genetic basis of addiction Flashcards
Introduction
Addictions are chronic relapsing psychiatric disorders characterized by the compulsive and dyscontrolled use of a drug or activity, with maladaptive and destructive outcomes. Although addiction leads to loss of volitional control, initial use of addictive agents is volitional. Therefore it would be expected that, as shown by research, individuals with various addictions differ systematically from controls on particular factors. These include trait impulsivity, prevalence rates for pychopathology and familial substance use, to name just a few. It is of interest to researchers to know what is the basis of addiction that allows for such systematic differences between those with addictions and the general population, because information about the etiology of addiction is needed to improve treatment and thus treatment outcomes. It has been suggested that addiction has, at least partially, a genetic basis. This essay will critically discuss whether there is indeed a genetic basis for addiction.
Family study
Quantitative genetics is an area of research based around the notion that multiple genes effect quantitative traits. Therefore, phenotypic resemblance should vary according to degree of genetic relatedness. This is tested using adoption studies, family studies and twin studies.
Merikangas et al 1998 study looked at 231 people who were diagnosed with drug or alcohol addiction, and compared them to 61 people who did not have an addiction. Then it looked at the first-degree relatives (parents, siblings, or children) of those people. It discovered that if a parent has a drug or alcohol addiction, the child had an 8 times greater chance of developing an addiction. This suggests that alcohol addiction is heritable i.e. has a genetic basis.
Limitations-The problem with simple studies of incidence within families is that we cannot dissociate the effects of genes and the environment. For example, the children of alcoholics in this study may be at greater risk for alcoholism due to socialization processes whereby parental norms have been adopted by the individual, as is often an interpretation of parental substance use as a risk factor.
We need study designs where we can separate out these effects to examine the relative effects of environment and gene, i.e. adoption studies
Twin study
Twin studies compare resemblance between MZ twins, who share 100% of their DNA, to DZ twins who share 50% of their segregated DNA, which is the same as normal sibling pairs. The resemblance between MZ twin pairs and the resemblance between DZ twin pairs for a particular phenotypic trait can be compared. If genes exert an influence on that trait, then MZ twins would be more similar to each other on that trait than DZ twins, thus showing that resemblance varies as a function of genetic relatedness. This is known as the heritability estimate (which refers to the proportion of variation between individuals in a population that is influenced by genetic factors, not the degree of genetic determination of individual risk). Quantitative genetic studies also show the extent to which the environment influences phenotypes. For example, any dis-concordance between MZ twins can be attributed to non-shared environment. Shared environmental influences can also be estimated from this design by looking at any of the concordance rate for DZ twin pairs which exceeds 50% of that for MZ twin pairs.
• Agrawal and Lynskey 2008 provide a comprehensive review of twin studies investigating genetic influences on various forms of addiction. They review studies using the Minnesota twin cohort, the Colorado twin cohort as well as Australian, finnish and dutch studies. Estimates of the heritability of alcohol abuse/dependence have ranged from 50% to 70%. Nicpotine dependence also tends to yield very high heritability estimates, ranging from 30-72%. There has been no support for the role of shared environmental influences on nicotine dependence across the studies examined. They note that there is somewhat less twin research investigating illicit drug use. Kendler et al. have reported heritability of cannabis (and other substance) use disorders from a Norwegian sample, a study of particular interest as the prevalence of cannabis and other illicit drug use is substantially lower in Norway than in the United States or Australia, where the bulk of previously reported twin studies of cannabis dependence have been conducted. Despite the lower prevalence of abuse/ dependence diagnoses (1.6%) or any symptoms of abuse/dependence (2.9%), univariate genetic modelling indicated substantial additive genetic influences on both abuse/dependence diagnoses (77%) and any symptoms of abuse/ dependence (75%). Vietnam era twin sample, Tsuang et al.reported that 33% of the variance in stimulant abuse/dependence, 27% of the variance in sedative abuse/dependence, 54% of the variance in heroin abuse/dependence and 26% of the variance in abuse/dependence of psychedelics could be attributed to genetic factors.
Adoption study
Adoption studies, compare biologically related and biologically unrelated siblings or parent–child pairs allowing the comparison of environmental and genetic influences on phenotypes of interest.
• Cadoret et al 1995 A sample of 95 male adoptees, separated at birth from their biologic parents, were followed up as adults to determine their psychiatric diagnosis and their substance use/abuse in a structured interview administered blind to biologic parent diagnoses. A high-risk, case-control design was used wherein half of the adoptees came from biologic parents known to be alcohol abuser/dependent and/or have antisocial personalities (diagnoses from hospital or prison records). Two independent genetic influences were found. The first mechanism was where parental antisocial behaviour increased risk for offspring antisocial behaviour, which in turn increased risk for drug abuse. The second was characterized by parental alcohol problems directly influencing risks of drug abuse in their biological offspring, even in the absence of offspring antisocial behaviour.
