COMT EFFECT ON AGGRESSION IN CHILDREN WITH & WITHOUT ADHD (British Cohort) blems (t-scores) Aggressive Behaviour Prob. n =

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1 GENE-ENVIRONMENT ENVIRONMENT INTERDEPENDENCE By Michael Rutter 445oslo1109a 1 SOME BACKGROUND CONSIDERATIONS RE DISORDERS With rare exceptions, most mental disorders are multifactorial Heritability of mental disorders quite variable - very high for autism, schizophrenia & ADHD Neurodevelopmental impairment in childhood important for some disorders (autism, schizophrenia, ADHD) but not for others (bipolar disorder, depression/anxiety) Substantial co-occurrence occurrence among mental disorders meaning Multiple genes and multiple environmental factors Many disorders involve a spectrum Most involve overlapping disorders/symptom patterns Often there are developmental changes in symptom patterns 2 SOME BACKGROUND CONSIDERATIONS RE GENES I Genes may be important through their protective effects Each single gene that codes for proteins actually involves multiple DNA elements affecting transcription and expression Most genes have pleiotropic i effects Genes often affect biological pathways relevant for multiple disorders and for variation in individuals without disorder Genetic effects may depend on interacting patterns of genes Genes do not code for psychiatric diagnoses! 3 1

2 SOME BACKGROUND CONSIDERATIONS RE GENES II (see Uher, 2009) Both schizophrenia and autism are associated with reduced fecundity But both conditions not eliminated: Why not? Implication is that genetic mechanism associated with schizophrenia and autism likely to differ from disorders (such as depression) without reduced fecundity 4 SOME BACKGROUND CONSIDERATIONS RE GENES III Some genetic effects operate within disorders (eg COMT effects on antisocial behavior within ADHD) Some genetic effects involve genomic imprinting and some involve transgenerational change (eg trinucleotide expansion) Some genetic effects operate via quantitative trait loci (Q.T.L.s) rather than categorical differences Genetic effects on mental disorders may operate via neuroendocrine system or immunity mechanisms rather than via neurotransmitters 5 COMT EFFECT ON AGGRESSION IN CHILDREN WITH & WITHOUT ADHD (British Cohort) blems (t-scores) Aggressive Behaviour Prob Met/Met Val/Met Val/Val 45 n = No ADHD ADHD 6 2

3 COMT EFFECT ON CONVICTIONS IN ADULTS WITH & WITHOUT ADHD AS A CHILD (Dunedin cohort) Convicted for offenc ce (%) Met/Met Val/Met Val/Val 0 n = No ADHD ADHD 7 SOME BACKGROUND CONSIDERATIONS RE NON-GENETIC EFFECTS (see Academy of Medical Sciences, 2007) Good evidence of strong environmental causes of disease Many claims on environmental causes are unsound because they fail to consider genetic mediation, reverse causation and unmeasured confounders Non-genetic effects may involve developmental perturbations (rather than specific environmental hazards) Environmental influences may be prenatal (and not just postnatal) Environmental effects on biology (i.e. they get under the skin ) (via biological programming, HPA effects, mental models, etc.) Some nongenetic effects (such as high paternal age) may involve effects on mutations 8 WHY DO INDIVIDUAL GENES HAVE SUCH TINY EFFECTS? Twin studies convincingly demonstrate that the overall effects of genes on psychiatric disorders accounts for some 30% to 90% of the variance But The odds ratios for individual genes are rarely above 1.2 or 1.3 Why? 9 3

4 TRADITIONAL ANSWERS TO WHY SINGLE GENES HAVE SUCH SMALL EFFECTS Hundreds of different genes involved Huge genetic heterogeneity 10 MODERN ANSWERS TO WHY SINGLE GENES HAVE SUCH SMALL EFFECTS I Genetic influences operate on behaviours that are within diagnostic categories (cf COMT effect on antisocial behaviour that is within ADHD) Genetic influences differ between the sexes Genetic influences operate on dimensions that are only indirectly associated with psychopathology 11 MODERN ANSWERS TO WHY SINGLE GENES HAVE SUCH SMALL EFFECTS II Importance of epigenetic effects Importance of copy number variations (CNVs) Importance of gene-environment environment correlations (rge) Importance of gene-environment environment interactions (GxE) Importance of gene-gene interactions (GxG) 12 4

5 MULTIPLE VARIETIES OF GENETIC - NONGENETIC INTERPLAY A. NONGENETIC EFFECTS ON GENE ACTIONS 1. Epigenetic effects on gene expression 2. Nongenetic effects on copy number variations and chromosomal anomalies 3. Effects of environment on variations in heritability B. GENETIC EFFECTS ON ENVIRONMENT RISK EXPOSURE 1. Gene-environment environment correlations (rge) influence shaping/selecting of environments indirectly through effects on behavior C. GENE-ENVIRONMENT ENVIRONMENT CO-ACTION 1. Gene-environment environment interaction (GxE) involves environmental moderation of genetic influences and vice- versa (NB This means that effects of G plus effects of E summate to more than 100%) 13 ARE THERE POSITIVE REASONS FOR EXPECTING G-E CO-ACTION? I. EPIGENETICS Numerous animal studies have demonstrated the reality and importance of epigenetic effects e.g. Meaney rat studies of archback nursing Jirtle studies of genomic imprinting But Epigenetic effects are tissue and developmental phase-specific specific So Need for animal models and post-mortem studies (as well as testing of extent to which the degree of expression in the brain makes lymphocyte studies worthwhile) (See refs: Jirtle, R.L. & Skinner, M.K. (2007). Environmental epigenomics and disease susceptibility. Nature Reviews Genetics, 8, Mill, J. & Petronis, A. (2007). Molecular studies of major depressive disorder: the epigenetic perspective. Molecular Psychiatry, 12, ) 14 ARE THERE POSITIVE REASONS FOR EXPECTING G-E CO-ACTION? II. DEVELOPMENTAL PERTURBATIONS 1. Brain development is probabilistic i.e. neuronal overproduction is followed by neuronal pruning to correct initial errors 2. Minor errors are very common (congenital anomalies, CNVs, etc.) 3. Reality of parental age effects (e.g., on autism) Research implication is that it is crucial to determine the origins of developmental perturbations as well as their effects Why, for example, are chromosomal anomalies, congenital anomalies & CNVs apparently unusually frequent in autism? 15 5

