The Genetic Epidemiology of Substance Use and Substance Use Disorders Kenneth S. Kendler, MD Virginia Institute of Psychiatric and Behavioral Genetics Virginia Commonwealth University NIDA Workship VIPBG Oct 18, 2010

Outline of Talk 1. Review of paradigms in psychiatric genetics 2. Basic genetic epidemiology Heritability of Substance Use Disorders (AD). How stable over time and place?

Outline of Talk 3. Advanced genetic epidemiology Multivariate models of SUDs and other psychiatric disorders Sex effects Development Cross-generational transmission Gene x environment interaction G-E correlation Integrated etiologic model of AD Multivariate model of DSM-IV AD criteria.

Paradigm 1- Basic Genetic Epidemiology - What Have We Learned? Genetic factors play a substantial role in the etiology of Substance Use Disorders (AD). Heritability – the proportion of individual differences in a particular disorder or trait in a particular population that results from genetic differences between individuals. Heritability estimates typically in the range of 50-60% How does this compare to other psychiatric and biomedical disorders?

Heritability Of Psychiatric Disorders Other Important Familial Traits ~zero Language Religion 20-40% Anxiety disorders, Depression, Bulimia, Personality Disorders Myocardial Infarction, Normative Personality, Breast Cancer, Hip Fracture 40-60% Alcohol Dependence Drug Dependence Blood Pressure, Asthma Plasma cholesterol, Prostate Cancer, Adult-onset diabetes 60-80% Schizophrenia Bipolar Illness Weight, Bone Mineral Density 80-100% Autism Height, Total Brain Volume

How Consistent are the Estimates of Heritability of AD Across Space and Time? Heritability is not a characteristic of a disorder – rather it is a feature of a disorder in a specific population at a specific time. We will look quickly at twin studies of AD and other SUDs. First, a quick peak at adoption studies of AD – only SUD for which we possess adoption data.

IB. Results from Gen Epi Studies of SUDs Rates of alcoholism among adoptees with and without biological alcoholic parents Figure 1, Prescott, Maes & Kendler, 2005 Studies of male adoptees Studies of female adoptees

Genetic & environmental proportions of variance in alcoholism estimated from studies of male twins Clinical sample cotwin followup Population registry archival diagnosis Volunteer registry personal interview Figure 2a, Prescott, Maes & Kendler, 2005

Genetic & environmental proportions of variance in alcoholism estimated from studies of female twins Clinical sample cotwin follow-up Volunteer registry personal interview Population registry archival diagnosis Figure 2b, Prescott, Maes & Kendler, 2005

Summary Slide Based on published meta-analyses or ones we did ourselves (with Joe Bienvenu) – pretty large CIs. Main results of non-alcohol SUDs from two studies – VATSPSUD and Vietnam Era twin study. Some reports from the Australian and Norwegian registiries.

How Consistent are the Estimates of Heritability of AD Across Time? Swedish Temperance Board Registration Data – 8,935 pairs of male-male twins born 1902-1949.

How Consistent are the Estimates of Heritability of AD Across Space and Time? Swedish Temperance Board Registration Data – 8,935 pairs of male-male twins born 1902-1949. Complete birth cohort. Sweden underwent several dramatic changes. Income increased 6-fold Government experimented with changes in governmental control of access to alcohol.

How Consistent are the Estimates of Heritability of AD Across Space and Time? In 1917, Sweden adopted a nationwide alcohol rationing system that strictly limited the amount of alcohol that an individual was permitted to purchase. An individual's official limit varied according to sex, age, and financial situations, and was, for men older than 25 years, usually between 1 and 3 L of hard liquor per month.

How Consistent are the Estimates of Heritability of AD Across Space and Time? So, to the best of our knowledge, the heritability of AD is relatively robust – across multiple European populations living in Australia, North American and Europe and across a half century of Swedish history that saw dramatic changes in that country.

Paradigm 2- Advance Genetic Epidemiology Many questions relevant to alcohol dependence Begin with question of multivariate models – What is the relationship between the genetic and environmental risk factors for SUDs and for psychiatric disorders?

Paradigm 2- Advance Genetic Epidemiology – Multivariate Models 7 common psychiatric and substance use disorders assessed at personal interview in over 5,600 male and female twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorder (VATSPSUD).

