IMPLICATIONS OF GENE- ENVIRONMENT INTERPLAY FOR APPROACHES TO SUBSTANCE ABUSE AND COMORBIDITY

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1 Ppt. Oslo 3 th Nov 9 IMPLICATIONS OF GENE- ENVIRONMENT INTERPLAY FOR APPROACHES TO SUBSTANCE ABUSE AND COMORBIDITY By Michael Rutter PERCENTAGE OF GENETIC INFLUENCE REPORTED IN BEHAVIORAL GENETIC STUDIES OF ANTISOCIAL BEHAVIOR (derived from Moffitt, ) s No. of studies % % % Heritability Estimates SUBSTANCE ABUSE INVOLVES PATHWAYS Experimental trying of substances Regular use of substances Heavy use of substances Substance abuse 3

2 MOST SUBSTANCE ABUSE INVOLVES MULTIPLE SUBSTANCES This means that an unusual response to a single substance is most unlikely to constitute a general explanation of substances abuse. Causal processes likely to involve risk-taking and peer-group influences. RATE OF SUBSTANCE USE/ABUSE IN TEENAGERS (from Heath et al., 8) Smoking regularly Drinking alcohol heavily/regularly Illicit drug use - ever Use c.-% c.8% c.-% Abuse c.% CRITERIA FOR SUBSTANCE USE DISORDER (Heath et al., 8) Heavy Use (indexed by tolerance). Loss of control (including difficulty quitting). Continued use despite adverse consequences. Problems associated with cessation of use (withdrawal). 6

3 RESULTS OF ALCOHOL SLEEP-TIME SELECTION STUDY (taken from Plomin et al., 8) (sec) 7 Long sleep Short sleep Sleep time Generation 7 DISTRIBUTIONS OF ALCOHOL SLEEP TIME AFTER GENERATIONS OF SELECTION (adapted from Plomin et al., 8) 3 Number of anim mals Sleep time (sec) 8 CAUSES OF STRESSFUL LIFE EVENTS (SLEs) ESTIMATED IN A LONGITUDINAL STUDY OF TWINS (Kendler & Prescott, 8) Enduring factors factors mental factors shared by twins Enduring -spec. factors Risk for SLE Time-specific factors Bad luck Measurement error Transient individual factors 9 3

4 HERITABILITY OF ENVIRONMENTAL FEATURES (rge) (based on Kendler & Baker, 7) Weighted h for 3 environ nmental measures 3 Self-report Informant report Observation N.B. h twice the above for temporally stable measures EFFECTS OF DISORDER IN BIOLOGICAL PARENT ON DISCIPLINARY PRACTICES OF ADOPTIVE MOTHER MEDIATED BY BIOLOGICAL EFFECTS ON CHILD BEHAVIOR (based on Ge et al., 996) Adoptive parents marital warmth -.6* Adoptive mother s harsh/inconsistent parenting -..8*.* Biological parents antisocial, drug or alcohol problems.3* Adoptee s antisocial/disruptive/ defiant behaviors ODDS RATIOS FOR COTWIN-CONTROL ANALYSES OF CHILDHOOD SEXUAL ABUSE AND RISK FOR PSYCHIATRIC AND SUBSTANCE USE DISORDERS IN FEMALE TWIN PAIRS (taken from Kendler & Prescott, 6) OR 8 6 All subjects Discordant pairs Alcohol dependency Drug dependency + disorders

5 ESTIMATED PROPORTIONS OF VARIANCES FOR ILLICIT SUBSTANCE USE DISORDERS FROM COMMON AND SPECIFIC GENETIC AND ENVIRONMENTAL FACTORS (taken from Kendler & Prescott, 6) A c C c E c 7 < < 6 6 < 6 Cannabis Sedatives Stimulants Cocaine Opiates Hallucinogens ESTIMATED PROPORTIONS OF COMMON AND SPECIFIC VARIANCE FOR PSYCHIATRIC AND SUBSTANCE USE DISORDERS SOURCES OF SHARED ENVIRONMENTAL VARIANCE (taken from Kendler & Prescott, 6) C C 9 < 9 7 Major Depression Generalized Anxiety Phobia Alcohol Dependence Drug Dependence Adult Antisocial Behavior Conduct Disorder < < TWIN ANALYSES OF ASSOCIATION BETWEEN AGE AT FIRST DRINK AND LATER ALCOHOL DEPENDENCE (data from Prescott & Kendler, 999) Males % <% 3% % % % 3% % 8% Age at First Drink Alcohol Dependence Females % <% 3% % 39% 36% 6% 8% 9% Age at First Drink Alcohol Dependence

