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Gene-environment interaction and Gene-environment correlation Charlotte Huppertz VU University Medical Center Amsterdam Netherlands Twin Register Book recommendation Chapter: “The interplay between genes and environment” References to studies that will be mentioned Background • Assumption: no GxE interaction or correlation • However: genes and the environment are not two separate entities • They can interact and they can be correlated • This may influence the phenotypic variance GENE-ENVIRONMENT INTERACTION Gene-environment interaction Definition • The effects of the environment can depend on genetics, and the effects of genetics can depend on the environment • Genes evolved to respond to the environment • Environment = all influences other than inheritance, including intracellular and extracellular factors Pima Indians in Arizona • Followed since 1965 • Highest reported prevalence of type 2 diabetes • Traditional agricultural goods processed foods Effects on estimates If G-E interaction is not modelled, it will bias the estimated parameters Effects on twin resemblance: A C AxC MZ pairs 1 1 1x1= 1 DZ pairs 0.5 1 0.5x1= 0.5 An interaction with C would end up in the A-component, if not modelled. A E AxE MZ pairs 1 0 1x0= 0 DZ pairs 0.5 0 0.5x0= 0 An interaction with E would end up in the E-component, if not modelled. Effects on estimates • Hidden G-C interaction may be one of the reasons why we rarely see C: The effects of the shared environment may be modified by genes • We should at least discuss this possibility • Still, our results are meaningful – given a certain environment Gene-environment interaction How to identify interaction? • Animal studies – Both genotype and the environment can be manipulated – E.g. inbreeding • Adoption studies • Twin studies • Molecular genetic studies Gene-environment interaction How to identify interaction? • Animal studies – Both genotype and the environment can be manipulated – E.g. inbreeding • A) Adoption studies • B) Twin studies • C) Molecular genetic studies Gene-environment interaction A) Adoption studies • Adoptee • Biological parents (shared genes) • Adoptive parents (shared environment) EXAMPLE: criminal convictions (CC) CC adoptive parents + CC biological parents → CC child CC adoptive parents + No CC biological parents → Less so... Gene-environment interaction B) Twin studies „Does h² differ in two environments?“ EXAMPLE: More permissive environment larger h² of alcohol use and abuse Environment needs to be the same for both twins Very large samples needed (e.g., 1000 pairs of each zygosity to identify a difference in h² of 40% vs. 60%) Gene-environment interaction C) Molecular genetic studies „Does the effect of specific genes differ in two environments?“ EXAMPLES: • MAOA gene antisocial behavior, given childhood maltreatment • 5-HTT gene depression, given stressful life events • Cannabis use psychotic symptoms (hallucinations …), given a particular allele of the COMT gene GENE-ENVIRONMENT CORRELATION Gene-environment correlation Many measures of the „environment“ show genetic influence (~30%) ● SES ● Exposure to accidents ● Family environment ● Divorce ● Work environment ● Other life events ● Classroom environment ● Subjective processes ● Stress ● Friends ● Social support in filling out a Life involved events and circumstances not „just happen“ to us! questionnaire Genes & experiences are correlated. … Gene-environment correlation Implication • If an environmental measure is correlated with a behavior, this doesn‘t automatically imply environmental causation – it could also reflect underlying genetic factors • Parents affect children through their genes and through the family environment – often difficult to disentangle! EXAMPLE: books & reading ability Gene-environment correlation 3 types of correlations • PASSIVE – Children receive genotypes correlated with their family environment – Requires interactions between genetically related individuals • REACTIVE/EVOCATIVE – Individuals are reacted to on the basis of their genetic propensities • ACTIVE – Individuals seek or create environments correlated with their genetic propensities Gene-environment correlation How to identify correlation? • 1) Compare adoptive vs. nonadoptive families – Detects the passive type • 2) Adopted children and their parents – Detects the reactive and the active type • 3) Multivariate genetic models – Detects all types Gene-environment correlation 1) Compare adoptive vs. nonadoptive families • Factor in family environment child‘s behavior • Measure this factor and children‘s behavior both in nonadoptive families and adoptive families • Crucial difference: – Adoptive families: parents pass on E – Nonadoptive families: parents pass on A and E • GE correlation is implied if the correlation is larger in nonadoptive families Gene-environment correlation 2) Adopted children and their parents • Requires: – adopted children – their adoptive parents – their biological parents • Traits of biological parents = (weak) index of children‘s genotypes • Correlation of adoptive family environment with traits of biological parents environment & genetically influenced characteristics of the adopted children are correlated Gene-environment correlation 3) Multivariate genetic models Calculate the genetic correlation (overlap) between the environmental measure and the trait the environmental measure must be specific to each individual (e.g., family SES is not possible) QUESTION: How would you estimate this overlap? Take home messages • Genes and the environment are not two separate entities • The effects of genes can depend on the environment and vice versa (INTERACTION) • Many environmental measures show genetic influence (CORRELATION)