Associations of GABAA receptor gene variations with alcohol use disorder and conduct disorder phenotypes in Korean-, Chinese-, and European-American college students

Aims: This study aimed to determine whether gamma-aminobutyric acid (GABAA) receptor gene variations differed across individuals of Korean, Chinese, and European ancestry and to test for genes associations with four phenotypes: alcohol dependence diagnosis, alcohol use disorder (AUD; alcohol abuse and dependence) symptom count, conduct disorder diagnosis, and conduct disorder symptom count. Methods: Male and female college students (n=1,310) were genotyped for ALDH2, ADH1B, and 21 SNPs spanning four GABAA receptor genes, GABRA2, GABRA4, GABRA1, and GABRG3. Phenotypes were assessed using DSM-IV criteria. Complete genotypic and phenotypic data were available for 1,154 participants. Results: There were significant differences in the allele frequencies of ALDH2, ADH1B, and all 21 GABAA receptor gene SNPs across individuals of Korean, Chinese, and European ancestry. Four GABRA2 SNPs were significantly associated with lifetime AUD symptoms in Korean-American men. Three GABRG3 SNPs were significantly associated with conduct disorder diagnosis in Korean-American men. Conclusion: Results suggest significant variation across ancestry in GABAA receptor genes and that there may be varied associations with phenotypes in different ancestral groups. These findings highlight the need for replication and increased understanding of the mechanism underlying putative associations of GABAA receptor gene variation with AUD and conduct disorder phenotypes. Correspondence to: Tamara L. Wall, Ph.D., VA San Diego Healthcare System, Psychology Service (116B), 3350 La Jolla Village Drive, San Diego, CA 92161. Tel. : 858-552-8585, E-mail: twall@ucsd.edu Received: June 12, 2016; Accepted: July 28, 2016; Published: August 02, 2016 Introduction The etiology of alcohol use disorders (AUDs; alcohol abuse and dependence) includes genetic and environmental influences. Twin studies using samples of primarily European ancestry indicate 5060% of the variability in alcohol dependence is explained by the combined effects of multiple genes [1,2]. However, rates of AUDs differ substantially by sex and in different populations [3]. In particular, Asians in the U.S. have lower rates of AUDs than Whites, Blacks, Native Americans, and Hispanics [3,4]. Two genetic variants, ALDH2*2 (rs671) and ADH1B*2 (rs1229984), are found predominantly in Asian populations and associated with lower rates of alcohol dependence [5-7]. The hypothesized mechanism underlying the associations of ALDH2*2 and ADH1B*2 with alcohol dependence is that the isoenzymes encoded by these alleles lead to increased acetaldhyde and enhanced reactions to alcohol, which then reduces heavy drinking and AUDs [8]. As an aggregated group, Asians in the U.S. have lower rates of AUDs [3], but there are substantial differences across subgroups [9,10]. In a large cross-national study, the lifetime rate of alcohol abuse and dependence was 23% for South Koreans (43% of men, 3% of women) and 7% for Taiwanese (13% of men, 0.7% for women) compared with 17% for Americans (29% of men, 4% of women) [9]. This large difference in lifetime AUD rates between South Koreans and Taiwanese is similar, but more pronounced, to rates found in more recent epidemiologic studies in Asia and the U.S. [10-12]. Consistent with epidemiologic data, a study from our laboratory found ChineseAmerican college students had lower rates of alcohol dependence (8% of men, 2% of women) than Korean-American (18% of men, 8% of women) and European-American (22% of men, 12% of women) college students [13]. In most cultures, men have higher rates of AUDs than women, but the sex discrepancy is particularly pronounced in many Asian groups [3,9] and may be due, in part, to societal, familial, and peer pressures on women not to drink. In support of this hypothesis, the male-to-female AUD ratio in South Korea and China has decreased as Westernization has occurred [14,15]. These findings suggest the possibility that the Orlowska D (2016) Associations of GABAA receptor gene variations with alcohol use disorder and conduct disorder phenotypes in Korean-, Chinese-, and EuropeanAmerican college students Volume 1(3): 54-59 Biomed Genet Genomics, 2016 doi: 10.15761/BGG.1000111 relative influence of genetics on AUDs in Asian men and women may differ from that found in studies of predominantly European men and women [2] and could vary over time. In our prior study of Korean-, Chinese-, and European-American college students, analyses indicated that the relationship of ancestry with alcohol dependence was mediated by ALDH2 gene status and conduct disorder, although Chinese ancestry remained significant [13]. ADH1B gene status was not related to alcohol dependence with ALDH2 included in the analyses and no interactions were significant. These results suggest that different rates of risk (e.g., conduct disorder) and protective (e.g., ALDH2 status) factors account for some the variability in rates of alcohol dependence between Korean, Chinese, and European Americans. One set of genes that might contribute to differences in rates of AUDs and conduct disorder observed between Koreans, Chinese, and Europeans are the gamma-aminobutyric acid (GABAA) receptor genes. Multiple reports have identified associations between single nucleotide polymorphisms (SNPs) of the GABAA receptor genes with AUD and/ or conduct disorder phenotypes. For the current study, we selected 21 SNPs spanning four GABAA receptor genes, GABRA2 (chromosome 4), GABRA4 (chromosome 4), GABRA1 (chromosome 5), and GABRG3 (chromosome 15) based on prior significant associations with either AUD phenotypes [16-36] or conduct disorder phenotypes [20,34,3638]. It is important to note that the majority of these reports were case-control studies, which have greater power to detect significant associations than general population studies. In addition, few, if any, participants of Asian descent were included in these prior investigations and not all studies examining the same SNPs have reported consistent associations [23,27,29,31,34,39,40]. To date, no functional variants have been identified that account for the associations of the GABAA receptor genes with AUDs and/ or conduct disorder, and the mechanism of action of these gene associations is unknown. Some investigators have hypothesized that GABRA2 SNPs may exert their effect on alcohol dependence via differences in levels of response to alcohol [32,33]. Roh and colleagues [33] assessed a Japanese sample and stratified by ALDH2 genotype. Individuals heterozygous and homozygous for several GABRA2 variants were more sensitive to the effects of alcohol irrespective of their ALDH2 genotype. This finding suggests that GABRA2 variation, similar to ALDH2 variation, may contribute to individual variability in response to alcohol. Other investigators have hypothesized GABRA2 variants might relate to alcohol dependence and conduct disorder via general externalizing pathways given associations of several SNPs not only with alcohol phenotypes, but also with conduct disorder, antisocial personality disorder, and other (non-alcohol) drug dependencies [20,31,37,39]. To extend our prior research [13], we genotyped for ALDH2, ADH1B, and 21 SNPs spanning four GABAA receptor genes, GABRA2, GABRA4, GABRA1 and GABRG3 and tested for associations with both AUD and conduct disorder phenotypes in a larger sample of Korean-, Chinese-, and European-American college students. We hypothesized that there would be differences in the allele frequencies of GABAA receptor genes across ancestry but not across sex. Given that genetic and environmental influences may differ across groups and across phenotypes, we conducted analyses separately by ancestry and sex and analyzed both dichotomous (i.e., diagnosis) and continuous (i.e., symptom count) outcomes [41]. Based on prior investigations, we hypothesized that there would be significant associations between GABAA receptor gene SNPs and two AUD phenotypes (alcohol dependence diagnosis, AUD symptom count) controlling for variation in the ALDH2 and ADH1B genes. We also hypothesized that there would be significant associations between GABAA receptor gene SNPs and two conduct disorder phenotypes (diagnosis and symptom count).