Year: 2013
Type: article
Abstract: The review by Professor Darke 1 highlights several conceptual issues related to the etiology and development of heroin dependence. Our research has focused largely on the genetic underpinnings of heroin dependence. Twin and family studies show a consistently significant role of heritable influences on opioid (including heroin) dependence 2, 3. The extent to which these heritable influences are specific to opioids remains unclear. Indeed, a component of the high degree of comorbidity noted by Darke could be a consequence of shared genetic influences on the liability to misuse of multiple drugs. For opioids, in particular, there is also evidence for the role of drug-specific genetic influences 4. Regrettably this has not, as yet, translated to the identification of genetic variants that exert their impact solely upon opioid/heroin dependence. Even for the mu opioid receptor (OPRM1), association studies supporting (or failing to replicate) the role of these variants on alcohol, tobacco and other illicit drug dependence are abundant 5-8. The importance of neighborhood adversity and childhood exposure to trauma, elegantly termed ‘shattered childhoods’, cannot be diminished, in particular, in genetically informed studies. Even within genetically related pairs of individuals (i.e. identical and fraternal twin pairs) discordant for exposure to childhood sexual abuse, the likelihood of opioid abuse/dependence (but not other illicit drug abuse/dependence) is elevated considerably (odds ratio of 6.5) in the member of the twin pairs who was exposed to abuse relative to his or her same-sex co-twin 9. That such a potent risk factor contributes to the use and misuse of one of the most dangerous illicit drugs, over and above shared familial risks (including genetic and rearing environment), underscores the importance of considering the shattered childhood and other environmental risks and protective factors in genetic paradigms. Whether these traumatic events exert their pathogenicity via comorbid psychopathology or via epigenetic modification of gene expression (or, most probably, both) requires careful study. For instance, rodent models strongly support the modifying role of maternal care on the regulation of genes responsible for stress–response 10. In humans, hippocampal levels of gene expression of NR3C1 (neuron-specific glucocorticoid receptor) are reduced substantially in suicide victims with a history of childhood abuse relative to non-abused suicide completers and controls, indicating increased activity of the stress-regulating hypothalamic–pituitary–adrenal (HPA) axis in abuse victims 11. Consideration of macro-environmental conditions (such as neighborhood adversity) has also yielded insights into gene identification. In our recent study of a sample of opioid-dependence cases from opioid replacement therapy (ORT) clinics, we identified variants in OPRD1 (delta opioid receptor) that were associated with opioid dependence 12. Intriguingly, these effects were apparent only when opioid-dependent cases were compared to non-dependent control subjects from the general population and had minimal exposure (opportunity and access) to heroin. The association signal attenuated to non-significance, however, when a novel control group of individuals with a higher likelihood of exposure to heroin, ascertained from neighborhoods surrounding the ORT clinics, was used. In stark contrast, in the same sample the association between genetic variants in ANKK1 and TTC12 and opioid dependence are gleaned only in comparisons between cases and neighborhood controls 13. Why is the choice of a control group so pivotal to gene identification studies? As Darke notes, heroin use and dependence develop in the context of marked environmental adversity and comorbid psychopathology—is it then appropriate to contrast the genetic liability of a heroin-dependent individual to those in the general population who perhaps, and most fortunately, may have escaped exposure to that shattered childhood? If so, genetic effects on heroin dependence are likely to be confounded with the liability of exposure to heroin. In contrast, an effort to match heroin-dependent cases to those who, despite dwelling (in our research, during adulthood) in adverse environments and even subsequent to some degree of experimentation with opioids/heroin, do not develop dependence may reveal more clearly the genetic architecture of heroin dependence. This review by Darke is a welcome reminder that the milieu in which a potently life-altering behavior such as heroin dependence is cultured cannot be ignored when examining its etiology, even from a biological standpoint. Genetic vulnerability is necessary but never solely sufficient—drug exposure and environmental context are required for genetic vulnerability to manifest. Considering nature and nurture as a dichotomy oversimplifies the problem: those at the greatest genetic risk are often raised in trauma-laden environments with ready access to drugs—their likelihood of exposure to this environment is related to their genes (i.e. parental pathology produces adverse rearing environments) and the subsequent toxicity of this environment exacerbates the role of that inherited predisposition to heroin dependence. Thus, there is a growing demand for integrating the impact of these shattered childhoods into biologically informative studies. Regardless of their interface with biology, that concerns about exposure to these early and adverse life events should not be minimized goes without saying. That they might exacerbate genetic predisposition via multiple genetic and epigenetic mechanisms, however, requires that much more be said (and done). A.A. receives peer-reviewed grant funding from ABMRF/Foundation for Alcohol Research. A.A. is supported by K02DA32573; E.C.N. is supported by DA017305.
Source: Addiction
DOI: 10.1111/add.12043
Institution: Washington University in St. Louis
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1570331469