Paradigm 2- Advance Genetic Epidemiology Sources of Comorbidity –Do genes respect DSM-IV or ICD-10? Recall your As, Cs and Es A = additive genetic effects C = common or shared environment Family, school, peer or community effects that make twins similar E = individual or unique environment “slings and arrows” experiences that make twins different.

The full model for 7 common psychiatric and drug abuse disorders Kendler, K. S. et al. Arch Gen Psychiatry 2003;60:929-937. Copyright restrictions may apply.

Paradigm 2- Advance Genetic Epidemiology – Multivariate Models AD and SUD form a common geneitic cluster with CD and ASPD. Heritability of AD ~ 50%. Of this, around 70% shared with externalizing disorders, 29% unique to AD and 1% shared with internalizing disorders. For SUD, heritability ~ 66% of which 64% shared with externalizing disorders, 31% unique to SUD and 5% shared with internalizing disorders.

Paradigm 2- Advance Genetic Epidemiology – Multivariate Models Re-examine this question in 2,111 personally interviewed young adult members of the Norwegian Institute of Public Health Twin Panel. Statistical analyses were performed with the Mx and Mplus programs.

Panic Disorder Major Depression Agoraphobia Somatoform Disorder Specific Phobia Generalized Anxiety Disorder Dysthymia Schizoid PD Schizotypal PD Avoidant PD Dependent PD Social Phobia Axis I Internalizing Axis II Externalizing Antisocial PD Histrionic PD Narcissistic PD Obsessive – Compulsive PD Borderline PD Paranoid PD Eating Disorders Drug Abuse / Dependence Conduct Disorder Alcohol Abuse / .63 .71 .72 .80 .56 .65 .44 .88 .81 .67 .87 .73 .51 .66 .84 .35 .95 .37 .48 .61 .45 .49 .16 .36 .38 .23 .28 Factor 1 Factor 2 Factor 3 Factor 4

Paradigm 2- Advance Genetic Epidemiology – Multivariate Models So, we replicate results – AD and SUD are genetically part of the externalizing group of disorders.

Paradigm 2- Advance Genetic Epidemiology – Multivariate Models Let’s drill down deeper into the relationship between AD and SUD to directly address the question of the specificity or non-specificity of genetic risk factors for AD.

.82 Illicit Substance Genetic Factor Licit Substance Genetic Factor .82 .77 .68 .15 .52 Cannabis Dependence Cocaine Dependence Alcohol Dependence Caffeine Dependence Nicotine Dependence .20 .31 .35 .56 .68 A A A A A E1 .27 .48 .37 .14 .18 Cannabis Dependence Cocaine Dependence Alcohol Dependence Caffeine Dependence Nicotine Dependence .47 .28 .53 .80 .48 E E E E E

Paradigm 2- Advance Genetic Epidemiology – Multivariate Models Similar to prior analyses from this sample, these results suggest that ~ 70% of heritabiity for AD is shared (this time with other drugs of abuse) and 30% unique to AD. For cocaine dependence, for example, 85% of total heritability is shared with other drugs and 15% is unique. In general, pretty clear that non-specific genetic effects outweigh specific effects.

Paradigm 2- Advance Genetic Epidemiology – Sex Effects Sex can impact on genetic effects in two ways. Quantitative effects – genetic effects stronger in one sex than the other. Qualitative effects – different genetic risk factors operating in the two sexes. One extreme - sex-specific gene expression Examples – genetic risks for breast and prostate cancer

Paradigm 2- Advance Genetic Epidemiology – Sex Effects In our large Virginia twin study, where we over-sampled opposite sex DZ twins, we found Modest evidence for quantitative sex effects: heritability of AD is slightly higher in females than males. Strong evidence for qualitative sex effects. Genetic correlation in risk between men and women for AD estimated at ~ +0.48.

Paradigm 2- Advance Genetic Epidemiology – Development Genes and environment act through time. Focus on alcohol intake in 1796 members of male-male pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Assessed retrospectively using a life-history calendar.

Kendler, K. S. et al. Arch Gen Psychiatry 2008;65:674-682. The frequency of any use of caffeine, alcohol, nicotine, and cannabis by year from ages 9 to 41 years Kendler, K. S. et al. Arch Gen Psychiatry 2008;65:674-682. Copyright restrictions may apply.

