REVIEW The Harvard Twin Study of Substance Abuse What We Have Learned Ming T Tsuang MD PhD Jessica L Bar MA Rebecca M Harley PhD and Michael J Lyons PhD The Harvard Twin Study of Substance Abuse was carried out with the members of the Vietnam Era Twin VET Registry The VET Registry comprises over 8000 male twins who served in the United States military between 1965 and 1975 and were subsequently interviewed regarding their use of licit and illicit substances as well as various types of psychopathology Our research has demonstrated signi cant in uences by genetic shared environmental and unique environmental factors on the abuse of illicit substances Multivariate analyses have indicated that the co occurrence of abuse of various types of illicit drugs re ects a common vulnerability in uenced by both genetic and environmental factors that cuts across all categories of illicit drugs We have also demonstrated that some drugs have unique determinants both genetic and environmental that are not shared with other drugs In part the genetic in uence on marijuana abuse is mediated by genetic in uence on subjective effects in response to the drug The determinants of transitions from one stage of drug use to another differ depending on which drug or which transition is examined We determined signi cant genetic in uences on several aspects of nicotine and alcohol use separately as well as genetic in uences shared by both substances We found that the co occurrence of illicit drug abuse and major depression is due to unique environmental in uences The phenotypic association between symptoms of conduct disorder and alcohol and marijuana dependence is due largely to shared environmental in uences Our results thus far indicate a complex pattern of genetic and environmental in uences on substance use and abuse HARVARD REV PSYCHIATRY 2001 9 267 279 Substance abuse is widely recognized as one of the most complex and problematic issues facing today s society A growing From the Harvard Institute of Psychiatric Epidemiology and Genetics Drs Tsuang and Lyons Massachusetts Mental Health Center Dr Tsuang and the Department of Psychology Boston University Ms Bar Drs Harley and Lyons Boston Mass Supported by a grant DA04604 from the National Institute on Drug Abuse Dr Tsuang and the Department of Veterans Affairs Health Services Research and Development Service and Cooperative Studies Program Study 992 Original manuscript received 20 March 2001 revised manuscript received 20 June 2001 accepted for publication 25 June 2001 Reprint requests Ming T Tsuang MD PhD Massachusetts Mental Health Center 74 Fenwood Rd Boston MA 02115 e mail ming tsuang hms harvard edu 2001 President and Fellows of Harvard College body of research has addressed several pertinent questions concerning this issue Does substance abuse run in families If so is the risk inherited If yes just what is inherited a vulnerability for abuse of a speci c substance or vulnerability factors underlying the risk for development of a number of substance use and addictive behavioral problems Twin studies are particularly well suited for investigating these questions The unique structure of twin data allows the relative effects of genetic shared environmental and unique environmental in uences to be explicated Monozygotic MZ twins share 100 of their genes while dizygotic DZ twins share on average 50 Both MZ and DZ twin pairs generally share 100 of their family environment such in uences are assumed to promote resemblance equally in MZ and DZ pairs Thus greater similarity among MZ twins compared with DZ twins suggests genetic in uences on the phenotype under investigation By comparing MZ and DZ correlations we can arrive at estimates for these three sets of in uences Over the past decade we have studied the genetic and environmental determinants of addic267 Harvard Rev Psychiatry 268 Tsuang et al November December 2001 tive behaviors using a large national cohort of twins who are members of the Vietnam Era Twin VET Registry This paper reviews our ndings in an attempt to summarize what has been learned from the VET Registry thus far about the phenomenology and etiology of substance use disorders THE VIETNAM ERA TWIN REGISTRY The VET Registry consists of over 8000 male male twin pairs born between 1939 and 1957 in which both siblings served on active military duty during the Vietnam era May 1965 to August 1975 Twins were originally identi ed in the late 1980s through a search of the Department of Defense computer les of discharged servicemen 1 2 Individuals with the same last name and date of birth but different rst names were identi ed as potential twins From a list of approximately 5 5 million veterans 15 711 potential twin pairs were identi ed Military records of possible pairs were then examined to con rm twinship Zygosity was evaluated by analyzing responses of twin siblings to a series of questions on twin similarity and limited blood group typing obtained from military records 3 This method achieved 95 accuracy In 1992 information about drug and alcohol use and lifetime prevalence of comorbid psychiatric disorders was collected from VET Registry members by telephone interview Of 10 300 individuals 5150 pairs determined to be eligible for the study 47 were deceased or incapacitated Data were successfully collected from 8169 of the remaining 10 253 individuals response rate 79 7 The 1874 MZ and 1498 DZ pairs in which both members responded to the drug abuse items constituted the nal sample Sociodemographic breakdown of the group revealed the following characteristics Age Race Education Employment Mean 44 6 years SD 2 8 range 36 55 years Non Hispanic white 90 4 African American 4 9 Hispanic 2 7 Native American 1 3 Other 0 7 High school graduate 33 3 Vocational school attendance 15 8 College graduate 38 6 Graduate training and or a graduate degree 10 6 Other data not available 1 7 Employed full time 92 6 Employed part time 1 8 Unemployed 5 6 Marital status Residence Married 75 Never married 11 Currently unmarried data not available 14 All 50 states of the U S Registry members are representative of all twins who served in the military during the Vietnam War on a variety of sociodemographic and other variables 4 A complete description of VET Registry construction has been published elsewhere 1 2 Subjects were interviewed using the Diagnostic Interview Schedule Version III Revised DIS III R 5 a structured interview employed in epidemiological research