2 Interplay between genes and environment Genetic models usually make an assumption that the genetic and environmental effects are independentAnimal and plant breeding experiments have, however, shown that G-E interactions are very commonRationality behind breeding is usually to develop plants and animals who can maximally utilize improved nutritionThere is clear evidence on G-E interactions also in humansClinical trials including MZ twinsEpidemiological settingsThe most famous example is Pima Indians in Arizona
3 Conceptualizing G-E interaction in the case of a single gene AAAaTrait Value/Risk of DisorderaaProtective PredisposingENVIRONMENT
4 G-E interactions in twin modeling In many situations it is reasonable to expect G-E interactions also in twin modelingFor example, the effect of place of residence (rural-urban) on the genetics of alcohol consumption in Finland (Rose et al, 2001)G-E interactions are seen as differences in the genetic (or environmental) variation at different levels of environmental exposureDuring this course we will use models which need measured environmental exposureHowever, also other types of G-E interaction models are availableThe most powerful design utilizes information on both measures of environmental exposures and genomic scansThe problem is that usually candidate genes explain only a small proportion of the phenotypic variance
5 G-E correlation vs. G-E interaction It is important to make distinction between G-E interaction and G-E correlation (rGE)G-E interaction refers to situation when the expression of genes is modified by environment or, the other way round, when the effect of environment is affected by genotypeFor example, nutrition may modify the effect of genes affecting obesity or some genotypes may be more sensitive to increase in nutrition intakeIn other words, the effects of genes and environment are not independentBy using the current model we cannot, however, make distinction between different causal pathwaysGene-environment correlation refers to situation when allele frequencies are not independent of environmentThus, the environment people are living is partly generated by their genotypeFor example, moderate heritability is found for experience of negative life events
6 Sources of gene-environment correlations There are three possible sources of gene-environment correlationPassive gene-environment correlationParents transmit both their genes and environmentGenetically musically talented parents more often listen music and own musical instrumentsActive gene-environment correlationSubjects with a certain genotype actively select environments that are correlated with that genotypeGenetically musically talented children like to participate musical educationReactive gene-environment correlationSubjects with a certain genotype evoke certain reactions from environmentMusic teachers pick up genetically musically talented children for special supervisionActive and reactive gene-environment correlations may be one of the reasons why heritability of many personality traits (e.g. intelligence) seem to rather increase than decrease during agingThe possibility of rGE should be taken into account in interpretations of resultsFor example if ADHD children suffer more maltreatment at home the reason may be that their parents has also genetic predisposition to antisocial behavior
7 G*E interaction based on multiple group analysis A simple way to analyze G-E interactions is to stratify the data by the environmental exposureThus, we can simply utilize multiple group comparison using univariate modelsSignificant differences in genetic and/or environmental variance components across the categories indicate the existence of G-E interaction
9 Heritability of height in different birth cohorts in men Source: Silventoinen et al, Am J Publ Health 2000
10 Heritability of height in different birth cohorts in women Source: Silventoinen et al, Am J Publ Health 2000
11 Problems in multiple group comparisons Multiple group comparisons have limitations, which make them unsuitable to many situationsEnvironmental exposure needs to be same for both co-twinsSuch as birth cohort or place of residenceIf environmental exposure is continuous, categorizing it loses a lot of information if the associations are linearHowever if this kind of limitations are not a problem, multiple group comparison is a good alternative to more sophisticated G-E interaction modelsInterpretation of the results is very straightforwardPossible non-linearity is not a problemWe can accept heterogeneity between the categories
14 Matrix algebra for G-E interactions The equation a+βXM is a linear functionWhy this can be used to analyze interactions?We are interested in the variance component a2 instead of the path coefficient aThus (a+βXM)2=a2+2*a*βXM+(βXM)2This can be easily generalized to multivariate case using matrix algebra rules
15 Multivariate G-E interaction model a1+βY1Ma12+βY12Ma2+βY2MTP
16 Non-linear interaction effects It is also possible that the effect of environmental exposure is not linear but curvilinearFor example, genetic variation may be low both at low and high level of environmental exposureThis can be modeled simply by including a new moderator term in the modelEven when curvilinear effects are not difficult to model, power may be a problemAlso the extreme ends of environmental exposures may be problematicReporting errors etc.Before analyzing curvilinear associations, there should be clear theoretical justification why we expect this kind of associationsSample size should also be large and the measurement of environment high quality
21 Effect of G-E interactions on heritability If G-E interaction is not modeled it naturally does not mean that it would not affect the resultsIn many cases we have not measured relevant environmental exposures, but we have to speculate whether they can still explain the found resultsG-E interaction may well be one reason why common environmental influences are rarely seen even in the case when this in counterintuitiveFor example, the lack of common environmental effect in many psychological traitsIt may reflect rather that the effect of family related factors is modified by genetic factors than the lack of this effect
22 Contributions of Genetic, Shared Environment, Genotype x Shared Environment Interaction Effects to Twin/Sib ResemblanceShared EnvironmentAdditive Genetic EffectsGenotype x Shared Environment InteractionMZ Pairs11 x 1 = 1DZ Pairs/Full Sibs1 x ½ = ½In other words—if gene-(shared) environment interaction is not explicitlymodeled, it will be subsumed into the A term in the classic twin model.
23 Contributions of Genetic, Unshared Environment, Genotype x Unshared Environment Interaction Effects to Twin/Sib ResemblanceUnshared (Unique) EnvironmentAdditive Genetic EffectsGenotype x Unshared Environment InteractionMZ Pairs10 x 1 = 0DZ Pairs/Full Sibs0 x ½ = 0If gene-(unshared) environment interaction is not explicitly modeled,it will be subsumed into the E term in the classic twin model.