Genetics Flashcards
Introduction
In considering the relative merit of attempts to identify genes conferring susceptibility to addictive diseases, a necessary first step is to evaluate evidence concerning the extent to which alcohol and other drug use disorders (or ‘addiction’, for the scope of this review) may be influenced by heritable factors. Such evidence can be derived from a range of family-based genetically informative research designs including adoption, twin and family
Designs.
Family studies
One approach is to simply study the incidence of substance use within families.
Merikanga and colleagues’ (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. The problem with simple studies of incidence within families is that we cannot dissociate the effects of genes and the environment. Study designs are needed where it is possible to separate out these effects to examine the relative effects of environment and gene.
Adoption studies
Adoption studies examine the concordance of the phenotype (or physical issue/behaviour that you are looking at, e.g. substance use) between the adoptee and both the biological parent and the adoptive parent. Similarity between the adoptee and adoptive parent would suggest environmental effects, similarity with the biological parent would suggest genetic effects.
Adoption studies
Procedure
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.
Adoption studies
The first limitation
The first limitation concerns the representativeness of families involved in adoption. Stoolmiller (1999), showed that families involved in the Colorado adoption project represented only the top third of scoieconomic status in the US. This may be due to screening criteria before being allowed to adopt i.e. all adoptive families meet a strict criteria, suggesting that the results of adoption studies may not be applicable to the general population.
Adoption studies
The second limitation
The second limitation concerns the assumption that biological mothers are similar to their children for genetic but not environmental reasons. However, biological mothers provide the child’s environment for 9 months, which could increase their similarity beyond that produced by genetic factors. This would result in an artificial inflation of genetic influences.
Adoption studies
The second limitation elaboration
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.
Twin studies
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. Twin studies also estimate shared and non-shared environmental influences by determining similarities of dissimilarities between twins that are not account for by degree of genetic relatedness
Twin studies
Evidence
Lobo and Kennedy 2009 Reviewed twin studies about pathological gambling, 18 studies. Twin studies using the Vietnam Era Twin Registry have found that: (i) the heritability of PG is estimated to be 50-60%; (ii) PG and subclinical PG are a continuum of the same disorder; (iii) PG shares genetic vulnerability factors with antisocial behaviours, alcohol dependence and major depressive disorder; (iv) genetic factors underlie the association between exposure to traumatic life-events and PG. Molecular genetic investigations on PG are at an early stage and published studies have reported associations with genes involved in the brain’s reward and impulse control systems.
Twin studies
Agrawal and Lynskey (2008) review
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.
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
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.
Limitations of twin studies 1
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.
Limitations of twin studies
Fosse, Joseph and Richardson (2015)
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. The authors suggested that the heritability estimates for Sz yielded from twin studies are inflated and invalid because the concordance in MZ twin pairs is largely due to higher shared environmental risk factors.
However
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.
