Addictive Behaviors, Vol. 25, No. 6, pp.

807–820, 2000
Copyright © 2000 Elsevier Science Ltd.
Pergamon Printed in the USA. All rights reserved
0306-4603/00/$–see front matter
PII S0306-4603(00)00129-5

Session: Implications of Etiological Research for Prevention:

Sheppard Kellam, Chair

IMPLICATIONS OF GENETIC EPIDEMIOLOGY FOR THE

PREVENTION OF SUBSTANCE USE DISORDERS
KATHLEEN RIES MERIKANGAS and SHELLI AVENEVOLI
Yale University School of Medicine

Abstract — Despite advances in characterizing human genotypes, the complex process

through which genes exert their influence limits the application of molecular genetics to hu-
man diseases. Substance use disorders are necessarily complicated by gene-environment in-
teraction because exposure to an exogenous substance is required for their development. The
methods of genetic epidemiology are specifically designed to identify sources of complexity
that impede etiologic findings and prevention efforts. The goal of this paper is to illustrate the
application of family study methods to identify risk factors for substance abuse and their im-
plications for prevention. The Yale Family Study is a controlled family study of the comorbid-
ity of substance and psychiatric disorders. The sample consists of 223 probands with substance
use and/or an anxiety disorders and community controls, 1218 adult first degree relatives and
spouses, and 203 offspring (ages 7–17) followed for 8 years. Results indicated familial aggrega-
tion of substance disorders in adults and children, independence of familial aggregation of al-
coholism and drug dependence, and specificity of familial clustering of some drugs of abuse.
Familial factors are more strongly associated with substance dependence than abuse, with an
attributable risk of 55%. Premorbid psychiatric disorders—social phobia and bipolar affective
disorder in adults, and depression, anxiety, conduct, and oppositional defiant disorders in chil-
dren—were strongly associated with the subsequent development of substance dependence
(attributable risks ranging from 44 to 86%). A family history of substance abuse and premor-
bid psychopathology are strongly associated with the development of substance use disorders.
Implications for primary and secondary prevention are discussed. As specific genetic vulnera-
bility markers for substance use disorders become identified, application of the tools of ge-
netic epidemiology may be employed to identify specific environmental risk factors that may
serve as targets for prevention. © 2000 Elsevier Science Ltd.

Key Words. Genetic, Epidemiology, Prevention, Substance use disorders.

B A C K G R O U N D : G E N E T I C S O F
C O M P L E X D I S O R D E R S

The recent announcement that the human genome has now been sequenced has
generated widespread excitement about our ability to understand and treat human
disease. Of the estimated 60,000 to 70,000 human genes, more than 30,000 have been
discovered, and the function of approximately 5000 has been established (Deloukas et
al., 1998; Rowen, Mahairas, & Hood, 1997). Many genes have been identified for dis-
orders caused by a single gene with high absolute and relative risk such as Hunting-
ton’s Disease (Gusella et al., 1983), muscular dystrophy (Kunkel, Monaco, Bertelson,
& Colletti, 1986), and Cystic Fibrosis (Beaudet et al., 1986). The Human Genome

Research supported by Grants R01 AA09978, R01 DA09055, a Research Scientist Development Award
K02-DA00293 (Dr. Merikangas), and a Postdoctoral Research Training Fellowship T32 MH14235 (Dr.
Avenevoli) from the National Institutes of Health.
Requests for reprints should be sent to Kathleen Merikangas, Yale University School of Medicine,
Genetic Epidemiology Research Unit, 40 Temple Street, Suite 7B, New Haven, CT 06510; E-mail:
Kathleen.merikangas@yale.edu

807
808 K. R. MERIKANGAS and S. AVENEVOLI

Project is expected to facilitate identification of genes and more importantly under-

