Neuropharmacology 47 (2004) 140–147

www.elsevier.com/locate/neuropharm

Molecular genetic underpinnings of human substance abuse

vulnerability: likely contributions to understanding addiction
as a mnemonic process
George R. Uhl

Molecular Neurobiology Branch, NIDA-IRP, NIH, Box 5180 Baltimore, MD 21224, USA

Received 11 May 2004; received in revised form 20 July 2004; accepted 22 July 2004

Abstract

Classical genetic studies document strong complex genetic contributions to abuse of multiple addictive substances. These gen-
etic influences are more prominent in the later phases of individuals’ progressions toward substance dependence. Individual differ-
ences in human addiction vulnerability could thus derive, in part, from individual differences in mnemonic systems. These
variations could add to allelic variations that could produce effects on addiction vulnerability phenotypes by other routes that
could include (1) differences in drug metabolism or biodistribution, (2) differences in drug’s rewarding properties, (3) differences in
traits manifest by the addict, including personality differences and (4) differences in the addict’s psychiatric comorbidities. Data
from linkage and association genome scans now identify chromosomal regions that are likely to contain allelic gene variants that
contribute to human addiction vulnerability. Converging positive results are found in several different substance-abusing popula-
tions studied in several laboratories. This convergence supports the idea that common allelic variants contribute to individual dif-
ferences in vulnerability to substance dependence. Genomic markers that identify allelic variants that reproducibly alter addiction
vulnerability in several populations provide tools for research in addictions, tools to improve addiction treatments, tools to
improve addiction prevention, clues to the genetic bases of individual differences in mnemonic processes and clues to the genetic
bases of individual differences in the other traits and disorders that co-occur with substance dependencies.
Published by Elsevier Ltd.

Keywords: Drug abuse; Complex genetics; Association genome scanning

1. Classical genetic studies that delineate genetic
and environmental contributions to human addiction
vulnerabilities
We know about the dimensions of genetic contribu-
tions to drug abuse from family, adoption and twin
study data. Drug abuse vulnerability is familial
(reviewed by Uhl et al., 1995). Twin data converge on a
common theme: drug abuse vulnerability has overall
genetic components that explain 40–60% of the overall
vulnerability (Pickens et al., 1991; Tsuang et al., 1996,
1998, 1999; Kendler et al., 1997, 1999, 2000; Kendler
and Prescott, 1998; True et al., 1999a,b; Uhl, 1999; Uhl
et al., 2002). Phenotypes that are heritable include


