After marijuana, cocaine is the most frequently abused non-prescription drug in the United States and the most commonly used “hard” drug. It is estimated that about 14% of U.S. residents have used cocaine in their lifetime and over 2% have done so in the past year (1
). Cocaine is highly addicting, with 25–45% of past-year users meeting DSM-IV criteria for cocaine abuse or dependence (2
). The emergence of crack-cocaine in the late 1980s led to an increase in heavy use, and a corresponding increase in adverse health and social consequences of cocaine use, which remain at historically high levels (5
). While the health-related sequelae of these trends are limited to drug-users, the social consequences extend to the population at large. Hence, cocaine dependence constitutes a significant public health problem, whose true costs are difficult to estimate.
Twin and family studies indicate a strong role for genetic factors in the development of drug dependence; it is estimated that 63 to 79% of the liability for the development of cocaine dependence is genetically mediated (8
). While a number of studies show considerable overlap in genetic factors responsible for dependence on various classes of drugs, there is also evidence for drug specific effects (8
). Therefore, genes encoding molecules known to interact directly with cocaine, as well as those known to be involved in reward pathways across classes of drugs, constitute logical candidates for association studies.
Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in multiple regulatory pathways within the mesolimbic dopamine system(14
), and could plausibly modulate the effects of multiple drugs of abuse. A number of association studies of addiction and other psychiatric phenotypes in humans have focused on genes encoding the canonical α4 and β2 nAChR subunits(15
). More recently, a non-synonymous coding polymorphism in CHRNA5
on chromosome 15, which encodes the α5 nAChR subunit, has been the focus of association and functional studies. In a case-control candidate-gene study of nicotine dependence among smokers, SNP rs16969968 was associated with nicotine dependence with p = 6.4 × 10−4
). This finding was replicated in an independent case-control series derived from a large family-based study focused on alcoholism (p = 7.7 × 10−4
, in contrasts of heavy-smoking vs. light smoking phenotypes), and the variant protein was shown to alter receptor function in transfected cell line assays (Bierut et al, under review).†
Most recently, a SNP that is completely correlated with rs16969968 (rs11317286) was found to be associated with cigarettes per day in a European sample (p = 2.6 × 10−6
). The minor (A) allele results in a change of a highly conserved aspartic acid residue to asparagine at position 398 (D398N) of the polypeptide chain, residing in the large intracellular domain of the α5 subunit.
The aim of the current study is to investigate the potential role of rs16969968 in cocaine dependence, a disorder that is disproportionately prevalent among persons with nicotine dependence (22). Heteromeric α4β2* (where the * denotes the presence of another subunit, frequently α5) nAChRs bind nicotine with high affinity, and therefore, as a frequent component of α4β2* heteropentamers, variation in the α5 subunit may preferentially influence nicotine dependence, rather than addiction liability in general. On the other hand, nAChRs are expressed in a variety of neurons and are involved in modulating drug related reward for numerous substances, and therefore, may have a role in modulating risk for multiple types of addiction (23
). Hence, using data from a candidate gene study of cocaine dependence in unrelated cases and controls, we sought to determine whether SNP rs16969968 in CHRNA5
is associated with cocaine dependence. We also sought to examine the potential contribution of comorbid nicotine dependence to the hypothesized association. Finally, as this is the first study of the association between CHRNA5
and cocaine dependence, to our knowledge, we sought to confirm our initial findings using data on cocaine dependence from an independent sample, derived from a large, family-based study of alcoholism.