Molecular genetics of addiction vulnerability

Abstract

Summary:Classical genetic studies document strong complex genetic contributions to abuse of multiple addictive substances, to mnemonic processes that are likely to include those involved in substance dependence, and to the volumes of brain gray matter in regions that are likely to contribute to mnemonic/ cognitive and to addictive processes. The working idea that these three heritable phenotypes are likely to share some of the same complex genetic underpinnings is presented. This review contains association-based molecular genetic studies of addiction that largely derive from my laboratory and their fit with linkage data from other laboratories. These combined results now identify many of the loci and genes that contain allelic variants that are likely to provide the heritable components of human addiction vulnerability. These data are also likely to have broad implications for neurotherapeutics. Drugs with potential abuse liabilities are widely used for indications that include pain, anxiety, sleep, seizure, and attentional disorders. There is increasing nonmedical use of these prescribed substances. Increasing information about addiction vulnerability gene variants should help to improve management of risks of dependence in individuals who receive such therapeutics. In addition, since mnemonic components that correlate well with individual differences in brain regional volumes are likely to play major roles in addiction processes, many addiction vulnerability genes are also good candidates to contribute to individual differences in mnemonic processes. Recently elucidation of addiction-associated haplotypes for the "cell adhesion" Nr-CAM gene illustrate several of these points.

Matrix Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma

“…We have focused on the 30 genes for which the differences between dependent and control individuals enhance the convergence of results previously obtained from four other abuser vs control whole genome association studies. The identification of allelic associations within so many genes that encode cell adhesion and extracellular matrix molecules support important roles for neuronal connectivities and memory-like functions in individual differences in vulnerabilities to addictions [32]. Data for each of these 30 genes provides new information about vulnerability to nicotine dependence.…”

Genome-Wide Association for Methamphetamine Dependence

“…The classes of genes identified and convergence with results from other GWA studies point toward substantial roles for individual differences in mnemonic, as well as rewarding, brain systems and individual differences in vulnerability to methamphetamine dependence. 20 The reliability and validity of the current approach are supported by many lines of evidence. These include data for clinical assessments made by multiple observers, the reliability and validity of the microarray-based genotyping approaches used herein, 32,52,57,62 the extent to which the markers that displayed nominally positive differences between abusers and controls clustered together in specific chromosomal regions, the extent to which observations made in these 2 samples converge with each other, and the extent to which these results converge with those from other studies that compare dependent vs control individuals.…”

“…The identification of this and other genes whose variants are good candidates to contribute to mnemonic aspects of addiction support the view that substantial components of the individual difference in vulnerability to dependence on addictive substances relate to individual differences in mnemonic systems. 20 The convergence between the genes identified by these samples and by genes identified in previous GWA studies for dependence on other legal and illegal addictive substances supports roles for allelic variants that are well represented in chromosomes from African, European, and Asian racial/ethnic groups. 32,57 Genes identified by these methamphetamine-dependence studies, but not as strongly by any of these other GWA comparisons, are also of interest.…”

“…We may improve understanding of the relative contributions of variants in the brain systems that underlie reward vs mnemonic components of addictions, for example. 20 Increasing our ability to determine which constellation of genetic and environmental factors plays a role in the methamphetamine dependence of each affected individual should improve "personalized" targeting of treatment and prevention efforts to those most likely to benefit from them.…”

“Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice

“…A genetic architecture with modest individual contributions from variants at a number of loci that are likely to exert influences in each addicted individual supports use of association based approaches. Genome wide association (see below) seems to be the best way to aid in defining which reported linkage results are more or less likely to be "real", eg to represent reproducible observations (reviewed in [61][62][63][64][65][66][67])…”