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Statistical Genetics of Substance Use (SU) and Substance Use Disorders

Statistical Genetics of Substance Use (SU) and Substance Use Disorders. Kenneth S. Kendler, MD Virginia Institute of Psychiatric and Behavioral Genetics Virginia Commonwealth University Advanced Genetic Epidemiology Statistical Workshop Oct 22, 2012.

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Statistical Genetics of Substance Use (SU) and Substance Use Disorders

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  1. Statistical Genetics of Substance Use (SU) and Substance Use Disorders Kenneth S. Kendler, MDVirginia Institute of Psychiatric and Behavioral Genetics Virginia Commonwealth University Advanced Genetic Epidemiology Statistical Workshop Oct 22, 2012

  2. 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?

  3. Heritability Of Psychiatric Disorders

  4. How Consistent are the Estimates of Heritability of AD Across Space and Time? • Heritability is nota 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.

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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. Interactions between gender, culture and genes – the role of social factors to constrain behavior. • Tobacco consumption and year of birth in Swedish twins. • Study done with Nancy Pedersen on the SATSA sample. • Study males and females separately

  11. Prevalence And Heritability OfRegular Tobacco UseThree Birth Cohorts Of Men And Women In Sweden Heritability

  12. How Consistent are the Estimates of Heritability of SUDs 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. • But a quite different picture is seen for regular smoking behavior with a large gene x cohort interaction in women. • Know much less about results for other psychoactive substance abuse and dependence.

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

  14. Paradigm 2- Advance Genetic Epidemiology – Multivariate Models • 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.

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

  16. Paradigm 2- Advanced Genetic Epidemiology – Multivariate Models • Replicating earlier results from our Virginia twin analyses and from the Minnesota group, SUDs are genetically part of the externalizing group of disorders.

  17. Paradigm 2- Advanced 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.

  18. .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

  19. 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.

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

  21. NICOTINE

  22. Paradigm 2- Advanced 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

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

  24. Paradigm 2- Advanced 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.

  25. Paradigm 2- Advanced 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!

  26. Gene x Environment Interaction Just show one classical example – in type I (adult non-ASPD) alcoholism from Cloninger’s Swedish adoption studies. Risk only high in subjects at high genetic risk and exposed to high risk environment.

  27. Paradigm 2- Advanced 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

  28. Paradigm 2- Advance Genetic Epidemiology – Gene x Environment Interaction • Many other interesting G x E findings for alcohol use. • A few other examples many from the work of my colleague Danielle Dick. • 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.

  29. 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)

  30. Adoption Studies • Let’s take a short detour in to adoption studies. • Obvious point about scientific inference • More secure about any finding when you can reach it by multiple routes, esp when they have different potential biases.

  31. Sample • Follow-up in 9 public data bases (1961-2009) in Sweden of adoptees and their biological and adoptive relatives. • Identified 18,115 adoptees born 1950-1993; 78,079 biological parents and siblings; 51,208 adoptive parents and siblings. • DA recorded in medical, legal or pharmacy registry records.

  32. Sources of Data • 1. The Swedish Hospital Discharge Register included all hospitalizations (including for DA) for all people in Sweden from 1964-2009. Every record has the main discharge diagnosis and eight secondary diagnoses. • 2. The Swedish Prescribed Drug Register included all prescriptions in Sweden picked up by patients from May 1st2005 through 2009. It is complete, as all prescriptions are registered at the National Board of Health and Welfare. • 3. The Swedish mortality register contained all causes of death and time of death from 1961-2009.

  33. Sources of Data • 4. The National Censuses provided information on education and marital status in 1960, 1970, 1980, and 1990. • 5. The Total Population Registry included annual data on education and marital status from 1990-2009. • 6. The Multi-Generation Register provided information on family relationships from 1932 to 2009 including all adoptions and adoptive and biological parents and siblings. Biological siblings reared with the adoptee were excluded. • 7. The Outpatient Care Register included information from all outpatient clinics in Sweden from 2001-2009.

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