Paul R. Buckland

Aim  To assess the likelihood of finding genes which predispose to addiction and to present this information in a form accessible to the general readership of Addiction.Methods  Review of the evidence that genetic factors play a significant role in the process of addiction and the proximity of the identification of these factors.Results  The search for the genetic susceptibility variants for many complex illnesses has been ongoing for decades, with increased pace in the last 20 years. However, until very recently only a small number of such variants have been found. Recent studies have used several thousand samples in genome‐wide association studies and the latest genotyping technology and have reported a growing number of successes, but have highlighted the need for even larger samples and new statistical methods or new experimental approaches to identify fully the genes involved in the disease process. The phenotype for addiction to drugs is not well defined, and the heritability of addiction to drugs of abuse is far from clear and may be small compared to that of many other complex disorders. The absolute requirement for the administration of drugs before addiction can occur, and other environmental factors known to have a major effect, makes the selection of both probands and controls challenging for genetic studies. Many candidate genes put forward so far as susceptibility genes may be unrelated to the underlying process referred to as addiction but, rather, are related to the propensity to take drugs in the first place.Conclusions  It is the underlying biological process which changes to an alternative state following addiction, which is the target of investigation, and it is not clear that even genome‐wide association studies with sample sizes a magnitude greater than those reported so far would identify the genes involved which have the largest effect. Ultimately, modern neurobiological approaches may identify this process and the genes involved, and even at this stage identifying the susceptibility variants will require both biological as well as genetic analysis.

A considerable proportion of heritable human phenotypic variation is thought to result from altered gene expression. Unfortunately, it is currently impossible to use bioinformatic analysis to discriminate between DNA sequence variants that are likely to influence gene expression and those that are not. In an attempt to define some of the characteristics of promoter polymorphisms with functional effects on gene expression, we examined 674 haplotypes representing 247 unique gene promoters using a standardized reporter gene assay system. Sequence variants that altered gene expression by 1.5-fold or more were strongly biased toward a location in the core and proximal promoter regions, 50% being within the first 100 bases 5′ to the transcription start site. No bias was seen in the allele frequencies of functional and nonfunctional sequence variants. Only 33% of the functional variants were found in known consensus transcription factor binding sequences or motifs, which suggests that either there are many unknown transcription factor binding motifs or other, unknown mechanisms are involved. The genes with functional polymorphisms that are reported here for the first time include AGTRL2, CAT, CHRNA5, CTSG, CYP2D6, DLD, ERCC1, GABRA1, GABRP, HNRPH3, HIP1, IGKV1-9, KCNJ15, KCNK6, KLK1, MSMB, MYOC, NPY2R, NOTCH4, ORM2, PEDF, PTPRCAP, ST16 (IL24), SULT1A1, and TSHR. Hum Mutat 26(3), 214–223, 2005.

Association has been reported between the C allele of a -759C/T polymorphism in the promoter of the 5-HT2C receptor gene (HTR2C) and antipsychotic-induced weight gain, suggesting that polymorphic HTR2C expression influences this phenotype. The authors tested this polymorphism, and other promoter variants, for effects on HTR2C transcription. Six HTR2C promoter haplotypes constructed from four polymorphisms were cloned into a luciferase reporter gene plasmid. Their transcriptional activities were then compared in two human cell lines. All haplotypes containing the -759C allele showed less transcriptional activity than haplotypes containing the -759T allele. The A allele of a -997G/A polymorphism was also associated with reduced expression. These findings suggest that the -759C allele is functional and results in relative underexpression of HTR2C. Reduced expression of HTR2C mRNA may underlie vulnerability to weight gain following antipsychotic treatment.

In the last decade, the search for the genetic origins of phenotypic variation has expanded beyond the non-synonymous variants which alter the amino acid sequence of the encoded protein, and many examples of sequence variants which alter gene expression have been found. Recently, using both traditional and novel technologies, a number of surveys have been carried out to examine the frequency with which cis-acting sequence variants or other cis-acting effects, alter gene expression either in vitro or in vivo. Microarray data have shown that the expression of many genes varies markedly between individuals and allele-specific expression studies have shown that the source of much of this variation appears to be cis-acting effects. A significant proportion of the variation may originate in gene promoter regions and a large number of sequence variants which have functional effect in vitro have been found. The evidence suggests that given a large enough population, most, if not all genes may have allele-specific expression differences in at least some individuals and finding the genetic origins of each of these and linking the former to a possible phenotype must be a major long term goal of the biomedical community.

A number of disorders are known to be caused by duplication of genes, but these are all rare events. However, there is evidence that polymorphic gene duplication may be common and a growing number of genes are known to be duplicated in a polymorphic manner although phenotypes cannot be associated with most of these. Gene duplication occurring due to cytogenetic abnormalities such as Down syndrome predisposes the patients to a variety of complex disorders. It is possible therefore that many complex disorders and variable phenotypes are associated with duplication of genes.

We have developed a rapid method for identifying functional promoter-region polymorphisms. Using a modified pGL3 luciferase expression T-vector, we can amplify by PCR, clone, identify allelic pairs...