1. 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

2. 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?

3. 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.

5. 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?

6. 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

7. 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.

8. 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

9. 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

10. 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

11. 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.

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

14. 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
Complete birth cohort.
Sweden underwent several dramatic changes.
Income increased 6-fold
Government experimented with changes in governmental control of access to alcohol.

15. 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.

19. 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.

21. 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?

22. 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).

23. 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.

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

25. 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.

26. 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.

27. 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

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

29. 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.

30. .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

31. 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.

32. 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

33. 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 ~

34. 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.

35. 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:
Copyright restrictions may apply.

39. NICOTINE

42. 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

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

48. 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.

51. 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!

52. 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

56. 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.

57. 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)

58. 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.

59. Mean Variance MZ-ICC DZ-ICC

62. 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.

65. 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!

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

67. 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

68. 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

69. 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

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

71. 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.

72. 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 --

73. 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

74. 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.

75. 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.

76. 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.

77. 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?

78. 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

80. 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