Limitations- • Similarly, selective placement, whereby adoptive families are matched on certain characteristics (e.g., SES, height, coloring etc) to biological parents, would mean that the biological mother and child may still be experiencing similar environments. This is supported by findings indicated that biological mothers are correlated for particular traits not only with their adopted child, but also with other siblings in the adoptive household who are not at all biologically related (Scarr and Carter-Saltzman, 1989). This latter possibility would make it difficult to estimate heritability as it may be inflated by shared environmental influences not taken into account. An alternative approach to studying heritability is the twin method.
Limitations of twin studies
• Limitations of twin studies in general-
o Critics point out that, as MZ twins look more similar and are believed by others to be more similar, people treat them more similarly and thus MZ twin pairs are exposed to more shared-environment than DZ pairs. This is interpreted to mean that any excess similarity between MZ pairs compared to DZ pairs, may be the result of shared environment rather than genetic factors. Therefore, heritability estimates from twin studies may be inflated by shared environmental factors not taken into account.
o Fosse, Joseph and Richardson (2015) note that childhood adversity is a significant risk factor for schizophrenia (e.g. McCabe et al, 20102) and conducted a study to test whether shared childhood adversities were greater for MZ than DZ twins. The study used data from previous studies on 9119 twin pairs. Results showed significantly higher correlations in MZ than DZ twin pairs for each exposure childhood adversities such as bullying and physical, sexual and emotional abuse. This is of particular importance when investigating addiction, as childhood and adolescent adversity may contribute to later substance addiction. It is therefore possible that heritability estimates from twin studies are also inflated due to shared environmental influences not taken into account with regards to MZ twins.
Argument against limitations of twin studies
o However, if it were true that MZ twins have more shared environmental experiences than DZ twins which impacts on behavioural similarity later in life, then it would be expected that similarity of appearance would be correlated with similarity on behavioural traits.
o Matheny et al (1976) showed that there was no correlation between physical appearances and behavioural traits (.i.e IQ and personality) for either MZ or DZ twins.
o Overall this supports that greater similarities between MZ twins may lead to some common life experiences, but this common experience is not trait-relevant, thus meaning that results from twin studies showing a heritable basis for addiction are reliable.
One interesting consideration, to made when considering the evident heritable basis of addiction is whether there is a general vulrnerability to addiction that is heritable, or whether the genetic influence is substance/behaviour specific.
How can this be assessed.
- More complex types of analyses can be performed where we look at multiple traits in one go.
- Known as multivariate twin analyses, these allow us to look at any heritable overlap across problems with different substances.
- Note however that many drug users tend to be poly-drug-users, using more than one substance.
- MV studies also allow us to track changes in heritability over time.
- Evidence suggests considerable overlap in vulnerability across substances, e.g. alcohol and another substance, but less so for opiates (i.e. heroin).
2 studies whether heritability of addiction is general or substance specific.
What do the findings relate to
- Tsuang et al 1998 We studied 3372 male twin pairs from the Vietnam Era Twin Registry. Multivariate biometrical modeling analyses were used to assess genetic and environmental influences on co-occurrence. Abusing any category of drug was associated with a marked increase in the probability of abusing every other category of drugs. We found evidence for a shared or common vulnerability factor that underlies the abuse of marijuana, sedatives, stimulants, heroin or opiates, and psychedelics. This shared vulnerability is influenced by genetic, family environmental, and nonfamily environmental factors, but not every drug is influenced to the same extent by the shared vulnerability factor. Marijuana, more than other drugs, was influenced by family environmental factors. Each category of drug, except psychedelics, had genetic influences unique to itself (ie, not shared with other drug categories). Heroin had larger genetic influences unique to itself than did any other drug.
- Young et al 2006 reported that nearly 25–36% of the genetic influences of alcohol, nicotine and cannabis problem use were attributable to overlapping factors.
- Together, these findings may suggest that there are common genetic influences which lead to vulnerabilities to addiction to a variety of substances, rather than being specific vulnerability factors to abuse of one drug in particular.
- This relates well to findings that there are common neural substrates for a range of substance addictions i.e. mescorticolimbic functioning is implicated in almost all forms of addiction. Indeed, research shows that functioning in these regions can be heritable. Molecular genetics research has identified specific genes which may contribute to neurochemical mechanisms of addiction.
