# Presentation: 733783

## Using Twin Data To Identify Alternative Drug Abuse Phenotypes

- Ming T. Tsuang, MD, Ph.D.
- University Professor, University of California & Director,
- Institute of Behavioral Genomics, Dept. of  Psychiatry,
- UC San Diego;
-  Director, Harvard Institute of Psychiatric Epidemiology and Genetics, Depts. of Epidemiology & Psychiatry, Harvard University

## Background

- Some of the difficulty in identifying genes for drug abuse stems from underlying etiologic complexity of this phenotype.
-  Unlike disorders such as Huntington’s disease, drug abuse is presumed to have a multifactorial polygenic etiology, in which numerous genes and environmental factors all make small contributions to the overall risk for the illness.

## Moving Beyond “Off the Shelf” DSM Phenotypes

- Empirical methods, such as factor analysis, may help to identify useful “quantitative traits.”
- Transitions may reflect different phenotypes with different genetic determinants
- Psychiatric disorders that co-occur with substance abuse may reflect the same genetic vulnerability

## Previous Relevant Research Using the Vietnam Era Twin Registry

## Sample Demographics

- Mean age - 44.6 years (_+_2.8 years)
- Age range - 36 to 55 years
- Ethnicity							non-Hispanic white 90.4%				African American 4.9%				Hispanic 2.7%	                                                	Native American 1.3%                                	“Other” 0.7%

## Sample Size

- Number of individuals: 8,169
- response rate: 79.7%
- completed pairs:						MZ - 1,874						DZ - 1,498

## Vietnam Era Twin Registry

- Consists of 7,375 male-male twin pairs
- Both served on active duty during the Vietnam Era (1965-1975)

- Born between 1939  and 1957
- Identified from Dept. of Defense data files by computer algorithm

## Vietnam Era Twin Registry

- Zygosity determined by questions on sibling similarity and blood group typing data from military records
- All were raised together

## Using Transitions in Drug Use to Define Phenotypes for Genetic Research

- “Unaffected” phenotype should be restricted to individuals with the opportunity to become “abusers” who did not become “abusers”
- Individuals without the opportunity to become “abusers” should be classified “phenotype unknown”

## Stages in Drug Usage

- Initiation –
- “First Use”

- Regular Use

- Abuse
- (Problematic Use)

- Dependence

- Discontinuation
- of Use

**Phenotype**
**Unknown**

**Affected**
**Phenotype**

**?**

## Conclusions

- There is no single, unitary “drug phenotype” that will encompass all aspects of the relevant phenomena.
- There is considerable overlap among the various “drug phenotypes” that could be formulated.

## Univariate Analyses of Drug Abuse

## Pairwise Concordance Rates for Drug Abuse

## Correlations for Drug Abuse

**P<.001**

**P<.001**

**P<.001**

**P<.001**

## Influences on Drug Abuse/Dependence

## Conclusions from Univariate Analyses

- Genetic factors are the most important determinants of heroin addiction.
- Genetic factors may be more important for heroin addiction than for addiction to other drugs.
- Results for heroin suggest there may be both polygenic effects and a single gene of major effect or epistasis.

## Question for Multivariate Analyses 
To what extent are determinants of addiction shared among all drugs versus unique to each individual drug?

- To what extent are determinants of addiction shared among all drugs ***versus*** unique to each individual drug?

## Vulnerability to Drug Dependence 

***Common Vulnerability***

***Stimulants***
***77%***

***Heroin/***
***Opiates***
***50%***

***Psychedelics***
***85%***

***Marijuana***
***71%***

***Sedatives***
***69%***

## Determinants of Common Vulnerability to Drug Dependence

## Family Environmental Influences on Drug Dependence 

***Common Family Environmental Vulnerability***

***100%***
***Stimulants***
- (c2=18%)

- (c2=15%)
***Heroin/***
***Opiates***
***100%***

- (c2=19%)
***Psychedelics***
***100%***

***59%***
***Marijuana***
- (c2=29%)

***100%***
***Sedatives***
- (c2=17%)

## Non-Family Environmental Influences on Drug Dependence 

***Common Non-Family Environmental Vulnerability***

***71%***
***Stimulants***
- (e2=48%)

- (e2=33%)
***Heroin/***
***Opiates***
***64%***

- (e2=52%)
***Psychedelics***
***71%***

***84%***
***Marijuana***
- (e2=38%)

***54%***
***Sedatives***
- (e2=56%)

## Genetic Influences on Drug Dependence 

***Common Genetic Vulnerability***

***73%***
***Stimulants***
- (h2=33%)

- (h2=54%)
***Heroin/***
***Opiates***
***30%***

- (h2=26%)
***Psychedelics***
***100%***

- (h2=33%)
***Marijuana***
***67%***

- (h2=27%)
***Sedatives***
***81%***

## Conclusions from Multivariate Analyses

- The best model to explain the co-occurrence of addiction to different drugs is a common latent vulnerability.
- The “Marijuana Gateway” model is a poor fit to the data.

## Conclusions from Multivariate Analyses

- About half of the influences on heroin addiction also impart risk for addiction to other illicit drugs.
- About half of the influences on heroin addiction are unique to heroin (i.e, they don’t affect the risk for addiction to other drugs).

## Conclusions from Multivariate Analyses

- Everything about the family environment that imparts risk for heroin addiction also imparts risk for addiction to all other illicit drugs.
- Only marijuana is affected by family environmental factors that don’t also influence other illicit drugs.

## Conclusions from Multivariate Analyses

- Some aspects of the non-family environment that affect heroin addiction also affect addiction to other drugs.
- Some aspects of the non-family environment that affect heroin addiction are unique to heroin addiction (i.e., don’t affect addiction to other drugs).

## Conclusions from Multivariate Analyses

- 70% of the genetic influence on heroin addiction is unique to heroin addiction (more than for any other drug).
- Heroin addiction is the most “heritable” addiction to an illicit drug (at least given the environmental circumstances of our sample).

## Future Directions for Investigating Phenotypes for Genetic Research on Drug Abuse

## Background & Significance	

- A genetic contribution to the liability toward illicit drug use has been firmly established.
- The task is now to identify specific genes that influence the liability to substance use disorders (SUDs).
- Defining genetically homogenous phenotypes is critical to the success of genetic linkage and association studies.

## Alternative Phenotypes

- Heterogeneous nature of phenotypes compounds difficulty of identifying genes that impart risk.
- DSM diagnosis of drug abuse may not map neatly onto its genetic foundations.

## Alternative Phenotypes

- May provide a stronger ‘signal’ in the search for underlying risk genes.
- We propose to utilize data from both twin and molecular genetic samples to generate and refine alternative phenotypic definitions of substance use disorders (SUDs).

## Summary

- There is good evidence for genetic influences on SUDs.
- The specific genes that influence SUDs have remained elusive.
- A rate-limiting step in finding genes for SUDs may be specifying the best phenotypes.