6 TWIN MODEL FOR INITIATION AND ABUSE OF ANY ILLICIT SUBSTANCE (taken from Kendler & Prescott, 6) Any influence after measured initiation A i C i E i A i C i E i 6% 8% % % % % Measured Initiation 66% Any Substance Abuse 6 ODDS RATIO FOR ASSOCIATION BETWEEN ALCOHOLISM IN ONE TWIN AND THE -YEAR OCCURRENCE OF STRESSFUL LIFE EVENTS IN OTHER TWIN (data from Kendler & Karkowski-Shumann, 997) 3. MZ DZ OR.. Network death Network illness Network conflict Job loss Lost confidant Marital problems Divorce Legal problems Robbery Assault Financial prob... Illness/injury 7 ODDS RATIOS FROM COTWIN-CONTROL ANALYSES OF ASSOCIATION BETWEEN DRINKING BEFORE AGE AND LATER ALCOHOL DEPENDENCE (taken from Kendler & Prescott, 6) All participants DZ pairs MZ pairs 3 OR Males Females 8 6

7 BIVARIATE TWIN MODEL FOR OVERLAP OF NOVELTY SEEKING AND CANNABIS INVOLVEMENT AMONG MALES (taken from Kendler & Prescott, 6) 3% 7% % % % 7% % 83% 8% Novelty Seeking Cannabis Use % 8% 6% % 6% 7% % 83% Novelty Seeking % Cannabis Dependence 9 MENDELIAN RANDOMIZATION TO TEST ASSOCIATION BETWEEN ALCOHOL USE AND OTHER PROBLEM BEHAVIORS (from Irons et al., 6) % with specified outcome Alcohol abuse Adult antisocial behaviour Illicit drugs in past year ALDH deficient ALDH not deficient HUMAN EXAMPLES OF GxE WITH RESPECT TO SUBSTANCE USE. ALDH leads to inactivity of a key enzyme in the metabolism of alcohol. Gene present in % of Chinese and % Japanese (marked by an unpleasant flushing response to alcohol). Its presence is associated with a -fold reduction in the rate of alcohol consumption and marked reduction in alcoholism.. High risk studies of Schuckit showing that young adult offspring from high-risk families showed that a low level of response to an alcohol challenge test characteristic of young people with a family history of alcoholism (i.e., suggests that low level of responsivity predisposes to heavy drinking). 3. Evidence from pharmacogenetics. 7

8 SCHIZOPHRENIA SPECTRUM DISORDER: CANNABIS USE INTERACTS WITH GENOTYPE (data from Caspi et al., ) disorder (%) schizophreniform d COMT genotype Met/Met Met/Val Val/Val No adolescent use Adolescent use GENERAL MESSAGES DERIVING FROM rge FINDINGS. Humans actively create (through selection and shaping) their social environment and interpersonal relationships.. Strong support for bi-directional models of person-environment inter-relationships. 3. An important part of genetic influences will be outside the skin, meaning that their impact on disease/disorder will be mediated through effects on environmental risk exposure.. Standard heritability estimates cannot differentiate inside and outside the skin pathways. 3 IMPLICATIONS OF GENE-ENVIRONMENT INTERPLAY FINDINGS FOR CONCEPTS OF COMORBIDITY If much of the co-occurrence of supposedly different disorders reflects a shared genetic liability, this suggest that much comorbidity is artefactual. That is, it reflects mixed clinical manifestations of a single disorder, rather than overlap between entirely different disorders. Message: The findings of co-occurrence should lead to a study of competing explanatory possibilities, rather than a conclusion of true comorbidity. 8

9 SUBSTANCE USE/ABUSE NECESSARILY IMPLIES GENE-ENVIRONMENT INTERPLAY. Substances are themselves an E (i.e., an environmental element outside the body).. If there is choice in use of substances (there is), individual differences in behavior will play a part in the shaping & selecting of environment. If such behavior is open to genetic influence (all behavior is), then there will be geneenvironment correlations (rge). 3. If there are individual differences in susceptibility to substances (there are) these will be subject to some degree of genetic influence and, therefore, there will be a geneenvironment interaction (GxE). CONCLUSIONS Gene-environment interplay (both rge and GxE) is intrinsic to substance abuse. genetic liability underlies much of comorbidity. 6 IMPLICATIONS OF GENE- ENVIRONMENT INTERPLAY FOR APPROACHES TO SUBSTANCE ABUSE AND COMORBIDITY By Michael Rutter 7 9