La genética de la adicción a drogas: de los marcadores genéticos al comportamiento humano

The genetics of drug addiction: from genetic markers to human behavior

La genética de la adicción a drogas: de los marcadores genéticos al comportamiento humano

M. PERSICO, A.

Laboratorio de Neurociencia. Libera Universita'' Campus Bio-Medico. Roma (Italia).

Correspondencia:

Dr. A. M. PERSICO.

Laboratorio de Neurociencia.

Libera Universita'' Campus Bio-Medico.

Vía Longoni, 83.

I-00155 Roma (Italia).

e-mail: [e-mail]

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ABSTRACT: Objective: provide an update of evidence supporting genetic components to the etiology of drug addiction.

Material and methods: critical review of published findings in family studies and dopaminergic candidates.

Results: genetic factors confer a sizable amount of substance abuse vulnerability. Issues concerning an association of DRD2 gene variants with alcoholism and drug absue are controversial. No firm conclusions of DRD4 alleles and novelty seeking are currently established.

Conclusions: criteria for evaluation of association studies should be developed. Analyses on subgroups of patients identified through biological markers may increase etiological homogeneity.

KEY WORDS: Drug addiction. Vulnerability. Human genome.

RESUMEN: Objetivo: presentar una actualización de las evidencias que sugieren un componente genético en la etiología de los trastornos adictivos.

Material y métodos: revisión crítica de los hallazgos publicados en estudios familiares y genes candidatos del sistema dopaminérgico.

Resultados: los factores genéticos contribuyen a la vulnerabilidad al abuso de sustancias. Los hallazgos relativos a los genes del receptor dopamina D2 (DRD2) y su relación con el alcoholismo y el abuso de sustancias son controvertidos. No existen conclusiones firmes respecto a la relación entre los genes del receptor dopamina D4 (DRD4) y la tipología de búsqueda de sensaciones nuevas.

Conclusiones: deben desarrollarse criterios para la evaluación de los estudios de asociación. El estudio de subgrupos de pacientes identificados a través de marcadores biológicos puede incrementar la homogeneidad de las muestras estudiadas.

PALABRAS CLAVE: Adicción a drogas. Vulnerabilidad. Genoma humano.

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Introduction

The interest of scientific investigators has been increasingly focused upon genetic contributions to substance abuse vulnerability in recent years. Defining the precise role of genetic factors in the etiology of addictive disorders and isolating single gene variants specifically predisposing to drug addiction represent extremely challenging tasks. Drug addiction consists of a complex set of behaviors difficult to define according to a simple «affected/unaffected» dicotomy; it clearly stems from an interaction between genetic and environmental factors, whose specific role is difficult to delimit and characterize; it displays genetic underpinnings conferred not by one single gene, as would typically occur in Mendelian disorders, but rather by a set of genes in epistatic interaction among themselves and even with the environment. The difficulties and limitations of classical genetic methodologies, when applied to complex polygenic disorders such as drug addiction, are profoundly affecting the field of behavioral genetics still today, and have been thoroughly reviewed several times in recent years^{20,34,38,47,86,89-91,118,119}. Here, afterproviding a brief update on evidence supporting genetic components to the etiology of drug addiction, the ongoing quest for single gene variants will be exemplified discussing findings pertaining to two dopaminergic «candidate» genes, namely the dopamine D2 and D4 receptor genes, putatively involved in addictive behaviors, preferential drug choice, and personality traits related to experimenting with drugs.

Drug addiction vulnerability: nature and nurture

Family, twin, and adoption studies all provide converging lines of evidence supporting genetic contributions to drug addiction vulnerability. We shall hereby provide a brief summary of work published in recent years, following our latest reviews on the topic^89,91.

Initial family studies documenting increased frequencies of drug addicts in families selected on the basis of a drug abusing proband^{22,66,67,74,85,103} have been confirmed and extended. In particular, two studies^7,73 have lend further support to the existence of general familial risk factors for the development of addictive behaviors and of familial risk factors specific to each particular class of drugs (see commentary by Goldman and Bergen⁴¹). Merikangas and colleagues⁷³ have found rates of drug abuse or dependence as high as 14.5% among relatives of probands dependent on opioids, 9.6% if probands were dependent on cocaine, 8.4% if dependent on cannabis, 4.4% if probands were alcoholics. All rates were significantly higher than the 1.2% found among relatives of control probands. Interestingly, alcoholism was more frequent only among relatives of probands abusing alcohol or cannabis, but not cocaine or opioids. In another family study⁷, siblings of alcoholic probands displayed much higher lifetime rates of alcohol, marijuana, cocaine, and nicotine dependence, than siblings of non-abusing controls. Also in this sample, a significant degree of familiality for the type of drug preferentially abused by the proband was recorded.

