Independent and Interactive Effects of OPRM1 and DAT1 Polymorphisms on Alcohol Consumption and Subjective Responses in Social Drinkers.

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Authors: Weerts, Elise M; Wand, Gary S; Maher, Brion; Xu, Xiaoqiang; Stephens, Mary Ann; Yang, Xiaoju; McCaul, Mary E
Year: 2017
Journal: Alcoholism, clinical and experimental research
PMID: 28376280
DOI: 10.1111/acer.13384
PMCID: PMC5483245

BACKGROUND: The current study examined independent and interactive effects of polymorphisms of the mu opioid receptor gene (OPRM1, A118G) and variable number tandem repeats of the dopamine transporter gene (DAT1, SLC6A3) on alcohol consumption and subjective responses to alcohol in 127 young, healthy, social drinkers. METHODS: Participants completed an in-person assessment, which included self-reported alcohol drinking patterns and blood sampling for DNA, and in a second visit, a cumulative alcohol dosing procedure with subjective ratings across multiple time points and breath alcohol contents (0.03 to 0.1%). DNA was analyzed for OPRM1 AA versus AG/GG (*G) genotypes, DAT1 10-repeat allele (A10) versus 9 or lesser alleles (A9), and ancestral informative markers. RESULTS: There were significant epistatic interactions between OPRM1 and DAT1 genotypes. Subjective High Assessment Scale scores after alcohol consumption were highest in *G and A9 carriers, and lowest in *G and A10 carriers. Negative subjective effects were also highest in *G and A9 carriers. Effects were similar in a sensitivity analysis limited to Caucasian subjects. There were independent and epistatic interactions on drinking. The OPRM1 *G allele was independently associated with fewer heavy drinking days. The A9 allele was associated with a greater number of drinking days, which was attenuated in carriers of the *G allele. CONCLUSIONS: These findings highlight the biological importance of interactions between these 2 genes and interactions between brain opioid and dopamine systems.

Figure 1

Breath Alcohol Content (BAC) during the cumulative alcohol dosing procedure. Data are mean +SEM BAC for each genotype subgroup as determined at baseline, 15 min after consumption of each drink, and at 45-minute intervals for the remainder of the session. The x-axis is the time line for the session, and administration times of the placebo drink (P) and each active alcohol drink (A1, A2, A3) are indicated with arrows. Data points are slightly displaced on the x-axis for visual clarity.

Figure 2

Mean total SHAS scores reported at each time point during the cumulative alcohol dosing procedure. The x-axis is the time line for the session, and administration times of the placebo drink (P) and each active alcohol drink (A1, A2, A3) are indicated with arrows. Data are adjusted means (SEM) for each of the genotype subgroups. Means were adjusted for sex, AIMs and number of drinking days.

Figure 3

Mean DEQ VAS negative scores reported at each time point during the cumulative alcohol dosing procedure. Other details as in Figure 2.

Figure 4

Mean total scores for A. stimulation and B. sedation subscales of the Biphasic Alcohol Effects Scale (BAES), C. positive effects on the Drug Effects Questionairre Visual Analog Scale (DEQ VAS), and D. the Tension and Anxiety subscale of the Profile of Mood States scale (POMS T&A) as reported at each time point during the cumulative alcohol dosing procedure. Other details as in Figure 2.

#	Section	Preview
0	Introduction	Alcohol use disorder (AUD) has a strong genetic component with heritability estimates of about 50%…
1	Introduction	One of the most common variants encoding the mu opioid receptor gene (OPRM1, gene ID 4988,) is a…
2	Introduction	As reviewed by Gardner (2011), the primary reward circuitry consists of an ‘in-series’ circuit…
3	Introduction	accumbens increases extracellular DA in the nucleus accumbens (Gianoulakis, 2009). DAergic…
4	Introduction	One possible source of the variability in prior studies examining the role of the A118G SNP in…
5	Introduction	Indeed, there is some evidence for functional interactions of the OPRM1 gene and the DA system. In…
6	Introduction	Building on this prior research the current study focused on whether DAT1 A9 and A10 genotypes…
7	Introduction	the current study were genotyped for both DAT1 (A9 vs A10) and OPRM1 (AA vs *G) genotypes after…
8	Materials and Methods — Subjects	Male and female healthy volunteers between the ages of 21 and 30 were recruited for participation…
9	Materials and Methods — Subjects	panel, and urinalysis), and an alcohol breathalyzer test and urine toxicology screen. Recent…
10	Materials and Methods — Subjects	To minimize adverse reactions to alcohol administration, nondrinkers were excluded from study…
11	Materials and Methods — Laboratory Alcohol Sensitivity Procedures	On the session day, subjects arrived in the morning (9 am) and completed a urine toxicology screen,…
12	Materials and Methods — Cumulative Alcohol Dosing (CAD)	CAD was initiated between 11am and 12pm. Subjects consumed 1 placebo drink followed by 3 active…
13	Materials and Methods — Cumulative Alcohol Dosing (CAD)	for expectation of alcohol effects that are independent of pharmacological effects of alcohol.…
14	Materials and Methods — Determination of Breath Alcohol Content (BAC)	BAC was measured 15 minutes after consumption of placebo (+25) and each alcohol drink (+ 70, +115,…
15	Materials and Methods — Subjective response Assessment Instruments	During the alcohol sensitivity procedure, subjects completed the Biphasic Alcohol Effects Scale…
16	Materials and Methods — Genotyping and Ancestry Informative markers (AIM)	A total of 85 males and 42 females (n=127) completed the alcohol sensitivity sessions, consented to…
17	Materials and Methods — Genotyping and Ancestry Informative markers (AIM)	and assumed a model with the possibility of admixture and correlated allele frequencies between…
18	Materials and Methods — Genotyping and Ancestry Informative markers (AIM)	OPRM1 A118G SNP genotypes in our sample included A/A (n=94), A/G (n=31) and G/G (n=2). In these same…
19	Materials and Methods — Statistical Analyses	The choice of statistical modeling was based on distribution of the data, and the assumptions of the…

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