HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power—an intermediate phenotype for alcoholism and co-morbid behaviors

Abstract

Alcohol use disorders (AUD) with co-morbid antisocial personality disorder (ASPD) have been associated with serotonin (5-HT) dysfunction. 5-HT3 receptors are potentiated by ethanol and appear to modulate reward. 5-HT3 receptor antagonists may be useful in the treatment of early-onset alcoholics with co-morbid ASPD. Low-voltage alpha electroencephalogram (EEG) power, a highly heritable trait, has been associated with both AUD and ASPD. A recent whole genome linkage scan in one of our samples, Plains American Indians (PI), has shown a suggestive linkage peak for alpha power at the 5-HT3R locus. We tested whether genetic variation within the HTR3A and HTR3B genes influences vulnerability to AUD with comorbid ASPD (AUD + ASPD) and moderates alpha power. Our study included three samples: 284 criminal alcoholic Finnish Caucasians and 234 controls; two independent community-ascertained samples with resting EEG recordings: a predominantly Caucasian sample of 191 individuals (Bethesda) and 306 PI. In the Finns, an intronic HTR3B SNP rs3782025 was associated with AUD + ASPD (P = .004). In the Bethesda sample, the same allele predicted lower alpha power (P = 7.37e -5 ). Associations between alpha power and two other HTR3B SNPs were also observed among PI (P = .03). One haplotype in the haplotype block at the 3′ region of the gene that included rs3782025 was associated with AUD + ASPD in the Finns (P = . 02) and with reduced alpha power in the Bethesda population (P = .00009). Another haplotype in this block was associated with alpha power among PI (P = .03). No associations were found for HTR3A. Genetic variation within HTR3B may influence vulnerability to develop AUD with comorbid ASPD. 5-HT3R might contribute to the imbalance between excitation and inhibition that characterize the brain of alcoholics.

Heritability and molecular‐genetic basis of resting EEG activity: A genome‐wide association study

“…Increases in delta power have been reported in community volunteers who were methamphetamine (Newton et al, 2004) or MDMA users (Herning, Better, Tate, & Cadet, 2005). Reductions in alpha power have also been reported among alcohol-dependent individuals, particularly those with comorbid anxiety disorders (Enoch et al, 1995; Enoch et al, 1999) and antisocial behavior (Ducci et al, 2009). …”

“…American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 150B , 359–368. doi: 10.1002/ajmg.b.30818 5 Ducci, F., Enoch, M. A., Yuan, Q., Shen, P. H., White, K. V., Hodgkinson, C., … Goldman, D. (2009). HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power--an intermediate phenotype for alcoholism and co-morbid behaviors.…”

Genetics of impulsive behaviour

“…Many pharmacological studies with serotonin 2A, 2B and 2C antagonists and agonists have implicated these receptors in impulsive behaviour [101]. Two subunits of serotonin type 3 receptors, 3A and 3B, have so far been identified; variation within the HTR3B gene was associated with alcohol use disorder in comorbidity with ASPD [102].…”

Bullying behaviour and criminality: A population-based follow-up study of adolescent psychiatric inpatients in Northern Finland

“…As it has been shown earlier that being a bully in childhood increases the risk of later antisocial personality disorder [14] and that antisocial personality disorder is known to be associated with habitual violent behaviour [15], we suggest that bullying among severely psychopathological adolescents may be a sign of a developing antisocial personality disorder which will manifest itself later in life. A novel and interesting topic for further research would be whether bullying behaviour shares a similar type of genetic background to that found in early-onset alcoholism with co-morbid antisocial personality disorder [16,17]?…”