The Genetics, Neurogenetics and Pharmacogenetics of Addiction

Abstract

Addictions are prevalent psychiatric disorders that confer remarkable personal and social burden. Despite substantial evidence for their moderate, yet robust, heritability (approx. 50%), specific genetic mechanisms underlying their development and maintenance remain unclear. The goal of this selective review is to highlight progress in unveiling the genetic underpinnings of addiction. First, we revisit the basis for heritable variation in addiction before reviewing the most replicable candidate gene findings and emerging signals from genomewide association studies for alcohol, nicotine and cannabis addictions. Second, we survey the modest but growing field of neurogenetics examining how genetic variation influences corticostriatal structure, function, and connectivity to identify neural mechanisms that may underlie associations between genetic variation and addiction. Third, we outline how extant genomic findings are being used to develop and refine pharmacotherapies. Finally, as sample sizes for genetically informed studies of addiction approach critical mass, we posit five exciting possibilities that may propel further discovery (improved phenotyping, rare variant discovery, gene-environment interplay, epigenetics, and novel neuroimaging designs).

Multigenerational and transgenerational inheritance of drug exposure: The effects of alcohol, opiates, cocaine, marijuana, and nicotine

“…In addition alcohol mediates increased dopamine and opioid release. Genetic variation in GABRA2 , the gene encoding for the alpha 2 subunit of the GABA A receptor has been associated with alcohol dependence in humans and alcohol response in animals (Demers et al, 2014). In addition, polymorphisms in alcohol dehydrogenase and aldehyde dehydrogenase are associated with alcohol consumption; both genes encode for enzymes responsible for metabolism of alcohol.…”

“…In addition, polymorphisms in alcohol dehydrogenase and aldehyde dehydrogenase are associated with alcohol consumption; both genes encode for enzymes responsible for metabolism of alcohol. Interestingly, variation in alcohol dehydrogenase and dopamine receptor or dopamine transporter genes has been found to epistatically influence alcohol dependence (reviewed in Demers et al, 2014). Finally, there is evidence to suggest that genetic variation in serotonin, opioid, and other neuromodulatory systems can affect alcohol use (reviewed in Kreek et al, 2004).…”

“…Polymorphic variation in the gene that codes for cannabinoid receptor 1 ( CNR1 ) has been implicated in marijuana craving during times of abstinence and withdrawal (Demers et al, 2014). In addition, polymorphic variation in CYP2C9, a member of the cytochrome family of enzymes responsible for the metabolism of Δ9-THC, results in greater active metabolite and heightened sensitivity to the sedative effects of marijuana (Sachse-Seeboth et al, 2008).…”

Addiction and crime: The importance of asymmetry in offending and the life-course

“…The readership of JAD is well-versed in the addiction-related themes, such as contemporary notions of addiction as a brain disease and associated "hijacking" of the reward pathway [5][6][7] and that there is genetic vulnerability to addiction. 8 The relationship between addiction and crime, however, might not be so readily apparent or discussed in the addictions literature. The first is that crime is asymmetrical; that is, a small subset of individuals account for the majority of offenses.…”

Is Sugar a Gateway Drug?

“…Heritability for addiction has been estimated at 50% [45] with multiple genes contributing to this predisposition.…”