6 ARE THERE POSITIVE REASONS FOR EXPECTING G-E CO-ACTION? III. rge Many of the key environmental risk/protective factors, derive from human behaviour (e.g. marital conflict/break-up, sexual abuse, social support, loss of jobs) If human behaviour influences environmental exposure it follows that there will be genetic influences on risk exposure Research implication is that investigations need to focus on which behaviours have which effects on which environments (the extent to which there is a genetic influence is a secondary consideration) 16 ARE THERE POSITIVE REASONS FOR EXPECTING G-E CO-ACTION? IV. GxE 1. Genetically influenced differential response to the environment constitutes the mechanism thought to give rise to evolutionary change 2. To suppose that there is no GxE would require the assumption that environmental responsivity is the one biological feature that is uniquely outside of genetic influence 3. A wide range of human and animal naturalistic and experimental studies have shown huge heterogeneity in response to all manner of environmental features physical and psychosocial. It is implausible that this variation involves no genetic influence 17 EMPIRICAL EVIDENCE ON GxE 1. Range of pointers from quantitative genetics 2. Replicated GxE from epidemiological/ longitudinal studies using identified genes and measured environments 3. Evidence of GxE from human experimental studies 4. Evidence of GxE from animal models 5. Evidence on biological pathways from basic science 18 6

7 SOME BACKGROUND STATISTICAL CONSIDERATIONS Essential to check: i. Whether scaling has resulted in artefactual GxE ii. Whether G-G G could account for GxE interaction iii.whether additive or multiplicative synergistic interaction iv.whether proper attention paid to multiple tests Not necessary to rely on main genetic effect (note that both forward & backward modelling have mixture of pluses and minuses) 19 SOME BACKGROUND CONSIDERATIONS RE INTERMEDIATE PHENOPTYPES (IPs) Point of IPs is to have a feature that: a. Is on the same biological pathway as that leading to disorder b. Involves a stress challenge that is manipulable c. Gives rise to an immediate or non-delayed response that can be objectively measured d. (Ideally) that is also usable in animal models 20 EFFECT OF LIFE STRESS ON DEPRESSION MODERATED BY 5-HTT GENE (from Caspi et al., 2003) major pisode Probability of depression ep s/s = short allele homozygous l/l = long allele homozygous s/l = heterozygous s/s s/l l/l Number of stressful life events 21 7

8 ASSOCATION BETWEEN ALLERGIC SENSITIZATION AT 5yrs & EXPOSURE TO ENDOTOXIN IN HOUSE DUST BY CD14/ GENOTYPE (Martinez, 2008) ity for Predicted probabili sensitization x10 Endotoxin Load (EU/m2) CC CT TT 22 EFFECTS OF 5-HTT GENOTYPE ON RIGHT AMYGDALA ACTIVATION IN RESPONSE TO FEARFUL STIMULI (from Hariri et al., 2002) change % BOLD fmri signal Long allele group Short allele group 5-HTT genotype 23 EFFECTS OF SEROTONIN TRANSPORTER GENE AND PATTERN OF REARING ON CENTRAL SEROTONIN FUNCTIONING (from Bennett et al., 2002) ations: z-score CSF 5-HIAA concentra Homozygous Heterozygous Homozygous Heterozygous Long Allele Long Allele Long Allele Long Allele Peer-reared Parent-reared 24 8

9 WHY ARE SO MANY BEHAVIOURAL GENETICISTS HOSTILE TO ANY CLAIMS ON G-E CO-ACTION? 1. Focus on GxE as a statistical, rather than biological, concept 2. An exclusive focus on epidemiological studies and a stubborn refusal to take account of either experimental studies with humans or animal models 3. Defensive over historical dismissal of GxE 4. Awareness that adequate study of G-E co-action requires high quality E measures that have not received much attention in genetics research 5. Adequate study of G-E co-action requires new samples and strategies 6. Possibly also resentment over non-geneticists entering the genetic field 25 RESEARCH NEEDS IN RELATION TO GxE 1. Experimental, as well as epidemiological, studies 2. Hypothesis-driven approaches 3. Use of proximal E effects shown to be environmentally mediated 4. Test for timing of GxE effects (to consider possibility of GxG) 5. Use of intermediate phenotypes 6. Study of biological mechanisms 7. Use of animal models (see Moffitt, T.E., Caspi, A., & Rutter, M. (2005). Strategy for investigating interactions between measured genes and measured environments. Archives of General Psychiatry, 62, ) 26 CONCLUSIONS ON G-E INTERDEPENDENCE Should be major growth area of research into G and into E No one research strategy adequate Must not be tied to DSM-IV (or any other) diagnostic categories Must focus on biological mechanisms Must involve good measures of proximal environmental influences 27 9

10 GENE-ENVIRONMENT ENVIRONMENT INTERDEPENDENCE By Michael Rutter 28 10