NICOTINE

Paradigm 2- Advance Genetic Epidemiology – Development One more developmental question – Do we see differential developmental changes in the impact of specific genetic risk factors for AD versus non-specific risk factors for externalizing disorders. Again ~ 1700 males from VATSPSUD

Paradigm 2- Advance Genetic Epidemiology Twin-family designs – ask a new set of questions.

Paradigm 2- Advance Genetic Epidemiology How to capture the conditionality of genetic influences on SUDs. No initiation, no chance to express genetic risk. How to model? CCC model – causal, contingent, common pathway.

Paradigm 2- Advance Genetic Epidemiology – Gene x Environment Interaction Definition – the impact of genetic risk factors on disease risk is dependent on the history of environmental exposures. OR – the impact of environment risk factors on disease risk is dependent on genotype. Probably no area of psychiatric genetics research that is more controversial and artifact prone. A range of conceptual and statistical issues - Buyer beware!

Paradigm 2- Advance Genetic Epidemiology – Gene x Environment Interaction Again ~ 1700 males from VATSPSUD Asked – would the heritability of alcohol consumption in adolescence be modified by key environmental risk factors Alcohol Availability Peer Deviance Prosocial Behaviors

Paradigm 2- Advance Genetic Epidemiology – Gene x Environment Interaction Many other interesting G x E findings for alcohol use. A few other examples. One general theme – Genetic effects on alcohol use are more pronounced when social constraints are minimized and/or when the environment permits easy access to alcohol and/or encourage its use.

Gene-Environment Interaction Alcohol Use Marital Status (Heath et al., 1989) Religiosity (Koopmans et al., 1999) Urban/rural residency (Rose et al., 2001) Neighborhood characteristics (Dick et al., 2001) Parenting/Peers (Dick et al., 2006, 2007)

The Creation of our Social World Through Development Measures of peer group deviance retrospectively reported by a life history method. ~750 male-male twin pairs. Five ages assessed.

Mean Variance MZ-ICC DZ-ICC 8-11 4.49 18.52 0.66 0.47 12-14 7.48 38.03 0.68 0.43 15-17 11.39 45.78 0.67 0.40 18-21 14.04 49.02 0.66 0.39 22-25 13.35 48.68 0.65 0.39

Genetics of Nicotine Dependence Here we have “real” candidate genes. Last year has seen a series of quite consistent findings for a tight block of nicotine receptor genes on chromosome 15q25.

Gene-Environment Correlation Several studies have now shown that these same set of variants in the nicotinic receptor genes impact on risk for adenocarcinoma of the lung. What is going on here? Genetic variant → greater pleasurable effects from nicotine → increased risk for nicotine dependence → seeking cigarettes in the environment → greater exposure to cigarette smoke → increased risk of lung carcinoma. A strange kind of oncogene!

Paradigm 2- Advance Genetic Epidemiology Integrated etiologic models. To just get a start looking at causal pathways.

Genetic Risk Alcoholism Ext Disorders Birth Year Low Church Attendance Household Use Parental Alcohol Attitude Childhood Phys Sexual Abuse .37 .08 ADHD Conduct Disorder 15-17 Alcohol Use 15-17 Neuroticism Sensation Seeking Low Parental Monitoring 15-17 Peer Group Deviance 15-17 Availability 15-17 Early Onset Anxiety Disorder .24 .07 .23 .14 .13 .32 .27 .09 .06 .30 -.06 .12 .16 .18 .17 .34 -.10 .19 .15 Symptoms of Alcohol Use Disorders .05 .26 .10 .21 .22 -.08

Genetic Risk Alcoholism Ext Disorders Birth Year Low Church Attendance Household Use Parental Alcohol Attitude Childhood Phys Sexual Abuse .37 ADHD Conduct Disorder 15-17 Alcohol Use 15-17 Neuroticism Sensation Seeking Low Parental Monitoring 15-17 Peer Group Deviance 15-17 Availability 15-17 Early Onset Anxiety Disorder .23 .12 Symptoms of Alcohol Use Disorders .30 .05 -.06 .26 .10 .06 .07 .24 .21 .22 .08