Familial factors conferring vulnerabilities toward substance abuse in general and toward abuse of specific illicit drugs can be environmental or genetic in essence. During the past few years, twin studies have helped elucidate the respective roles of nature and nurture in drug abuse genetics, following pioneering twin work on illicit⁹⁴ and licit¹⁵ drug dependence, previously summarized elsewhere⁸⁹. Excluding studies focused on alcoholism, four distinct twin samples have thus far been assessed for illicit drug use, namely a sample drawn from alcohol and drug abuse treatment programs in Minnesota¹²², the Virginia Twin Registry sample^55-55,69, the Vietnam Era Twin Registry sample^115,116 and the Washington University Twin Series⁴⁴. At least three additional samples have been assessed for licit drug use, particularly smoking¹⁰²: the National Heart, Lung, and Blood Institute''s Twin Study sample^111,112, the Kaiser Permanent Women Twin Study sample²⁹ and a sample of Australian twins assessed for nicotine dependence⁴⁶. In summary, studies published to date have shown that: a) genetic factors contribute about one third of the overall variance in drug abuse liability; b) heritability estimates are higher for males than for females; c) genetic contributions increase with severity of addictive behavior, being more prominent for drug abuse/dependence than for mere illicit drug use; d) general liability factors predispose toward addiction to licit, as well as illicit drugs, in conjunction with specific genetic factors contributing to almost all preferentially-abused drugs of choice, and e) environmental influences common to both twins provide significant contributions to drug use, but have negligeable impact on the development of drug abuse/dependence, which stems from genetic and non-shared environmental factors. Furthermore, two important studies have both shown that the closer relationship which typically characterizes monozygotic twins compared to dizygotic twins provides only marginal contributions to their higher concordance rates in drug abuse/dependence^50,60.

The first adoption study by Cadoret and colleagues¹² has been subsequently replicated on larger samples of male¹³ and female¹⁴ drug-abusing adoptees, reinforcing the hypothesis of two genetic pathways leading to drug addiction in both sexes: a) the «indirect pathway», i.e. drug-abusing adoptees with Antisocial Personality Disorder or Conduct Disorder displaying significantly enhanced frequencies of Antisocial Personality Disorder in their biological parents, indirectly related to drug addiction in the adoptee as well as in the general population¹⁰⁰, and b) the «direct pathway», i.e. drug-abusing adoptees without Antisocial Personality Disorder displaying significantly higher frequencies of alcohol-abusing biological parents devoid of prominent antisocial traits, and possibly inheriting a general predisposition to addictive behaviors. Also environmental factors, namely separation or divorce and psychiatric problems in adoptive parents, significantly enhanced the probability of adoptees developing antisocial personality and drug addiction.

In conclusion, genetic factors confer a sizable amount of substance abuse vulnerability, either directly or by contributing to the development of antisocial traits often associated with drug abuse. A general predisposition toward addictive behaviors is further modulated by genetic factors specifically predisposing toward each drug of choice. This complex genetic background interacts with environmental factors which, in an extremely simplified model, can be distinguished into life experiences shared by many (i.e., «peer-pressure»), possibly contributing to experimenting with drugs but not to developing a real drug addiction, and life experiences specific to each single individual (i.e., developmental and family history), potentially predisposing toward drug abuse/dependence.

The gold rush of drug abuse genetics: searching for single genes

Genes predisposing to addictive disorder could a priori fall into at least three categories: a) genes conferring personality traits increasing the probability that an individual will use drugs; b) genes influencing farmacokinetic or farmacodynamic traits that will modulate the subjective effects of acute drug exposure and the consequences of chronically-repeated drug self-administration, namely tolerance, sensitization and withdrawal, and c) gene variants conferring enhanced frequency and/or intensity of craving, which is most directly responsible for relapse into drug addiction.

Moving from «genetic factors» to single gene variants predisposing to addictive behaviors is fraught with difficulties and caveats, which have been thoroughly reviewed elsewhere^{18,20,34,86,89-91,118,119}. These hurdles can be briefly summarized as follows:

-- Drug addiction is the outcome of a bio-psycho-social process which, from a genetic standpoint, requires a predisposition polygenic in nature, with each gene contributing only a small percentage of the total vulnerability.

-- The phenotype is not always clinically clear-cut.

-- Classical linkage analysis does not possess the statistical power necessary to detect single gene effects in complex disorders with maneagable sample sizes^20,38,47.

