6333) and opioid dependent (n=3513) participants in a multi-site study of substance dependence. Mean age was approximately 40 and 40% of participants were women; 51.9% of cocaine dependent participants and 29.5% of opioid dependent participants self-identified as Black/African-American. The time from first use to dependence was calculated for each substance and a range of demographic, psychiatric, and childhood risk factors were entered into ordinal logistic regression models to predict the (categorical) transition time to CD and OD., Results: In both the cocaine and opioid models, conduct disorder and childhood physical abuse predicted rapid development of dependence and alcohol and nicotine dependence diagnoses were associated with slower progression to CD or OD. Blacks/African Americans were at greater risk than European Americans to progress rapidly to OD., Conclusions: Only a subset of factors known to be associated with CD and OD predicted the rate at which dependence developed. Nearly all were common to cocaine and opioids, suggesting that sources of influence on the timing of transitions to dependence are shared across the two substances., (© 2013.)