However, research also shows that environmental influences can modify heritable risk.
Study for a gene-environment interaction
• Agrawal et al 2009 Using data on 6,257 adult monozygotic and dizygotic male and female twins from Australia, we examined the extent to which age at first drink (i) increased mean alcohol dependence symptoms and (ii) whether the magnitude of additive genetic, shared, and nonshared environmental influences on alcohol dependence symptoms varied as a function of decreasing age. Risk for alcohol dependence symptoms increased with decreasing age at first drink. Heritable influences on alcohol dependence symptoms were considerably larger in those who reported an age at first drink prior to 13 years of age. In those with later onset of alcohol use, variance in alcohol dependence was largely attributable to nonshared environmental variance (and measurement error). This is important to consider, not only from a public health standpoint, but also in future genomic studies of alcohol dependence.
Limitations- our sample consisted of Caucasian young adult Australians. To the extent that heritability of age at 1st drink and AD symptomatology vary by race or ethnicity, our results may not extrapolate to populations with other demographic characteristics.
There are, however, some specific genes which have been shown to influence risk of addiction. Given the role of neurotransmitters in addiction, genes coding for various aspects of neuro-chemical activity are often used at candidate genes when investigating the specific effects of genes on addiction.
Molecular genetics study
Similar to other complex traits, addiction is likely to involve many small genetic effects and interactions.
• Blomeyer et al 2008 Used 280 ps aged 15, were genotyped and filled out a self-report questionnaire of alcohol consumption. Increased severity of adolescent SLEs was associated with earlier age at first drink and heavier alcohol consumption, but only in carriers of the CRHR1 rs1876831 CC major homozygote (gene conferring to corticotroping-releasing-factor).
• Blomeyer et al 2010 Used 270 ps age 19. Similar results were obtained.
• Limitations- While the results appear robust, the sample size is relatively small for a genetic association study. Further research with larger samples would be required to support the reliability of this finding.
Quantitative genetics studies estimate that addiction is strongly influenced by gene. As is a common problem in genetics research, there is missing heritability whereby molecular genetics studies are yet to discover the genes which account for this heritability. One way of addressing this is to investigate endophentoypes.
• One reason for missing heritability of SUDs may be due to poor definitions of the trait of interest. This may be because with complex traits, there are many behavioural factors that contribute to what is considered to be one trait. Therefore, a better way to investigate genes responsible for complex traits would be to find genes responsible for particular individual parts involved in producing the complex behaviour pattern, i.e. investigate endophenotypes.
What is an edophenotype and describe a study which investigates endophenotypes.
- Endophenotype is a genetic epidemiology term which is used to separate behavioral symptoms into more stable phenotypes with a clear genetic connection.
- More homogeneous in nature and have a simpler pattern of inheritance than more complex phenotypes
- For the purpose of investigating endophenotypes that contribute to addiction, researchers need to establish endophenotypes that are over-represented in the unaffected relatives of the affected individual, compared to in the general population.• Iacono et al 2003 Compared p300 waves in controls, nicotine addicts and sons of nicotine addicts. Sons of nicotine addicts had lowered p300 waves even when they themselves did not have a nicotine addiction. Shows that this may be one of the heritable phenotypes that contributes to nicotine addiction.
Personality traits associated with risk for addictions also seem to be hertiable.
Describe a study
- Ersche et al 2012 . By comparing the phenotypic profile of individuals with and without a family history of addiction, the authors sought to clarify the extent to which cognitive dysfunction and personality traits are shared by family members—and therefore likely to have predated drug dependence—and which aspects are specific to drug-dependent individuals. Method: The authors assessed cognitive function and personality traits associated with drug dependence in stimulant dependent individuals (N=50), their biological siblings without a history of drug dependence (N=50), and unrelated healthy volunteers (N=50). Results: Cognitive function was signi- ficantly impaired in the stimulant dependent individuals across a range of domains. Deficits in executive function and response control were identified in both the stimulant-dependent individuals and in their non-drug-dependent siblings. Drug-dependent individuals and their siblings also exhibited elevated anxious-impulsive personality traits relative to healthy comparison volunteers. Conclusions: Deficits in executive function and response regulation as well as anxious-impulsive personality traits may represent heritable endophenotypes which contribute to the heritability of substance use.
- Limitations- Potential limitations of the study include the use of a sibling design instead of a twin design; the latter would have allowed the disentangling of genetic from environmental influences, but it would have been prohibitively difficult to complete.