-- Association analysis does possess the statistical power needed to detect such effects¹¹³, but the case-control design is exposed to a high risk of false-positive or false-negative results, whereas intrafamilial approaches, such as the Haplotype Relative Risk^30,56,114 and the Transmission Disequilibrium Test^23,108, which minimize this risk, do requires large sample sizes, possibly including several hundred families⁵⁶.

-- Interindividual differences in single bases or base repeats, commonly called «genetic markers», may have functional meaning if they influence either the function or the amounts of a protein relevant to addictive behaviors. This influence must, however, be demonstrated by in vitro assays and possibly in vivo using transgenic technology.

-- Most genetic markers typically have no functional meaning. A marker may still be associated with a disease in the general population if it is in «linkage disequilibrium» with the mutation conferring genetic predisposition, meaning that the two have not been separated by crossing-over during meiotic recombination as frequently as anticipated for two equally distant DNA sites identified at random. In this case, however, if an association is found, linkage disequilibrium at the locus of interest cannot be assumed to exist but must be proven, and the mutation must be subsequently identified. It is important to keep in mind that the amount of linkage disequilibrium at any given locus will frequently vary depending on race and ethnic group (for a detailed discussion of linkage disequilibrium see^86,89).

These difficulties have already led to conflicting reports in several instances, generating confusion and heated debates in a field where the difficulty to shift gear passing from monogenic to polygenic disorders has become apparent. As an example, we shall now provide a brief update on dopamine D2 (DRD2) and D4 (DRD4) receptor gene variants, putatively conferring drug response patterns and personality traits possibly predisposing to the development of addictive disorders.

The never-ending story of dopamine D2 receptor gene markers and substance abuse

The DRD2 gene may represent the first candidate gene providing detectable contributions to substance abuse vulnerability and possibly modulating preferential drug use^{9,79,86,89-91,117-119}. Genes involved in dopaminergic neurotransmission represent good «candidate» genes for substance abuse, as dopaminergic systems are prominently involved with the effects of addictive substances^24,58,126. Cocaine and amphetamine act directly on dopaminergic systems^58,92,101, whereas addictive substances such as alcohol and nicotine, which do not directly alter dopamine function, can indirectly activate the mesolimbic/mesocortical dopaminergic system linked to reward^24,98. Initial reports suggested that a specific DRD2 gene variant marked by the TaqI A1 and B1 polymorphisms was much more frequent among alcoholics⁸ and drug abusers¹⁰⁵, respectively, than in normal controls. Several groups have since then attempted to replicate this finding, both in alcoholics and in substance abusers, with conflicting outcomes (see below).

The DRD2 gene encompasses 8 exons and encodes a G-protein linked, 7-transmembrane domain receptor protein^42,43,45. Several polymorphic markers have been identified within or in close proximity of the DRD2 locus. The TaqI A and B polymorphisms^45,87 unveil a striking degree of linkage disequilibrium at this locus in Caucasian, but not in African-Americans, making it ideal for genetic association studies in Caucasian populations^81,118. Polymorphism-generating single-base mutations located in non-coding regions, such as those yielding the TaqI A and B polymorphisms, are unlikely to have direct functional relevance. However, the linkage disequilibrium present at the DRD2 locus suggests they could be located in proximity of a functionally-relevant mutation, most likely located in the 3'' or 5'' non-coding regions of the gene. This mutation could seemingly modulate transcriptional regulation and/or in mRNA stability, ultimately affecting DRD2 receptor number, as strongly suggested by significant reductions in DRD2 receptor B_max found post-mortem in the striata of individuals with at least one copy of the A1 marker, regardless of the presence of alcoholism⁷⁶, and recently replicated in non-alcohol non-drug abusing individuals assessed in vivo using positron emission tomography^48,97. These findings are also consistent with decreased DRD2 binding in brains of alcohol-preferring rodents^68,109, reduced DRD2 sensitivity evidenced through blunted GH responses to apomorphine in chronic and abstinent alcoholics^4,5, quantitative trait loci (QTL) analyses supporting the existence of a gene in close proximity of the DRD2 locus providing genetic contributions to enhanced ethanol sensitivity²¹, lack of opiate reward and decreased ethanol sensitivity in DRD2 knockout mice^70,93 and the lack of mutations in the coding regions of «A1-marked» DRD2 alleles³².

Numerous studies have assessed the association and linkage between DRD2 alleles and alcoholism, and have been reviewed elsewhere^9,33,79. Several studies have been published to date, comparing distributions of DRD2 gene polymorphic markers in drug abusers and control samples^{19,36,77,81,88,106}. Combined results from all these studies do support an association between DRD2 TaqI A1 and B1 markers and polysubstance abuse in Caucasian individuals (see metanalyses^90,91), but not in individuals of African origin⁶, as predictable based on their lack of linkage disequilibrium at the DRD2 locus⁸¹.

