Rationale-Genetic and environmental influences on the development of alcohol and drug dependence are equally important. Exposure to early life stress, that is unfortunately common in the general population, has been shown to predict a wide range of psychopathology, including addiction.Objective-This review will look at the characteristics of early life stress that may be specific predictors for adolescent and adult alcohol and drug dependence and will focus on studies in humans, non-human primates and rodents.Results-Experiencing maltreatment and cumulative stressful life events prior to puberty and particularly in the first few years of life is associated with early onset of problem drinking in adolescence and alcohol and drug dependence in early adulthood. Early life stress can result in permanent neurohormonal and hypothalamic-pituitary-adrenal axis changes, morphological changes in the brain and gene expression changes in the mesolimbic dopamine reward pathway, all of which are implicated in the development of addiction. However, a large proportion of children who have experienced even severe early life stress do not develop psychopathology indicating that mediating factors such as gene-environment interactions and family and peer relationships are important for resilience.Conclusions-There appears to be a direct pathway from chronic stress exposure in prepubertal children via adolescent problem drinking to alcohol and drug dependence in early adulthood. However, this route can be moderated by genetic and environmental factors. The role that gene-environment interactions play in the risk-resilience balance is being increasingly recognized.

Philip Brooks and colleagues discuss evidence linking the alcohol flushing response (predominantly due to ALDH2 deficiency) with a much higher risk of esophageal cancer from alcohol consumption.

Childhood trauma is associated with hypothalamic-pituitary-adrenal axis (HPA) dysregulation and is a known risk factor for suicidal behavior. In this study we sought to determine whether the impact of childhood trauma on suicide risk might be modified by FKBP5, an HPA axis regulating gene. Sixteen FKBP5 haplotype tagging SNPs were genotyped in a sample of African Americans: 398 treatment seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 non-substance dependent individuals (40% men; 21 suicide attempters). In all, a total of 474 participants (112 suicide attempters) also completed the Childhood Trauma Questionnaire (CTQ). Primary haplotype analyses were conducted with the four SNPs implicated in earlier studies: rs3800373, rs9296158, rs1360780 and rs9470080. We found that childhood trauma was associated with suicide attempt (p < 0.0001). Although there was no main effect of the two major yin yang haplotypes in the four SNP haplotype block, there was a haplotype influence on suicide risk (p = 0.006) only in individuals exposed to high levels of childhood trauma. In this group, 51% with two copies of the risk haplotype, 36% with one copy, and 20% with no copies had attempted suicide. The total logistic regression model accounted for 13% of the variance in attempted suicide. Analyses of the 16 SNPs showed significant main effects on suicide attempt of rs3777747, rs4713902 and rs9470080 and interactive effects of rs3800373, rs9296158, and rs1360780 with CTQ score on suicide attempt. These data suggest that childhood trauma and variants of the FKBP5 gene may interact to increase the risk for attempting suicide.

The results of the present study suggest that an inherited difference in catecholamine metabolism is important in the pathogenesis of anxiety in women.

Alcoholism is a common, heritable, chronic relapsing disorder. GABA A receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA A receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA A receptors: tolerance is associated with generally decreased GABA A receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA A receptors may be implicated in the switch from heavy drinking to dependence. GABA A receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA A receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA A receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

The brain-derived neurotrophic factor (BDNF) gene is critical for neuronal function and survival, and is likely to be important in psychiatric disorders. In this study, we used single-nucleotide polymorphism (SNP) discovery, functional analyses, and genetic association studies to better understand the potential role of BDNF sequence variation in behavior. Screening 480 unrelated individuals for SNPs and genotyping was performed in US Caucasian, American Indian, and African American populations. Lifetime DSM-III-R psychiatric diagnoses were assigned and the Tridimensional Personality Questionnaire (TPQ) was administered to measure anxious temperament (harm avoidance (HA)) and novelty seeking (NS). A novel SNP (À281 C4A) in promoter 1 was discovered that had decreased DNA binding in vitro and decreased basal reporter gene activity in transfected rat hippocampal neurons. The frequency of the À281 A allele was 0.03 in a Caucasian sample, but was virtually absent in other populations. Association analyses in a community-based sample showed that individuals with the À281 A allele (13 heterozygotes) had lower TPQ HA (F ¼ 4.8, po0.05). In contrast, the Met 66 allele was associated with increased HA (F ¼ 4.1, p ¼ 0.02) and was most abundant in individuals with both anxiety disorders and major depression (po0.05). Among the Val66Val homozygotes, individuals who were -281 CA heterozygotes had significantly lower HA than the -281 CC homozygotes (po0.01). Our results suggest that in this population, the low activity -281 A allele may be protective against anxiety and psychiatric morbidity, whereas Met 66 may be a risk allele.

Haplotype linkage of TPH2 to suicide attempt and major depression and to a mediating phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid, provides preliminary evidence of a functional locus potentially within a haplotype block at least 52 kb in size.

Since 2005, a rapidly expanding literature has evaluated whether environmental factors such as socio-cultural context and environmental adversity interact with genetic influences on drinking behaviors. This article critically reviews empirical research on alcohol-related genotype-environment interactions (GxE) and provides a contextual framework for understanding how genetic factors combine with (or are shaped by) environmental influences to influence the development of drinking behaviors and alcohol use disorders. Collectively, evidence from twin, adoption, and molecular genetic studies indicates that the degree of importance of genetic influences on risk for drinking outcomes can vary in different populations and under different environmental circumstances. However, methodological limitations and lack of consistent replications in this literature make it difficult to draw firm conclusions regarding the nature and effect size of alcohol-related GxE. On the basis of this review, we describe several methodological challenges as they relate to current research on GxE in drinking behaviors and provide recommendations to aid future research.