Genome-wide association study identifies 5q21 and 9p24.1 (KDM4C) loci associated with alcohol withdrawal symptoms

Abstract

Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p < 10(-4). The first best signal was rs770182 (p = 3.65 × 10(-6)) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p < 10(-4) (p = 7.15 × 10(-6), 2.79 × 10(-5) and 4.93 × 10(-5), respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10(-4) in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10(-4) and 9.48 × 10(-5), respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p < 10(-2)) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS.

Epigenetic basis of the dark side of alcohol addiction

“…For example, histone H3 lysine 9 dimethylation and trimethylation (H3K9me2/3) and H3K27me3 are considered repressive marks to transcription, while H3K4me2/3 is considered a mark of actively transcribed chromatin (Kouzarides, 2007; Krishnan et al, 2014). Interestingly, genome-wide association studies (GWAS) have identified the genomic region encompassing the histone demethylase KDM4C gene as a hotspot associated with alcohol withdrawal symptoms (Wang et al, 2012). As research into the negative affective states seen during alcohol withdrawal and addiction continues, additional epigenetic modifications such as histone methylation, phosphorylation, and others may emerge as novel biomarkers of alcohol-induced anxiety in brain circuits such as the amygdala (Krishnan et al, 2014; Berkel and Pandey, 2017).…”

Emerging roles for chromatin as a signal integration and storage platform

“…Interestingly, a large number of causative genetic mutations have been found in genes encoding enzymes that catalyse the addition or removal of the trimethylation mark of Lys4 on H3 (H3K4me3) and H3K9me2 109, 110, 111–115 (see the table). Histones at the promoter regions of transcriptionally active genes are marked with H3K4me3.…”

The Epigenetic Landscape of Alcoholism

“…Histone methylation is a dynamic reversible process and is under the control of two opposing groups of enzymes-the lysine methyltransferases and the lysine demethylases (Kouzarides, 2007). Genome-wide association studies have found KDM4C (a lysine demethlyase of the jumonji domain 2 (JMJD2) family) loci associated with alcohol withdrawal (Wang, Liu, Zhang, Wu, & Zeng, 2012). Other drugs of abuse, such as cocaine, resulted in a reduction of G9a and G9a-like protein (GLP) (lysine dimethyltransferases), which corresponded to a decrease in H3K9me2, and an increase in spine density in the NAc and cocaine place preference, whereas overexpression was able to reverse these effects (Maze et al, 2010).…”