Tel.: +1-410-550-2843x146; fax: +1-410-550-1535.
E-mail address: guhl@intra.nida.nih.gov (G.R. Uhl).
0028-3908/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.neuropharm.2004.07.029
diagnostic and statistical manual (DSM) diagnoses of
drug dependence and quantity/frequency of drug use.
Studies of the ways in which addictions move
through families fail to support single-gene models for
inheritance of most addiction vulnerability. Addictions,
like other human disorders that display both genetic
and environmental contributions to vulnerability, are
thus ‘‘complex disorders’’ that are likely to receive con-
tributions from allelic variations in several genes.
Environmental features that contribute to addiction
vulnerability have been identified in numerous epide-
miological studies. Nevertheless, some individuals
avoid addiction even in environments rich in addictive
drugs. It seems likely that few addiction vulnerability
alleles will express themselves equally in all environ-
ments and that few environments will make addicts of
all of the individuals who have highly protective genetic
 G.R. Uhl / Neuropharmacology 47 Supplement No. 1 (2004) 140–147
backgrounds. Neither genetic nor environmental con-
tributions to addiction vulnerability can thus be
ignored.
Twin data support the idea that much of the genetic
vulnerability to abuse of different legal and illegal
addictive substances is shared (Tsuang et al., 1998;
Kendler et al., 1999). Although parts of addiction vul-
nerability are likely to be specific for specific sub-
stances, most genetic influences are common to
different addictive substances. Genetically identical
cotwins of smokers are more likely to use cocaine than
fraternal cotwins of smokers who share only half of
their vulnerability alleles, for example. These studies’
results buttress common clinical observations that most
substance abusers abuse multiple addictive substances.
2. Working ideas about genetic architecture and
commonly co-occurring diagnoses or traits
We are rapidly approaching a major goal of drug
abuse molecular genetics: discovering which chromo-
somal regions, which genes, which haplotypes and
which allelic variants provide the genetic influences on
drug abuse vulnerability that are documented in classi-
cal genetic studies. Many of the initial results of mol-
ecular genetic studies have buttressed our initial
assumptions about the ‘‘genetic architecture’’ of these
disorders.
One group of our assumptions about the genetic
architecture of substance abuse comes from the high
frequency of addictions in the population. The ‘‘com-
mon disease/common allele’’ hypothesis states that
many of the same allelic variants could contribute to
vulnerability to drug abuse in many addicted indivi-
duals in the population (Reich and Lander, 2001).
Since twin study observations suggest that a large
amount of the genetic vulnerability to abuse of addic-
tive substances of several chemical classes is shared
(Tsuang et al., 1998; Kendler et al., 1999), abusers of
multiple substances that are commonly found in clini-
cal and research volunteer populations appear to pro-
vide reasonable samples for molecular genetic studies.
However, there is also evidence for heterogeneity of the
genetics of substance vulnerability. Some heterogeneity
of this genetic vulnerability fits with data from studies
of abusers of different ethnic backgrounds, those with
different patterns of co-occurring psychiatric disease,
those with different personality features, those with dif-
ferent cognitive features and those with different sub-
stances of choice.
The allelic variations that have been most strongly
associated with differential vulnerability to addiction
are the striking variants in the alcohol and acetalde-
hyde dehydrogenase (ADH and ALDH) genes that
produce flushing when alcohol is consumed. Individuals
141
with these striking ADH/ALDH variants are pro-
tected against alcoholism in the Asian populations in
which these variants are common (Yamashita et al.,
1990). Interestingly, more subtle allelic variants in
these same genes may produce the convergent
association and linkage findings identified at the
chromosome four ADH/ALDH locus in European-
Americans and African Americans (see below).
Substance abusers have diagnoses of depression, anti-
social personality disorder/conduct disorder and adult
residua of attention deficit/hyperactivity disorder
more frequently than control populations (Regier
et al., 1990; Rowland et al., 2002). Each of these
diagnoses is likely to display heritable components.
Each also appears to be comorbid with substance
abuse more than with the other comorbid diagnoses.
Genetic contributions to addiction in individuals with
antisocial personality disorder may thus differ from
those found in addicts with depression. Groups of
individuals with apparently similar addictions but
with different psychiatric comorbidities could provide
plausible samples for studies seeking evidence of mol-
ecular genetic heterogeneity of substance abuse.
Personality types provide another perspective. There
are substantial heritabilities for several of the principal
currently accepted personality domains (Costa and
Widiger, 1998; Cloninger et al., 1993). Individuals who
score at the extremes of several tests of heritable per-
sonality types display enhanced risk of addiction. High
‘‘neuroticism’’ scores are found in substance abusers
(Costa and Widiger, 1998; Carter et al., 2001), while
this trait shows substantial heritability in twin studies
(Jang et al., 1996; Costa and Widiger, 1998). Some of
the same allelic variants that predispose to high neur-
oticism could thus also predispose to substance abuse.
Twin studies have addressed the impact of genetics
on aspects of individuals’ progression from experimen-
tation with drugs to use to regular use to DSM diag-
noses of dependence. Few genetic influences impact
initiation of drug use (Tsuang et al., 1999; Kendler
et al., 1999). Only a few influence progression from
initial use to regular use. Most genetic, heritable deter-
minants appear to influence progression from regular
use to dependence. Some evidence does support genetic
mediation of individual differences in acute drug
responses. Individuals who have elevated genetic risk
for developing alcoholism can display different respon-
