A GABRA2 polymorphism improves a model for prediction of drinking initiation.

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Authors: Kuperman, Samuel; Chan, Grace; Kramer, John; Wetherill, Leah; Acion, Laura; Edenberg, Howard J; Foroud, Tatiana M; Nurnberger, John; Agrawal, Arpana; Anokhin, Andrey; Brooks, Andrew; Hesselbrock, Victor; Hesselbrock, Michie; Schuckit, Marc; Tischfield, Jay; Liu, Xiangtao
Year: 2017
Journal: Alcohol (Fayetteville, N.Y.)
PMID: 28847377
DOI: 10.1016/j.alcohol.2017.03.003
PMCID: PMC5657392

BACKGROUND: Survival analysis was used to explore the addition of a single nucleotide polymorphism (SNP) and covariates (sex, interview age, and ancestry) on a previously published model's ability to predict onset of drinking. A SNP variant of rs279871, in the chromosome 4 gene encoding gamma-aminobutyric acid receptor (GABRA2), was selected due to its associations with alcoholism in young adults and with behaviors that increased risk for early drinking. METHODS: A subsample of 674 adolescents (ages 14-17) participating in the Collaborative Study on the Genetics of Alcoholism (COGA) was examined using a previously derived Cox proportional hazards model containing: 1) number of non-drinking related conduct disorder (CD) symptoms, 2) membership in a high-risk alcohol-dependent (AD) family, 3) most best friends drank (MBFD), 4) Achenbach Youth Self Report (YSR) externalizing score, and 5) YSR social problems score. The above covariates along with the SNP variant of GABRA2, rs279871, were added to this model. Five new prototype models were examined. The most parsimonious model was chosen based on likelihood ratio tests and model fit statistics. RESULTS: The final model contained four of the five original predictors (YSR social problems score was no longer significant and hence dropped from subsequent models), the three covariates, and a recessive GABRA2 rs279871 TT genotype (two copies of the high-risk allele containing thymine). The model indicated that adolescents with the high-risk TT genotype were more likely to begin drinking than those without this genotype. CONCLUSIONS: The joint effect of the gene (rs279871 TT genotype) and environment (MBFD) on adolescent alcohol initiation is additive, but not interactive, after controlling for behavior problems (CD and YSR externalizing score). This suggests that the impact of the high-risk TT genotype on the onset of drinking is affected by controlling for peer drinking and does not include genotype-by-environment interactions.

#	Section	Preview
0	Introduction	Alcohol use is common among adolescents (Johnston, O'Malley, Miech, Bachman, & Schulenberg, 2016)…
1	Introduction	The literature delineates a number of predictors, categorical and quantifiable, linked to early…
2	Introduction	Schlosser, Lidral, & Reich, 1999; Legrand, McGue, & Iacono, 1999); relationships with antisocial…
3	Introduction	most of a subject's best friends drank, and if the subject smoked a cigarette before initiating…
4	Introduction	The current study's goal was to explore whether the inclusion of genetic information would further…
5	Introduction	individuals who were homozygous for this allele (Dick, Agrawal, et al., 2006). These data suggested…
6	Introduction	demonstrate an association between this SNP and the YSR externalizing score (Dick, Aliev,…
7	Materials and methods — Subjects and variables	Subjects were participants in the multi-site Collaborative Study on the Genetics of Alcoholism…
8	Materials and methods — Subjects and variables	To achieve our goal, the GABRA2 SNP rs279871 was selected following the rationale detailed in the…
9	Materials and methods — Subjects and variables	The SNP had a genotyping rate >96.5% and was in Hardy-Weinberg equilibrium in both the EA (p = 0.27)…
10	Materials and methods — Subjects and variables	To determine the contributions of interview age, sex, and ancestry, these variables were included in…
11	Materials and methods — Statistical analyses	Cox proportional hazards modeling using SAS PROC PHREG (SAS, 2011), with the COVSANDWICH (AGGREGATE)…
12	Materials and methods — Statistical analyses	(0 to 15); 3) YSR externalizing score (0 to 64); 4) YSR social problems score (0 to 22); and 5)…
13	Results — Subject characteristics	Table 1 provides the descriptive statistics of the nine variables of interest in the final sample of…
14	Results — Preliminary Analysis	Table 2 presents single-predictor Cox proportional hazards models for each of the five original…
15	Results — Main Analysis	The results of the five multi-predictor Cox proportional hazards models are shown in Table 3. Model…
16	Results — Main Analysis	became the new reference model when evaluating the impact of the chosen candidate SNP. Model 4…
17	Results — Main Analysis	Exploratory GXE interactions were performed for the variables and covariates in Model 5. After…
18	Results — Main Analysis	Closer examination of Model 5 (the last column in Table 3) indicated that the four binary predictor…
19	Results — Main Analysis	Using Model 5 to plot fitted cumulative incidence curves, Fig. 1 visually illustrates the relative…

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A GABRA2 polymorphism improves a model for prediction of drinking initiation.

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