Early-Life Adversity and Blunted Stress Reactivity as Predictors of Alcohol and Drug use in Persons With COMT (rs4680) Val158Met Genotypes

Abstract

Background: Risk for alcoholism may be enhanced by exposure to early-life adversity (ELA) in persons with genetic vulnerabilities. We examined ELA in the presence of a common variant of the gene for the enzyme catechol-O-methyltransferase (COMT, Val158Met, rs4680) in relation to cortisol reactivity, the onset of early drinking, and experimentation with drugs.

Methods: Saliva cortisol reactivity to speech and mental arithmetic stress was measured in 480 healthy young adults (23.5 years of age, 50% females) who experienced either 0, 1, or ≥ 2 forms of ELA during childhood and adolescence, provided information on use of alcohol and recreational drugs, and were genotyped for the Val158Met polymorphism.

Results: ELA led to progressively smaller cortisol responses in the Met/Met and Val/Met allele groups but to progressively larger responses in Val homozygotes, F = 3.29, p = 0.011. ELA independently predicted earlier age at first drink, F = 14.2, p < 0.0001, with a larger effect in Met-allele carriers, F = 13.95, p < 0.00001, and a smaller effect in Val homozygotes, F = 4.14, p = 0.02. Similar effects were seen in recreational drug use. Cortisol reactivity was unrelated to drinking behavior or drug experimentation.

Conclusions: ELA leads to blunted stress reactivity and, independently, contributes to potentially risky drinking and drug-use behaviors in persons carrying 1 or 2 copies of the COMT 158Met allele. The results reinforce the impact of early experience on the stress axis and on risky behaviors, and they point to the 158Met allele as conveying a vulnerability to the early environment.

Keywords: Catechol-O-Methyltransferase; Cortisol; Dopamine; Drinking Behavior; Early-Life Adversity; Genotype; Stress.

Figure 1

Cortisol saliva measurements at home and during visits to the laboratory. Panel A: Cortisol stress responses in ELA exposure groups (0, 1, ≥ 2) who were Met vs. Val/Val carriers of COMT rs4680 on a stress day referenced to a nonstress control day. Panel B: Cortisol values on a nonstress control day (dashed lines) and on a stress day (solid lines) for Met and Val/Val allele groups. Cortisol measurement time points are: AM, immediately upon awakening; Pre, upon arrival at the lab; BL1, BL2, 30 min and 15 min prior to the onset of the stress procedure or comparable time on the resting control day; STRS1, at the start of the stress protocol, STRS2, following speech presentations, and STRS3, the end of the stress protocol, or the comparable time points on the resting control day; Rec, 45 min after the end of the stress protocol or comparable time point on the resting control day; PM, at bedtime. Panel C: Cortisol stress responses for ELA groups x separate allele groups. Panel D: Data from Panel C rearranged to show the effect of Val158Met genotypes within ELA groups. Figure labels. 0, 1, ≥ 2 indicates the number of childhood adversities experienced in childhood and adolescence. Met and Val refer to single nucleotide polymorphisms of COMT.

Figure 2

Drinking and drug use variables. Age at first drink and the number of recreational drugs the volunteers reported ever having tried. P-values refer to F ratios of stratified comparisons of ELA groups within genotype. Figure labels as in Figure 1.