Molecular Genetics of Addictions

Abstract

Addictions to both licit and illicit drugs are common chronic brain disorders that are extremely costly to the individuals and society. Although genetics contributes significantly to vulnerability to these affective disorders, the susceptibility genes underlying them are largely unknown. Various genetics approaches including genome‐wide linkage, candidate gene association, GWAS and sequencing analysis have implicated several common genomic regions and genes in the aetiology of addiction to multiple substances. For example, variants in the α2 subunit of GABAA receptor have been found repeatedly in association with alcoholism and alcohol‐related phenotypes. A gene cluster on chromosomes 15q24/q25.1 that encompasses the genes for nicotine acetylcholine receptor subunits α5, α3 and β4 was implicated in addiction to tobacco and other substances as well. Current efforts aim not only to replicate these findings in independent samples but also to determine the functional mechanisms of these associations.

Key Concepts

  • Drug addiction is a chronic brain disorder.
  • Both human and animal studies reveal that addiction is determined not only by genetic and environmental factors but also by their interactions.
  • There exist significant genetic overlaps among addictions to different substances.
  • It is important to determine not only genetic but also environmental factors involved in the aetiology of addictions.
  • Various genomic regions have been revealed to harbour susceptibility loci for multiple addictive disorders.
  • Genes such as those encoding GABA‐A and GABA‐B receptor subunits, neurexins 1 and 2 and some nicotinic receptor subunits are revealed to be associated with addictions.
  • Determination of gene–environmental interactions is as important and challenging as determining gene–gene interactions.
  • Small microRNAs may play important roles in the mediation of expression of genes implicated in addictions.

Keywords: genetics; addiction; dependence; alcohol; smoking; opioid; interaction

Figure 1. A summary of chromosomal locations of nominated peaks or intervals for addictions to alcohol, cannabis, cocaine, heroin, nicotine and their related phenotypes with ‘significant’ or ‘suggestive’ evidence of linkage by independent studies based on at least two substances of abuse. The determination of ‘significant’ or ‘suggestive’ evidence of linkage at each linkage peak was based on the rigorous criteria proposed by Lander and Kruglyak , which defines an LOD of >3.6 or a P value of <2.2 × 10−5 as a ‘significant linkage’ and an LOD of >2.2 but <3.6 or a P value of 7.4 × 10−4 as a ‘suggestive’ linkage. Each linkage is given either with a colour‐filled circle or a triangle representing a reported linkage peak or region, respectively. Each colour represents a type of abused substance that could come from the same or different reports/studies. The ‘units’ for each chromosome is ‘cM’. Partial contents of this figure have been reported in Li and Burmeister 2009 © Nature Publishing Group.
Figure 2. The ND genetic susceptibility map with nominated linkage peaks and candidate genes, as suggested by genome‐wide linkage, hypothesis‐driven candidate gene association (CAS), genome‐wide association (GWAS), and targeted sequencing (next‐generation sequencing; NGS) studies. Linkage peaks are marked in light grey; CAS, GWAS and NGS results are presented as gene names at the outer, middle and inner rings, respectively. Adapted from Yang and Li 2016 © Nature Publishing Group.
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Yang, Zhongli, and Li, Ming D(Aug 2017) Molecular Genetics of Addictions. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022425.pub2]