Genetic Risk Alcoholism Ext Disorders Birth Year Low Church Attendance Household Use Parental Alcohol Attitude Childhood Phys Sexual Abuse ADHD Conduct Disorder 15-17 Alcohol Use 15-17 Neuroticism Sensation Seeking Low Parental Monitoring 15-17 Peer Group Deviance 15-17 Availability 15-17 Early Onset Anxiety Disorder .13 .30 .12 .09 .16 .27 .34 .17 .14 .08 .15 Symptoms of Alcohol Use Disorders .26 .23 .06

Paradigm 2- Advance Genetic Epidemiology – Integrative Developmental Model Evidence for two etiologic pathways characterized by genetic and temperamental factors and by psychosocial adversity.

Paradigm 2- Advance Genetic Epidemiology – Multivariate Model for DSM-IV Criteria for AD Attempted to distinguish two hypotheses. 1. Each of the seven AD criteria index the same set of risk genes so that the diagnosis of AD is genetically homogeneous. 2. The DSM-IV syndrome of AD is genetically heterogeneous, arising from multiple sets of risk genes that are each reflected by a distinct set of diagnostic criteria. Rodent studies suggest relatively distinct set of risk genes for different alcohol-related traits.

Paradigm 2- Advance Genetic Epidemiology – Multivariate Model for DSM-IV Criteria for AD Long arduous task of complex model fitting. 7,548 personally interviewed male and female twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders Had to take account of the fact that lots of people did not meet our screening criteria and skipped out of the alcohol section. This is the best fit model --

Excessive Quantity / Frequency Perception of Alcohol Problem Tolerance .67 .22 .29 .42 .51 .26 .54 .30 .24 .33 .30 .54 .30 .43 .33 .19 .50 .27 .50 .51 .28 .33 .48 .44 .29 .38 .47 Excessive Quantity / Frequency Perception of Alcohol Problem Tolerance Withdrawal Loss of Control Desire to Quit Preoccu- pation Activities Given Up Continued Use Despite Problems .17 .36 .51 .22 .67 .01 .58 .19 .43 .45 .33 .45 .63 .28 .39 .58 .28 .47 .41 .34 .36 .30 .45 .42 .34 .29 .59 ES1 ES2 ES3 ES4 ES5 ES6 ES7 ES8 ES9 E1 E2

Paradigm 2- Advance Genetic Epidemiology – Multivariate Model for DSM-IV Criteria for AD This is the best fit model – Robustly supported second hypothesis – evidence for three genetic factors, which we tentatively called: heavy use and tolerance loss of control with alcohol associated social dysfunction withdrawal and continued use despite known problems.

8 Major Conclusions 1. SUDs are substantially heritable and heritability estimates at least for AD appear to be relatively stable across time and space. 2. Roughly 2/3rds of genetic risk factors for AD and other SUDs are not-disorder specific but are shared with other externalizing disorders generally and other forms of substance abuse more specifically. 3. In early adolescence, siblings resemblance for alcohol and nicotine consumption is entirely due to environmental factors. With increasing age, we see an increasing degree of genetic influence.

Conclusions 4. For at least AD, we do not have strong evidence from GE models for parent-offspring environmental transmission. 5. Genes for AD appear to be rather substantially moderated by environmental exposures, especially those which either relax social constraints and/or permit easy access to alcohol and/or encourage its use.

Conclusions 6. G-E correlation is probably an important etiologic factor in SUDs. Genes can impact on SUDs via outside the skin pathways. 7. I presented one very rough integrated etiologic model for AD – showing how genetic/termpermental and environmental adversity pathways might inter-relate in the etiology. 8. DSM-IV criteria for AD appear, from a genetic perspective, to be etiologically complex reflecting multiple dimensions of genetic risk. Would we see the same for other SUDs?

Key Collaborators Mike Neale PhD Danielle Dick PhD Carol Prescott PhD Hermine Maes PhD Charles Gardner PhD Steve Aggen PhD John Myers MA Ted Reichborn-Kjennerud MD

Support NIAAA Our NIAAA funded Alcohol Research Center at VCU NIDA NIMH Rachel Banks Endowment Funds Virginia Commonwealth University’s generous support for the Virginia Institute for Psychiatric and Behavioral Genetics No conflicts of interest