Several pathophysiological correlates of A1/B1 presence have been reported, including reduced brain glucose consumption⁷⁸, and possibly reduced P300 amplitude in event-related potentials⁷⁹. Nonetheless, DRD2 contributions to substance abuse have not yet been defined precisely in their nature. A1/B1-marked DRD2 variants may influence severity of addictive behaviors⁹, or antisocial personality and Novelty Seeking⁸⁰, although both these aspects have received support by some studies^19,77, but not by others^88,106,107. We found evidence for modulation of drug choice, rather than for general predispositions to addictive disorders⁸⁸: only polysubstance users with histories of heavy daily preferential psychostimulant use over opiate use displayed significantly greater frequencies of the TaqI marker A1 and B1 presence. Interestingly, age of first use of any drugs, namely alcohol, tobacco or marijuana, displays no correlation with extent of later polysubstance abuse, while an early concomitant exposure to both psychostimulants and opiates appears to occur in most «heavy» polysubstance users⁸⁸. Conceivably, craving-inducing stimuli may more promptly precipitate use of drugs which have «primed» genetically-predisposed individuals at an earlier stage. If confirmed in future studies, this interaction between genetic and environmental factors represents an excellent example of the complexities faced when dealing with the genetics of personality and behavioral disorders.

Results concerning DRD2 gene variants have notoriously been replicated by some, but not by other groups. The existence of an association with alcoholism or drug abuse has been questioned^33,34,39,40, as well as the significance of putative neurophysiological correlates, such as decreased DRD2 binding⁶². Issues concerning this controversy have been discussed in detail elsewhere^89,90, and will not be considered again. We would like only to point out that in our study on psychostimulant-preferring substance abusers, we found an association with DRD2 alleles but not with dopamine transporter (DAT) gene variants. The DAT gene was used as an «internal control», because we could prove the dishomogeneous distribution of its polymorphisms among distinct racial and ethnic groups, a finding recently replicated and expanded by Kang and colleagues⁴⁹. Therefore this association is unlikely to stem from population stratification, which would have yielded positive associations with both DRD2 and DAT gene variants, contrary to our findings⁸⁸. Furthermore, as underscored by recent experience with knockout mice, moderate changes in receptor binding could be physiologically more meaningful than full-blown DRD2 «knockouts» rarely found in humans and not associated with alcoholism⁴⁰, because gene knockouts can trigger dramatic compensatory changes during neurodevelopment leading to normal phenotypes. In conclusion, the multiple lines of evidence converging on DRD2 receptor-mediated mechanisms and on A1/B1-marked DRD2 gene variant involvement in addictive behaviors and alcoholism would deserve a more sober scrutiny than the one received so far, even in putatively high-ranked scientific journals.

Human personality and drug abuse: the novel story of dopamine D4 receptor gene variants

Personality disorders are increasingly viewed as «maladaptive extreme variants of common personality traits»¹²⁵, and studied according to a dimensional, rather than a categorical approach. The dimensions, or traits, composing normal and pathological personality have been named differently, depending upon the psychometric approach employed (for review see¹¹). The Tridimentional Personality Questionnaire, for example, has been designed according to a bio-psycho-social view of personality and describes four temperamental traits: Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence¹⁷. More recently, the existence of at least four general dimensions of personality both in normal and in pathological personality has been defined: Emotional Dysregulation, Dissocial Behavior, Inhibitedness and Compulsivity⁶⁴. Personality traits display striking genetic influences, with most studies converging on an estimate of two thirds of personality variance being due to genetic factors^10,11,95. Surprisingly, genetic and not shared environmental influences seem to be largely responsible for similarities among family members^10,11,95. Within this framework, «Dissocial Behavior», or «Antisocial Personality» has spurred the most interest in the field, having been directly linked to drug addiction using both epidemiological and genetic approaches^12-14,120. Since Antisocial Personality is characterized also by high levels of Novelty Seeking, initial reports that DRD4 gene variants were associated with high levels of this temperamental trait^5,25 spurred widespread interest in the scientific community.

