Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in
autism susceptibility candidate 2
gene (
AUTS2
) was associated with alcohol consumption at genome-wide significance (
P
= 4 × 10
−8
to
P
= 4 × 10
−9
). We found a genotype-specific expression of
AUTS2
in 96 human prefrontal cortex samples (
P =
0.026) and significant (
P
< 0.017) differences in expression of
AUTS2
in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an
AUTS2
homolog caused reduced alcohol sensitivity in
Drosophila
(
P
< 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.
Background
Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity.
Methods
Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function.
Results
Carriers of FAAH 385A, associated with reduced enzyme and, possibly, increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison to C385 homozygotes. Similar divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity.
Conclusions
Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Δ9-tetrahydrocannabinol and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.
Women who have experienced childhood sexual abuse (CSA) have an increased risk of alcoholism and antisocial personality disorder (ASPD). Among male subjects, a functional polymorphism (MAOA-LPR, monoamine oxidase A linked polymorphic region) in the promoter region of the monoamine oxidase A gene (MAOA) appears to moderate the effect of childhood maltreatment on antisocial behavior. Our aim was to test whether MAOA-LPR influences the impact of CSA on alcoholism and ASPD in a sample of 291 women, 50% of whom have experienced CSA; we also tested whether haplotypes covering the region where both MAOA and monoamine oxidase B (MAOB) genes are located predict risk of alcoholism and ASPD better than the MAOA-LPR locus alone. Participants included 168 alcoholics (39 with ASPD (antisocial alcoholics) and 123 controls (no alcoholics, no ASPD). Antisocial behavior was also modeled as a continuous trait: ASPD symptoms count. The MAOA-LPR low activity allele was associated with alcoholism (P = 0.005), particularly antisocial alcoholism (P = 0.00009), only among sexually abused subjects. Sexually abused women who were homozygous for the low activity allele had higher rates of alcoholism and ASPD, and more ASPD symptoms, than abused women homozygous for the high activity allele. Heterozygous women displayed an intermediate risk pattern. In contrast, there was no relationship between alcoholism/antisocial behavior and MAOA-LPR genotype among non-abused women. The MAOA-LPR low activity allele was found on three different haplotypes. The most abundant MAOA haplotype containing the MAOA-LPR low activity allele was found in excess among alcoholics (P = 0.008) and antisocial alcoholics (P = 0.001). Finally, a MAOB haplotype, which we termed haplotype C, was significantly associated with alcoholism (P = 0.006), and to a lesser extent with antisocial alcoholism (P = 0.03). In conclusions, MAOA seems to moderate the impact of childhood trauma on adult psychopathology in female subjects in the same way as previously shown among male subjects. The MAOA-LPR low activity allele appears to confer increased vulnerability to the adverse psychosocial consequences of CSA. Haplotype-based analysis of the MAOA gene appeared to strengthen the association, as compared to the MAOA-LPR locus alone. A MAOB haplotype was associated with alcoholism independently from ASPD.
Aims-Alcoholism is a chronic relapsing disorder with an enormous societal impact. Understanding the genetic basis of alcoholism is crucial to characterize individuals' risk and to develop efficacious prevention and treatment strategies.Methods-We examined the available scientific literature to provide an overview of different approaches that are being integrated increasingly to advance our knowledge of the genetic bases of alcoholism. Examples of genes that have been shown to influence vulnerability to alcoholism and related phenotypes are also discussed.
Background: Anxiety symptoms are relatively common among children and adolescents and can interfere with functioning. The prevalence of anxiety and the relationship between anxiety and school performance were examined among elementary, middle, and high school students.
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