Genetic studies of alcohol dependence in the context of the addiction cycle

Abstract

Family, twin and adoption studies demonstrate clearly that alcohol dependence and alcohol use disorders are phenotypically complex and heritable. The heritability of alcohol use disorders is estimated at approximately 50–60% of the total phenotypic variability. Vulnerability to alcohol use disorders can be due to multiple genetic or environmental factors or their interaction which gives rise to extensive and daunting heterogeneity. This heterogeneity makes it a significant challenge in mapping and identifying the specific genes that influence alcohol use disorders. Genetic linkage and (candidate gene) association studies have been used now for decades to map and characterize genomic loci and genes that underlie the genetic vulnerability to alcohol use disorders. These approaches have been moderately successful in identifying several genes that contribute to the complexity of alcohol use disorders. Recently, genome-wide association studies have become one of the major tools for identifying genes for alcohol use disorders by examining correlations between millions of common single-nucleotide polymorphisms with diagnosis status. Genome-wide association studies are just beginning to uncover novel biology; however, the functional significance of results remains a matter of extensive debate and uncertainty. In this review, we present a select group of genome-wide association studies of alcohol dependence, as one example of a way to generate functional hypotheses, within the addiction cycle framework. This analysis may provide novel directions for validating the functional significance of alcohol dependence candidate genes. This article is part of the Special Issue entitled “Alcoholism”.

Early‐life risk for domestic violence perpetration: Implications for practice and policy

“…This suggests similar patterns of genetic influence on the effects of early maltreatment on later domestic violence perpetration, a possibility once supported by one of the coauthors in the Caspi et al (2002) study (T. Moffitt, personal communication, November 11, 2002. In addition, the heritability of disorders with known associations with domestic violence, including antisocial personality (Ferguson, 2010), borderline personality (Few et al, 2014), and alcohol use (Reilly, Noronha, Goldman, & Koob, 2017), suggests a range of indirect genetic risk pathways.…”

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcript variants by excessive ethanol drinking and dependence

“…Excessive ethanol drinking is a leading cause of preventable death and was estimated to cost the U.S. $249 billion in 2010, $100 billion of which was paid for by the government (1,2). There are genetic factors that increase the propensity for risky drinking (3,4), and genetic background influences the efficacy of treatment options for individuals with AUD (5). In addition, prolonged excessive ethanol intake produces neuroadaptations in projection neurons and neural circuits that are proposed to sustain heavy drinking (6)(7)(8).…”

“…Blocking KCa2 channels in the NAcC with apamin increased voluntary ethanol drinking in mice (13), whereas increasing KCa2 channel function with positive modulators reduced home cage drinking and operant self-administration (11,17). Importantly, the ability of apamin to inhibit KCa2 channel function was completely lost in NAcC MSNs from ethanol 4 dependent mice, but not in rats that had access to 7-weeks of operant self-administration of moderate amounts of ethanol (11). Together, these studies identified KCNN3 as a potential regulator of ethanol consumption and revealed NAcC neuroadaptations in KCa2 channel function that may drive excessive drinking in preclinical rodent models of chronic ethanol exposure.…”

Cross-species molecular dissection across alcohol behavioral domains

“…Strong evidence from family and twin studies demonstrates that alcohol dependence and AUD are phenotypically complex with heritability estimated at approximately 50–60% of total phenotypic variability (Reilly, Noronha, Goldman & Koob, 2017). This degree of heritability is consistent with the polygenic nature of AUD, which includes numerous loci with small effect size.…”