ses to acute ethanol administration, for example,
Schuckit et al. (2000). Nevertheless, the major genetic
influences on human addiction vulnerability are found
in the later stages of the progression toward drug
dependence.
Many of the phenomena that accompany later stages
of progression toward drug dependence differ from
those found at earlier stages of increasing drug use.
Many of these differences appear likely to involve mnemonic
142 G.R. Uhl / Neuropharmacology 47 Supplement No. 1 (2004) 140–147
processes. Thus, increasing fractions of the drug use
manifest by more and more dependent individuals
appear to be driven to greater and greater extents by
habitual, implicit mnemonic systems. Habit-driven epi-
sodes of drug administration may not be reliably
accompanied by drug craving or other manifestations
of explicit drug memories. Nevertheless, habitual drug
use takes more and more dominant roles in the beha-
vioral hierarchies of many of the individuals who are
dependent. Habitual drug memory systems are thus
strong candidates for genetically mediated individual
differences in substance abuse behaviors. Even in drug
dependent individuals, however, some episodes of drug
use are likely to be triggered by other pathways and
thus to involve other mnemonic systems which can also
provide alternative sites for the influences of other gen-
etic variations.
Individual differences in performance on memory
tests are substantially heritable. Heritability for work-
ing memory is reported to range from 33–64% (Wright
et al., 2001). The volumes of brain structures important
for mnemonic processes are also substantially heritable.
Comparisons of MRI brain images of mono- and dizy-
gotic twin pairs suggest that ca. 60% of the individual
differences in the volume of frontal lobe regions are
heritable, while hippocampal volumes display ca. 0.4
heritabilities (Geschwind et al., 2002; Sullivan et al.,
2001). Taken together, these lines of evidence support
substantial heritable contributions to the structures of
brain regions important for mnemonic tasks, perform-
ance on memory tasks, and on the later aspects of
addictions that are likely to be memory related. Sub-
stantial inter-relationships between these three heritable
components appear likely.
Substance abusers differ from nonabusers in tests of
several cognitive functions that can also be associated
with brain regions whose sizes are heritable (Fein et al.,
2002a, b). Substance abusers score lower on tests of
‘‘executive function’’ (Sim et al., 2002; Simon et al.,
2002). Twin data suggest that executive function is
heritable (Swan and Carmelli, 2002). Comparisons of
MRI brain images of twin pairs support heritability of
the volumes of prefrontal and frontal cortical regions
(Carmelli et al., 2002). Substance abusers that differ
from each other based on executive or other cognitive
functions provide yet another way in which genetically
heterogeneous addict subgroups might be defined.
3. Molecular genetic genome scans and remarkable
convergence of results
We now have sufficient data from genome scans
using linkage and association approaches to allow us
to test the fit between hypotheses concerning the gen-
etic architecture of addictions and currently available
molecular genetic findings. Initial findings describing
linkage-based genome scans for legal addictions were
reported by Long et al. (1998) (172 sibpairs, 517 mar-
kers), Reich et al. (1998) (225 sibpairs, 291 markers),
Foroud et al. (2000) (266 additional sibpairs, 351
markers), and Straub et al. (1999) (391 sibpairs; 451
markers), using affected sibpairs from US and New
Zealand populations of several discrete ethnicities. We
reported the first association-based scan for illegal
addictions in two different samples of unrelated abusers
and controls (Uhl et al., 2001, 2002) and have com-
pleted a higher-density association genome scan of lar-
ger unrelated abuser and control samples (Q-R Liu,
GRU et al., in preparation). The results of these stu-
dies can be compared to linkage studies of poly-
substance use in affected sibpairs in which the proband
had conduct disorder (Stallings et al., 2003), smoking
in pedigrees in which the proband was identified by
anxiety or panic disorder phenotypes (Gelernter, 2002),
and association results from COGA pedigrees (Beglei-
ter, 2002). Each of these studies examined phenotypes
whose heritability is supported by twin data: (a) depen-
dence diagnoses made according to diagnostic and
statistical manual (DSM) criteria, and (b) quantity-
frequency estimates. Linkage-based studies examined
DNA from members of small pedigrees, studying the
ways in which allelic DNA markers and disease move
through pedigrees. Association approaches examined
the ways in which allelic DNA markers and disease
move through unrelated members of the population.
We have approached these datasets by seeking evi-
dence for converging findings. We have sought simi-
larity of chromosomal locations of genomic markers
that have been linked to or associated with addiction
vulnerability in association and linkage studies. In our
initial association genome scans using 1494 SNPs, we
identified 41 markers with allelic variants that were
associated with substance abuse vulnerability in both
Caucasian and African American research volunteer
samples (Uhl et al., 2001). When we examined the
chromosomal distribution of the 104 markers that
included these 41 SNPs and the chromosomal markers
linked to substance abuse vulnerability in at least one
other study, we found that 34 of these nominally posi-
tive markers clustered into 15 relatively small chromo-
somal regions (Uhl et al., 2001). Modeling studies
suggested that this clustering was unlikely to all be due
to chance alone (Uhl et al., 2002). Additional evidence
for convergence comes from data from Stallings and
coworkers (Stallings et al., 2003), Gelernter (2002),
association studies in a region of interest reported by
COGA investigators (Begleiter, 2002) and improving
data concerning the chromosomal locations of nomin-
ally positive markers. Table 1 lists the chromosomal
regions in which current genomic coordinates place at
least two nearby (within 5 Mb) markers that are linked
 G.R. Uhl / Neuropharmacology 47 Supplement No. 1 (2004) 140–147 143