standing of their role in human diseases, with the ultimate goal of developing success-
ful approaches to prevention and treatment (Collins et al., 1998).
Despite advances in characterizing human genotypes, application of this knowledge
to human diseases is still limited by the complexity of the process through which genes
exert their influence. At present, knowledge of a particular gene does not permit pre-
diction of the phenotype, nor does knowledge of a phenotype permit inferences re-
garding the genotype, particularly for human behavioral disorders. Phenomena such
as penetrance (i.e., probability of phenotypic expression among individuals with sus-
ceptibility gene), variable expressivity (i.e., degree to which susceptible individuals ex-
press components of genotype), gene-environment interaction (i.e., expression of geno-
type only in presence of particular environmental exposures), pleiotropy (i.e., capacity
of gene to manifest simultaneously several different phenotypes), and genetic hetero-
geneity (i.e., different genes leading to indistinguishable phenotypes) have been dem-
onstrated for several human disorders for which susceptibility genes have been identi-
fied. Therefore, it is not surprising that progress in identifying genes for complex
disorders, or those resulting from common heterogeneous human diseases such as dia-
betes, heart disease, and the psychiatric disorders has proceeded at a far slower pace
than expected. Some examples of these phenomena are presented below.
Marfan Syndrome is a classic example of pleiotropy. The genetic mutation causing
Marfan Syndrome—fibrillin I on chromosome 15 (Dietz & Pyeritz, 1995) leads to mani-
festations across multiple organ systems, including the eye, aorta, skeleton, and skin (De
Paepe, Devereoux, Dietz, Hennekam, & Pyeritz, 1996). Diverse manifestations may oc-
cur even within a particular family. Breast cancer is an illustration of genetic heteroge-
neity in which different mutations are associated with different familial patterns of dis-
ease. King, Rowell, and Love (1993) first employed family study data to identify
homogeneous subtypes of breast cancer that then led to the identification of the BRCA
genes for early onset breast cancer. Whereas families with female breast and ovarian
cancer are more likely to have the BRCA1 mutation (Miki et al., 1994), families with
male breast cancer are more likely to have the BRCA2 mutation (Ford et al., 1998).
Alzheimer’s disease (AD) provides an excellent model of a disease with both ge-
netic heterogeneity and gene-environment interaction. There are major autosomal
dominant genes for early onset familial AD with extremely high relative and absolute
risk (Slooter & van Duijn, 1997). However, such genes are very rare in the population
and have little public health significance. In contrast, there is increasing evidence that
the apolipoprotein E (Apo-E) E4 allele is associated with both late-onset familial AD
and the more common sporadic AD (Corder, Saunders, & Strittmatter, 1993; Saun-
ders et al., 1993; Tsai et al., 1994). Moreover, environmental risks, such as head inju-
ries and anti-inflammatory agents, have been shown to interact with the apo-E geno-
types to protect against or potentiate development of AD (Mayeux et al., 1998).
The classic examples of gene-environment interaction are the inborn errors of me-
tabolism, such as phenylketonuria, that manifest only when susceptible individuals are
exposed to a particular protein or exogenous substance. Glucose-6-phosphate-dehy-
drogenase (G6PD) deficiency, an X linked disorder, is another illustration of gene-
environment interaction. The expression of this disorder becomes manifest as
hemolytic anemia only when the susceptible individual is exposed to certain drugs or
fava beans (Cavalli-Sforza & Bodmer, 1971). Some examples of behavioral pheno-
types that may result from interaction between intrinsic biologic or genetic factors and
environmental exposures include:
 Implications of genetic epidemiology 809

• Susceptibility genes seem to be necessary, but not sufficient for the development of
schizophrenia (Tienari et al., 1994; Wahlberg et al., 1997);
• Learning disability in childhood is predictive of the subsequent development of psy-
chiatric problems only when coupled with a disadvantaged family environment (Es-
ser, Schmidt, & Woerner, 1990); and
• Childhood minor physical anomalies predict psychiatric status 10 years later only in
the presence of environmental risk (Pine, Shaffer, Schonfeld, & Davies, 1997).
Alternatively, certain genetic characteristics could elicit specific environmental expo-
sures (i.e., gene-environment correlations). Substance use disorders are necessarily
complicated by gene-environment interaction because exposure to an exogenous sub-
stance is required for their development (Cutrona et al., 1994).
The methods of genetic epidemiology are designed specifically to identify gene-en-
vironment interactions and other sources of complexity that impede etiologic findings
and prevention efforts (Khoury & Wagener, 1995; Ottman, 1995; Yang & Khoury,
1997). A review of the current state of knowledge on the genetic epidemiology of sub-
stance use disorders is presented below.

