Genome-wide association studies of maximum number of drinks

Abstract

Maximum number of drinks (MaxDrinks) defined as “Maximum number of alcoholic drinks consumed in a 24-hour period” is an intermediate phenotype that is closely related to alcohol dependence (AD). Family, twin and adoption studies have shown that the heritability of MaxDrinks is approximately 0.5. We conducted the first genome-wide association (GWA) study and meta-analysis of MaxDrinks as a continuous phenotype. 1059 individuals were from the Collaborative Study on the Genetics of Alcoholism (COGA) sample and 1628 individuals were from the Study of Addiction – Genetics and Environment (SAGE) sample. Family sample with 3137 individuals was from the Australian twin-family study of alcohol use disorder (OZALC). Two population-based Caucasian samples (COGA and SAGE) with 1 million single-nucleotide polymorphisms (SNPs) were used for gene discovery and one family-based Caucasian sample was used for replication. Through meta-analysis we identified 162 SNPs associated with MaxDirnks (p < 10−4). The most significant association with MaxDrinks was observed with SNP rs11128951 (p = 4.27×10−8) near SGOL1 gene at 3p24.3. Furthermore, several SNPs (rs17144687 near DTWD2, rs12108602 near NDST4, and rs2128158 in KCNB2) showed significant associations with MaxDrinks (p < 5×10−7) in the meta-analysis. Especially, 8 SNPs in DDC gene showed significant associations with MaxDrinks (p< 5×10−7) in the SAGE sample. Several flanking SNPs in above genes/regions were confirmed in the OZALC family sample. In conclusions, we identified several genes/regions associated with MaxDrinks. These findings can improve the understanding about the pathogenesis of alcohol consumption phenotypes and alcohol-related disorders.

Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking

“…It is unknown how K V 2.1 channels and its modifiers influence excitability of accumbens neurons or if ethanol dependence affects their function or expression in the PFC or NAc. However, intriguing evidence from a meta-analysis using samples from the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genetics and Environment (SAGE) revealed that two SNPs in KCNB1 (rs2128158 and rs2929567) showed significant associations with maximum number of alcoholic drinks consumed in a 24 hr period (Pan et al, 2013). Given these converging lines of evidence, future studies should determine if ethanol-induced dysregulation of or genetic polymorphisms in K V 2.1 channels and their modifiers/silencers impact risk for developing an alcohol use disorder.…”

“…For example, individuals with SNPs in OPRM1 , HTR3A/B , or GRIK1 genes moderate the reduction in heavy drinking by naltrexone, ondansetron, and topiramate treatment, respectively (Anton et al, 2008; Johnson, Seneviratne, Wang, Ait-Daoud, & Li, 2013; Kranzler, Armeli, et al, 2014; Kranzler, Covault, et al, 2014; Oslin et al, 2003). There is evidence that SNPs in KCNB1 , KCND2 , KCNJ6 , KCNMA1 , and KCNQ1/5 are associated with alcohol dependence or increased risk for developing an alcohol use disorder (Buhler et al, 2015; Clarke et al, 2011; Edenberg et al, 2010; Kendler et al, 2011; Namkung, Kim, & Park, 2005; Pan et al, 2013; Zuo et al, 2012). This emerging evidence that K + channel transcript levels correlate with drinking and polymorphisms in K + channels are related to alcohol dependence implicate select K + channels that may cause or maintain heavy alcohol intake and may represent a new relevant set of biomarkers for alcohol dependence.…”

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

“…The gene encoding the K V 2.2 channel protein, KCNB2, was found in a ciseQTL for alcohol consumption, and two SNPs in the KCNB2 gene are associated with maximum number of drinks consumed in 24 h [102]. Additionally, transcript levels of the gene encoding the K V 2.1 chan nel protein, KCNB1, was increased in hippo campus from alcoholic postmortem brain [103], and expression of both KCNB1 and KCNB2 in the superior frontal gyrus were strongly associated with lifetime drinking in alcoholics [78].…”

Les addictions sous l’angle de la génétique

“…L'analyse récente de cohortes américaines confirme l'association de la dépendance à l'alcool avec des variants qui changent des acides aminés des produits des gènes ADH1B et ADH1C [23]. D'autres métaanalyses de GWAS déjà publiées confirment l'implication des gènes que nous venons de décrire, et en identifient de nouveaux ainsi que de nouvelles voies neurobiologiques intervenant dans l'addiction à l'alcool et dans diverses pathologies qui lui sont associées [23,24].…”