The polymorphism assessed in these studies is a 48 base pair Variable-Number-of-Tandem-Repeats (VNTR), present in 1-10 copies in humans^123,124. The VNTR is located in the third exon of the DRD4 gene and encodes for a 16 aminoacid sequence encompassed within the third cytoplasmic loop of this G protein-coupled receptor. As predictable based on the intracellular localization of the polymorphic segment, allelic variants differing in VNTR copy number do not seem to differ in agonist or antagonist-binding properties, but rather in their capacity to inhibit adenyl-cyclase, with the seven-repeat allele displaying a 50% decrease in potency compared to the two and four repeat alleles². Further interest in this polymorphism is spurred by the distribution of DRD4 in human brain, prominent in limbic regions such as cingulate and frontal cortices, relevant to motivation and behavior^61,72,99. DRD4 knockout mice display enhanced sensitivity to ethanol, cocaine and methamphetamine induced locomotor activity¹⁰⁴. Finally, both human linkage analysis and Quantitative Trait Locus approaches in mice support a locus conferring liability to ethanol drinking in close proximity of the DRD4 gene^21,65.

Evidence of an association between the seven-repeat allele of DRD4 and higher levels of Novelty Seeking was initially reported studying an Israeli Ashkenazi and non-Ashkenazi sample²⁵. Results were strenghtened by an immediate replication, using both case-control and intrafamilial study designs in an American, 92% Caucasian sample⁵. As expected, given the complexity of the phenotype, the effect size for this gene on temperament was estimated to approximate only 5% of the total variance^25,26. Subsequently, several groups sought to replicate these findings either on samples assessed specifically for temperamental traits or in drug addicts and alcoholics, who frequently display higher levels of Novelty Seeking in turn related to reckless conduct and experimenting with drugs, among others. The association with Novelty Seeking was replicated by the same group producing the original findings²⁶, in Japanese¹⁸² and in one Caucasian-American sample⁸⁰, while no association was found in samples drawn from Finnish⁷¹, Swedish³¹, German⁵⁹ and Caucasian-American¹²⁰ populations. Importantly, the association was not replicated in a set of same-sex monozygotic and dizygotic twins⁹⁶). The association with substance abuse and/or alcoholism was again found among Israeli non-Ashkenazi^26,57, Japanese⁷⁵, Canadian³⁷ and Chinese individuals⁶³, while no association was found in samples drawn from Finland^1,71, Sweden³¹, Germany¹⁰⁵, New Zealand¹¹⁰, and in another set of Chinese¹⁶, as well as among other Caucasian- and African-American samples^35,83. Finally, an association between DRD4 VNTR alleles and four temperament traits, namely orientation, motor organization, range of state and regulation of state, has been described in neonates, assessed using the Brazelton Neonatal Assessment Scale²⁷.

At this stage, no firm conclusions can be reached as to putative biological phenotypic correlates of DRD4 alleles in vivo, such as differences in receptor function evidenced using brain imaging techniques, or in electrophysiological parameters. These kinds of investigations will help define to a larger extent whether the association between DRD4 and Novelty Seeking is a real «adventure»²⁶ or mere «nonsense»⁸⁴.

After the gold rush: is there a future for association studies?

The decade of the Nineties has seen the spreading of research aiming to discover single gene variants affecting pathological, and recently even normal human behavior. Pioneers driven out by this «gold rush» have mainly followed two major routes: animal research, mostly using inbred strains and QTL (see²¹ for review), and human genetic research, largely relying upon psychophysiological studies, classical genetic approaches and linkage/association studies of single genes ^18,20,34,89 . This effort has produced a fair amount of novel information, which is bound to grow exponentially during the next decade also thanks to gene chip technologies. At the same time, however, non-replications and new methodological challenges have raised confusion and some discouragement, particularly in the human genetic area. These issues are relevant also to knowledge acquired through animal genetics, which will eventually have to be transferred onto human genetics, neurobiology, and disease. Association studies still represent the most sensitive and appropriate tool to study oligogenic/polygenic disorders. However, changes in attitudes and methodological approaches are needed for genetic researchers to study successfully polygenic quantitative behavioral traits, so distant from classical monogenic mendelian disorders. These viewes are still being actively debated^20,34,89, but it is important that some theoretical basesand a consensus on basic guidelines for «acceptable» association studies be rapidly worked out at least to some extent, while the tremendous power of gene chip technologies is about to be applied to behavioral genetic research. Building with powerful technologies on shaky theoretical grounds may actually increase, rather than decrease, the probability of false-positive and false-negative results due to unrecognized genetic heterogeneity, incomplete penetrance, potential heterosis, environmentally-produced phenocopies, and population genetic stratification, leading to more non-replications and more heated debates in the literature. Criteria for evaluation of association studies recently spelled out by the editors of a very prominent genetic journal represent a valuable contribution in this direction²⁸. Also, focusing analyses on subgroups of patients specifically identified through biological markers, rather than only through clinical features, may increase etiological homogeneity and reduce discordance among different studies.

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