G E N E T I C E P I D E M I O L O G Y O F S U B S T A N C E
U S E D I S O R D E R S

Figure 1 shows the traditional epidemiologic triangle that represents the joint influ-
ences of host, environment and agent in inducing human disease. This is an excellent
model for substance abuse, which has a clear agent, the substance, and several well-
known environmental risk factors, not the least of which is exposure to a particular
substance. Although this model also serves as an excellent guide for prevention ef-
forts, much of prevention research has neglected host characteristics that may deter-
mine individual vulnerability to progress across the substance abuse trajectory. Meth-
ods of genetic epidemiology may be employed to examine the links between the
individual or host factors and the environment that may enhance vulnerability for the
development of substance use disorders. One of the most potent predictors of the de-
velopment of substance use disorders is a positive family history, as described below.
The familial aggregation of alcoholism has been well-established (for comprehensive
reviews of alcoholism see McGue, 1994; Merikangas & Gelernter, 1990). Controlled
family studies of alcoholic probands reveal a three-fold increased risk of alcoholism and

Fig. 1. Epidemiology of drug abuse.

810 K. R. MERIKANGAS and S. AVENEVOLI

two-fold increased risk of drug abuse among the relatives of probands with alcoholism,
as compared to those of controls. Although less widely studied, drug abuse also aggre-
gates in families. Numerous family history studies and systematic family studies of sub-
stance abusers in treatment settings (Croughan, 1985; Gfroerer, 1987; Hill, Cloninger,
& Ayre, 1977; Meller, Rinehart, Cadoret, & Troughton, 1988; Merikangas, Stolar, et al.,
1998; Mirin, Weiss, Griffin, & Michael, 1991; Mirin, Weiss, & Michael, 1988; Roun-
saville et al., 1991) reveal a significantly increased risk of both alcoholism and drug
abuse among relatives when compared to population expectations.
Family studies which investigate generational differences in the transmission of sub-
stance abuse reveal that drug use (Gfroerer, 1987) and abuse (Merikangas, Roun-
saville, & Prusoff, 1992) are elevated among siblings of drug abusers, and that there is
a direct relationship between parental drug use (Gfroerer, 1987) and abuse (Luthar,
Anton, Merikangas, & Rounsaville, 1992; Merikangas et al., 1992) and drug use and
abuse in offspring.
An increasing number of twin studies have provided evidence that genetic factors
play a major role in the familial aggregation of substance use and abuse (Grove et al.,
1990; Jang, Livesley, & Vernon, 1995; Kendler & Prescott, 1998a; Pickens et al., 1991;
Tsuang et al., 1996, 1998; Tsuang, Faraone, & Lyons, 1993). Twin studies have yielded
evidence for significant heritability of nicotine, caffeine, tranquilizer, and sedative use
(Claridge & Roth, 1973; Gurling, Grant, & Dangl, 1985; Pedersen, 1981), as well for
dependence on cannabis (Kendler & Prescott, 1998a) and cocaine (Kendler, Kar-
lowski, Neale, & Prescott, 2000; Kendler & Prescott, 1998b). Additionally, twin stud-
ies have shown moderate heritability for the frequency of use and tendency to use nu-
merous illicit substances (Jang et al., 1995), greater heritability for drug dependence
than drug abuse (Pickens et al., 1991), and greater heritability for drug abuse than
nonproblematic use (Tsuang et al., 1998).
The classic adoption studies of Cadoret (Cadoret, 1992; Cadoret, Troughton,
O’Gorman, & Heywood, 1986; Cadoret, Yates, Troughton, Woodworth, & Stewart,
1996) have revealed that genetic factors play a far more important role in the transi-
tion from drug use to abuse than in drug use itself. Additionally, their work identifies
two major biologic/genetic pathways to the development of drug abuse in adoptees:
one which is driven by substance abuse in the biologic parent and is limited to drug
abuse and dependence in the adoptee; and another which appears to be an expression
of underlying aggressivity and related to criminality in the biologic parent (Cadoret,
Yates, Troughton, Woodworth, & Stewart, 1995; Cadoret et al., 1996).
High risk studies are particularly informative for prevention efforts as they aid in
the identification of premorbid vulnerability factors that serve as sources of identifica-
tion for children at risk for particular disorders. Aside from pre-existing emotional
and behavior disorders, a family history of alcoholism has been shown to be the most
consistent risk factor for development of alcoholism in vulnerable youth (Chassin,
Rogosch, & Barrera, 1991; Merikangas, Dierker, & Szatmari, 1998; Sher, Walitzer,
Wood, & Brent, 1991; West & Prinz, 1987). Several investigators (Hill & Hruska,
1992; Johnson, Leonard, & Jacob, 1989; Merikangas, Dierker, & Szatmari, 1998; Re-
ich, Earls, Frankel, & Shayka, 1993) have also reported an increased risk of substance-
related problems among the offspring of alcoholic parents. Although there are fewer
controlled studies of offspring of drug abusers than of alcoholics, recent studies have
yielded consistent findings regarding an increased risk of substance use disorders
among offspring of parents with substance abuse or dependence when compared to
those of nonsubstance abusers (Martin et al., 1994; Moss, Majumder, & Vanyukov,
 Implications of genetic epidemiology 811

