Alcoholism is a complex disease with both genetic and environmental risk factors. To identify genes that affect the risk for alcoholism, we systematically ascertained and carefully assessed individuals in families with multiple alcoholics. Linkage and association analyses suggested that a region of chromosome 4p contained genes affecting a quantitative endophenotype, brain oscillations in the beta frequency range (13-28 Hz), and the risk for alcoholism. To identify the individual genes that affect these phenotypes, we performed linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs) within a cluster of four GABA(A) receptor genes, GABRG1, GABRA2, GABRA4, and GABRB1, at the center of the linked region. GABA(A) receptors mediate important effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2, but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the flanking genes, were associated with the brain oscillations in the beta frequency. The region of strongest association with alcohol dependence extended from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant. A three-SNP haplotype was associated with alcoholism, with P=.000000022. No coding differences were found between the high-risk and low-risk haplotypes, suggesting that the effect is mediated through gene regulation. The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation.

Relapsed alcoholic individuals frequently report that negative emotional states trigger their return to drinking. A parametric laboratory study was conducted to assess the separate and combined effects of exposure to alcohol-related stimuli and induced negative moods in abstinent alcoholic persons. The authors also sought to determine if reactivity to alcohol cues or reactivity to negative mood induction predicted relapse soon after treatment. Men with alcoholism (N = 50) undergoing inpatient treatment participated in a guided imagery procedure designed to induce negative moods and were then exposed to either their favorite alcoholic beverage or to spring water. Results indicated that both alcoholic beverage presentation and negative affect imagery led to increased subjective reporting of desire to drink. These effects were additive but not multiplicative (i.e., the interaction of mood state with beverage type was not significant). Reported urge to drink during the trial that combined negative mood imagery with alcoholic beverage exposure predicted time to relapse after inpatient discharge.

Previous studies have found that the P300 or P3 event-related potential (ERP) component is useful in the diagnosis and treatment of many disorders that influence CNS function. However, the anatomic locations of brain regions involved in this response are not precisely known. In the present event-related functional magnetic resonance imaging (fMRI) study, methods of stimulus presentation, data acquisition, and data analysis were optimized for the detection of brain activity in response to stimuli presented in the three-stimulus oddball task. This paradigm involves the interleaved, pseudorandom presentation of single block-letter target and distractor stimuli that previously were found to generate the P3b and P3a ERP subcomponents, respectively, and frequent standard stimuli. Target stimuli evoked fMRI signal increases in multiple brain regions including the thalamus, the bilateral cerebellum, and the occipital-temporal cortex as well as bilateral superior, medial, inferior frontal, inferior parietal, superior temporal, precentral, postcentral, cingulate, insular, left middle temporal, and right middle frontal gyri. Distractor stimuli evoked an fMRI signal change bilaterally in inferior anterior cingulate, medial frontal, inferior frontal, and right superior frontal gyri, with additional activity in bilateral inferior parietal lobules, lateral cerebellar hemispheres and vermis, and left fusiform, middle occipital, and superior temporal gyri. Significant variation in the amplitude and polarity of distractor-evoked activity was observed across stimulus repetitions. No overlap was observed between target- and distractor-evoked activity. These event-related fMRI results shed light on the anatomy of responses to target and distractor stimuli that have proven useful in many ERP studies of healthy and clinically impaired populations.

No abstract

ehaviors related to self-regulation, such as substance use disorders or antisocial behaviors, have far-reaching consequences for affected individuals, their families, communities and society at large 1,2 . Collectively, this group of correlated traits are classified as externalizing 3 . Twin studies have demonstrated that externalizing liability is highly heritable (~80%) 4,5 . To date, however, no large-scale molecular genetic studies have utilized the extensive degree of genetic overlap among externalizing traits to aid gene discovery, as most studies have focused on individual disorders 6 . For many high-cost, high-risk behaviors with an externalizing component-opioid use disorder and suicide attempts 7 being salient examples-there are limited genotyped cases available for gene discovery 8,9 .A complementary strategy to the single-disease approach is to study the shared genetic architecture across traits in multivariate analyses, which boosts statistical power by pooling data across