1994). Nearly all of the high risk studies reveal that different risk factors may be in-
volved in the different stages of development of alcoholism. Whereas individual char-
acteristics and peer influences strongly influence exposure and initial patterns of use
of alcohol and drugs, family history and psychopathology play a more salient role in
the transition to problematic alcohol use and dependence (Cadoret et al., 1986; Lyons
et al., 1997; Merikangas, Stevens, et al., 1998; Pickens et al., 1991).
Family studies, particularly those with a prospective design, provide important in-
formation on specific and nonspecific risk factors of substance use disorders, causes of
comorbidity, and mechanisms for sex differences, as well as providing more homoge-
neous samples than between-family designs. In the following section, we present data
from the Yale Family Study of Comorbidity of Substance Use Disorders and Psycho-
pathology to illustrate the relevance of the findings for etiology and prevention.

R E S U L T S O F Y A L E F A M I L Y S T U D Y O F
C O M O R B I D I T Y O F S U B S T A N C E U S E D I S O R D E R S
A N D P S Y C H O P A T H O L O G Y

The Yale Family Study is the first controlled family study of the comorbidity of sub-
stance and psychiatric disorders using contemporary family study methodology. Our
family study consists of 340 probands with substance use disorders including the opi-
ods, cocaine, cannabis, and alcohol, a psychiatric comparison group of probands with
anxiety disorders, and controls selected from the community at large. Information was
collected on a total of 1626 first degree relatives of probands. Some of the key findings
are presented below.
The Yale Family Study was designed primarily to examine familial aggregation of
substance use disorder in first degree relatives. Findings in this study demonstrate in-
dependence of familial aggregation of alcoholism and drug dependence as well as
specificity of familial clustering of specific drugs, particularly cannabis, and opioids.
Together these findings suggest that there may be specific factors that lead to prob-
lematic use and dependence on particular drugs (Merikangas, Stevens, et al., 1998).
The Yale Family Study was also designed to examine mechanisms for comorbidity.
Evidence for shared pathophysiology in family studies would be derived from an in-
crease in rates of the comorbid disorder alone among the relatives of probands with
only the index disorder, as compared to those among controls. Alternatively, if the co-
morbid disorder is elevated among the relatives of probands with the “pure” index
disorder, but only when coupled with the index disorder, an etiologic model would be
more likely to explain the association (Merikangas, 1990).
With respect to comorbidity among subtypes of anxiety and substance abuse, the find-
ings of the Yale Family Study revealed that social phobia and bipolar affective disorder
were causally linked to the development of substance dependence, whereas panic disor-
der, major depression, and substance use disorders result in part from shared familial risk
factors (see Figure 2). Employing both retrospective and prospective longitudinal analy-
ses regarding the order of onset of various forms of psychopathology and substance use
disorders, the results clearly indicated that the onset of both social phobia and bipolar af-
fective disorder preceded that of substance use disorders. Moreover, participants often
reported that alcohol or drugs were used to ameliorate symptoms of one of these condi-
tions, thereby providing evidence for a self-medication model of comorbidity.
The Yale Family Study also included a prospective study of the 203 children ages 7–
17 of the probands, who have now been followed for 8 years. The Kiddie-Schedule for
812 K. R. MERIKANGAS and S. AVENEVOLI

Fig. 2. Yale Family Study: Adjusted1 risk ratios of substance use disorders in relatives by proband substance
dependence and comorbidity in relatives.

Affective Disorders and Schizophrenia, modified for DSM-III-R (Chambers, Puig-

Antich, Tabrizi, & Davies, 1985; Gammon et al., 1983; Orvaschel, Thompson, Be-
langer, Prusoff, & Kidd, 1982), was administered independently with the offspring,
and with the mother about the offspring at three time points. Lifetime diagnoses were
derived by an independent child psychiatrist, who was also blind to the diagnostic sta-
tus of the parents and who was not involved in direct interviews. The design, methods
and findings from the first wave of the study are presented by Dierker, Merikangas,
and Szatmari (1999), Merikangas, Dierker, and Szatmari (1998), and Merikangas,
Swendsen, et al. (1998). The results reported below represent the first presentation of
the findings from the 8-year follow-up of the cohort.
Based upon lifetime diagnoses across the three waves, more than half of the off-
spring (ages 8–27 at last interview, median age ⫽ 16) have used alcohol, cannabis, or
another substance at some time in their lives; however, only 17% ever reported abuse
or dependence on a substance. Because the entire sample has not yet progressed
through the risk period for substance use problems, survival analyses were conducted.
Results from simple frequencies and survival analyses revealed that lifetime rates of
alcohol use are much higher than cannabis or other drug use in this sample, but rates
of cannabis abuse or dependence are similar to those of alcohol abuse/dependence.
Rates of abuse (1.5%) and dependence (2%) of other drugs are very low.
The chief finding from the follow-up is the strong association between parental and
offspring substance use disorder. Offspring of proband parents with substance depen-
dence had a twofold increased rate of substance use disorders themselves compared to
either psychiatric or unaffected controls. Table 1 demonstrates that although the rates of
substance use, abuse, and dependence are elevated among offspring of probands with
substance dependence, the association was generally greater for substance dependence
than substance abuse, and greater for abuse than use (particularly for cannabis). In addi-
tion to familial risk for use, offspring of probands with substance dependence began ex-
perimenting with alcohol and cannabis at an earlier age than offspring of psychiatric and
control probands (mean age ⫽ 13.8 vs. 14.8 for alcohol; 14.4 vs. 15.3 for cannabis).
Figure 3 shows that substance use disorders exhibited some specificity according to
the number of parents with substance abuse. This specificity did not appear to be at-
 Implications of genetic epidemiology 813

Table 1. Yale Family Study: Substance use disorders among offspring of probands with substance dependence

Probands

Substance n ⫽ 79 Control n ⫽ 124 Odds Ratio (95% Conf. Int.)

Alcohol
Use 65.8 51.6 1.8 (1.0–3.2)
Abuse 15.2 4.8 3.5 (1.3–9.4)
Dependence 11.4 4.0 3.1 (1.1–9.1)
Cannabis
Use 39.2 19.4 2.7 (1.4–5.0)
Abuse 8.9 3.2 2.9 (0.9–9.8)
Dependence 13.9 4.8 3.2 (1.2–8.6)
Other drugs
Use 16.5 5.6 3.3 (1.3–8.3)
Abuse 1.3 1.6 0.8 (0.1–8.8)
Dependence 2.5 1.6 1.6 (0.2–11.4)
Any substance
Use 69.6 51.6 2.1 (1.2–3.9)
Abuse 20.3 8.9 2.6 (1.2–5.9)
Dependence 16.5 6.5 2.9 (1.2–7.1)

tributable to any one substance or type of substance problem: Specificity was also
found when alcohol, cannabis, abuse, and dependence were examined separately.
Conduct disorder in offspring was also associated systematically with parental sub-
stance abuse. In contrast, anxiety and affective disorders in offspring were not associ-
ated with parental substance disorders.
The attributable risk of substance use disorders based on proband parent history
was 55%. Findings were similar when examining parental concordence for substance
use disorders. Offspring who have two parents with substance dependence were twice
as likely to abuse substances as offspring of parents with no substance use problems.
This suggests that parental history is an important risk factor specifically for substance
abuse and dependence.
The other major class of risk factors for the development of substance use disorders
is pre-existing psychopathology. Table 2 presents the odds ratios for the associations
between substance use, abuse, and dependence and different types of psychiatric dis-
orders, adjusted for sex, age, and proband group. Most psychiatric disorders were

Fig. 3. Yale Family Study: Substance disorders in offspring by parental substance disorders.
814 K. R. MERIKANGAS and S. AVENEVOLI

more highly comorbid with substance abuse and dependence than with substance use,
although conduct disorder and oppositional defiant disorder were strongly associated
with substance use, abuse, and dependence. The risk for substance abuse was more
than two times greater than the risk for use and the risk for dependence was more
than four times greater than the risk for use in the presence of any psychiatric disor-
der. The risk of substance abuse attributable to psychiatric disorder ranged from 2%
(ADHD) to 78% (Conduct Disorder); attributable risk for substance dependence was
much higher for all premorbid psychiatric disorders and ranged from 44% (ADHD)
to 86% (Conduct Disorder).
In sum, the major findings from the Yale Family Study reveal that: substance abuse
is strongly familial in adults and children; there is some specificity of familial clustering
of specific drugs of abuse, and independence between alcoholism and drug use disor-
ders; familial factors are more strongly associated with substance dependence than
abuse; and psychiatric disorders are strongly associated with the development of sub-
stance use disorders, both as premorbid risk factors as well as a sequelae. The implica-
tions of these findings for prevention and intervention are discussed below.

I M P L I C A T I O N S F O R P R E V E N T I O N

Family History
These findings demonstrate that a family history of substance abuse is one of the
most potent risk factors for the development of substance abuse among exposed off-
spring. The results of this study confirm the findings of prior research regarding the in-
dependence of familial aggregation of alcoholism and drug use disorders (Hill et al.,
1977; Meller et al., 1988). In light of the moderate degree of independence of familial
alcoholism and drug abuse, both risk factor research and prevention and intervention
efforts should consider the distinction between these two disorders.
These findings provide strong support for the importance of family-based programs
for prevention of substance abuse (e.g., Hogue & Liddle, 1999; Kumpfer, 1987). The
findings suggest that targeted prevention should be geared towards offspring of sub-
stance abusers, even those who have not been identified in treatment settings. Because
both specific and nonspecific factors in the family contribute to the increased risk of
substance abuse, incorporation of other individual and environmental risk factors
would enhance further the predictive value of the intervention, thereby potentially
having major public health impact.

Table 2. Yale Family Study: Comorbidity of lifetime substance use

and premorbid psychopathology among offspring (N ⫽ 203)

Substance Use
Adjusted Odds Ratios
(95% Confidence Intervals)

Use Abuse Dependence

Affective 0.6 (0.2–2.1) 1.7 (0.6–4.8) 3.2 (1.1–9.3)

Conduct 4.2 (0.5–38.4) 6.0 (1.7–21.4) 6.0 (1.7–20.9)
Oppositional 4.2 (1.0–17.8) 3.3 (0.8–12.7) 4.1 (1.1–14.7)
ADHD 0.9 (0.3–2.7) 2.0 (0.5–7.8) 3.6 (1.0–13.5)
Anxiety 0.9 (0.3–2.2) 1.9 (0.7–5.0) 5.5 (1.8–16.3)
Any disorder 1.3 (0.6–3.0) 3.0 (1.0–9.1) 5.7 (1.4–22.7)
 Implications of genetic epidemiology 815

Substance use trajectory

Another implication of these findings for prevention of substance abuse is the im-
portance of focusing efforts on delaying or preventing the transition from use to harm-
ful use and dependence rather than preventing experimentation. Since only a minority
of those who experiment with drugs proceed to harmful use, public health prevention
efforts would be far better if targeted to those who are most likely to continue to
abuse drugs and suffer from its personal and social impact.
The findings concerning specificity of vulnerability factors that predispose to the de-
velopment of dependence on specific classes of drugs rather than to deviant behavior
in general are also relevant to prevention. Prevention programs may not only need to
focus on drug use behavior in general, but on individual risk factors underlying depen-
dence on specific drugs as well.

Comorbidity
The fairly well-established pathways between certain forms of psychopathology and
substance use disorders also provide an outstanding opportunity to identify targets of
prevention. Since effective treatments do exist for many of the primary psychiatric dis-
orders described above, treatment of the underlying disorder may serve to prevent the
development of substance abuse. For example, recent advances in the prevention of
depression among adolescents have yielded extremely promising results which attest
to the feasibility of reducing the burden of depression in youth (e.g., Beardslee,
Wright, Salt & Drezner, 1997; Jaycox, Reivich, Gillham, & Seligman, 1994). Likewise,
several recent treatment studies have begun to investigate the effect of concomitant
administration of antidepressant drugs and behavioral approaches to the treatment of
alcoholics with depression. The finding of the superiority of lithium over placebo in re-
ducing symptoms of both depression and alcoholism in a recent randomized clinical
trial of adolescents with comorbid bipolar disorder and alcohol abuse or dependence
is particularly promising (Geller et al., 1998). The results of the present study are com-
patible with a self-medication model of the links between social phobia and bipolar af-
fective disorder with substance use disorders. Intervention efforts among individuals
with either of the former disorders may lead to the prevention of substance abuse.
With the emerging evidence that the attributable risk of the familial factors in the
development of substance disorders is greater than 50%, development of prevention
programs that include both the family and child, particularly those with emotional or
behavior problems, would appear to be promising in ultimately reducing the incidence
of substance disorders. Kessler and Price (1993) have recently advocated this ap-
proach, although to date, there are no prevention programs that simultaneously ad-
dress these important risk factors for substance disorders.

Etiology
The importance of etiologic research is also highlighted by these findings. Future re-
search should seek an understanding of the mechanisms through which the family con-
veys an increased risk of drug abuse to offspring since a family history of substance
abuse is a potent predictor of vulnerability to its development. Moreover, the data
suggesting some independence of familial transmission of alcoholism and drug depen-
dence argue for further research identifying risk factors that may be specific to alcohol
or drugs, as well as those specific to particular drugs of abuse. Indeed, the best etiolog-
ical evidence would derive from systematic intervention trials that demonstrate that
modification of a causal risk factor leads to reduction in the outcome. Such prevention
816 K. R. MERIKANGAS and S. AVENEVOLI

studies may not only have public health significance, but also may provide powerful
etiologic information.
Comprehension of the complex inter-relationships between individual, familial, and
the broader social environment is critical to identify key transition points and causal
mechanisms. Such research designed to examine the underlying processes in the de-
velopment of drug dependence will be necessary to identify the role of specific risk
factors and their inter-relations that may be amenable to prevention or intervention
efforts. Study designs that incorporate the complexity of factors involved in familial
transmission including genetic factors, transmitted biologic factors, social, and cultural
factors and nontransmitted biologic and social factors are critical to gaining an under-
standing of these processes.

Conclusions
The genetic epidemiologic approach is one of the most powerful to understanding
the mechanisms through which families exert their influence on the transmission of
substance abuse across generations. This approach can be used to incorporate the
components of the host vulnerability, factors associated with exposure to drugs, and
the contribution of the family, peer, neighborhood, and larger cultural environment
conducive to its development. Progress in characterizing genes of relevance to the me-
tabolism and response to specific drugs will ultimately enhance our ability to identify
those at risk for the development of substance abuse and its sequelae. Table 3 summa-
rizes the relevance of genetic epidemiology to prevention.
The relevance of advances in human genetics for prevention has been a somewhat
controversial issue. Whereas some appropriate concern has been raised regarding the
potential negative impact of identification of genetic risk factors in terms of stigma
and misuse in reproductive planning, others envision the beneficial effects in prevent-
ing human disease and disability. Prediagnostic testing is now in widespread use for
some well-characterized diseases. However, there is insufficient prognostic informa-
tion for more complex disorders. Juengst (1995) distinguished between phenotypic
prevention and genotypic prevention. Whereas the former employs genetic informa-
tion to prevent the clinical manifestations of susceptibility genes, the latter applies in-
formation on genotypes to prevent the transmission of the genes to subsequent gener-
ations through genetic counseling or prediagnostic testing. With respect to the latter,
there has also been some controversy about which phenotypes are appropriate topics
for genetic study. Whereas clinical genetics has focused historically on genetic dis-
eases, there are increasing efforts to identify the genetic basis of human traits such as
intelligence and personality. Khoury (in press) suggests that the most appropriate and
ethical model should be based on the public health significance of the phenotype with
targeted efforts to identify behavioral and/or environmental risk factors to prevent
disease, disability and mortality.

Table 3. Relevance of genetic epidemiology for prevention

• Provision of information for targeted prevention programs

• Identification of malleable environmental exposures in genetic case
control studies
• Estimation of population attributable risk of genetic markers
• Identification of mutual influence of host vulnerability, factors associated
with exposure to drugs, and relevant domains of family, peer,
neighborhood and broader culture
 Implications of genetic epidemiology 817

Another important consideration in applying genetic risk factors to prevention con-

cerns the low positive predictive value and population attributable fractions for most
common chronic diseases (e.g., cholesterol and coronary heart disease; Khoury, in
press). Advances in knowledge regarding genetic risk factors will enhance our power
to identify the environmental factors involved in gene-environment interactions. Ap-
propriate interventions with such environmental exposures will ultimately have the
most important public health impact of genetic technologies.

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