Table 1
Candidate ‘‘rSA’’ replicated chromosomal areas likely to harbor substance abuse vulnerability alleles

SA# Ch MV34 WIAF/SSLP Reference Samples Substance

rSA16 2 233.6-234.15 na Gelertner et al. Four Tobacco
2 234667480 WIAF-1700 Uhl et al. Polysubstance
2 237522162 D2S338 Stallings et al. Polysubstance

rSA1 3 27450316 WIAF-1765 Uhl et al. Three Polysubstance

3 32137007 D3S2432 Long et al. Alcohol

rSA17 3 152346291 D3S1279 Stallings Two Polysubstance

3 153050650 D3S1746 Long et al. Alcohol

rSA2 3 168560613 D3S1763 Long et al. Four Alcohol

3 169531042 D3S1614 Stallings et al. Polysubstance
3 172361071 WIAF-847 Uhl et al. Polysubstance
3 172808611 D3S3053 Long et al. Alcohol

rSA3 4 35601324 D4S2632 Long et al. Four Alcohol

4 39947943 D4S2382 Long et al. Alcohol
4 40749467 D4S174 Long et al. Alcohol
4 44094355 D4S1627 Long et al. Alcohol
4 44622461 WIAF-452 Uhl et al. Polysubstance
4 46221275 rs279871 Beigleiter et al. Alcohol
4 46843212 D4S3242 Long et al. Alcohol

rSA4 4 61986356 D4S1645 Long et al. Two Alcohol

4 65494871 D4S244 Reich et al. Alcohol

rSA5 4 na D4S2456 Long et al. Two Alcohol

4 77952893 D4S2393 Reich et al. Alcohol

rSA6 4 95596000 WIAF-373 Uhl et al. (2001) Four Polysubstance

4 99893367 D4S1647 99.7 Long et al. Alcohol
4 101541576 WIAF-2765 Uhl et al. (2001) Polysubstance
4 103210000 ADH3 Reich et al. Alcohol

rSA18 4 107037800 D4S2457 Reich et al. Two Alcohol

4 108344788 D4S3256 Long et al. Alcohol
4 110253428 D4S3240 Long et al. Alcohol

SA7 4 125278307 WIAF-3821 Uhl et al. Two Polysubstance

4 125278333 WIAF-3818 Uhl et al. Polysubstance

rSA19 6 11210857 WIAF-1567 Uhl et al. Two Polysubstance

11267058 WIAF-967 Uhl et al. Polysubstance

rSA8 9 27316060 WIAF-1900 Uhl et al. Three Polysubstance

9 29549719 D9S319 Long et al. Alcohol

rSA9 10 102860940 D10S1239 Straub et al. Three Tobacco

10 106310791 D10S2469 Straub et al. Tobacco
10 106317898 WIAF-268 Uhl et al. Polysubstance

rSA10 11 1533898 D11S1984 Long et al. Four Alcohol

11 1533898 D11S1984 Uhl et al., un Polysubstance
11 1927951 D11S4046 Gelertner, un Tobacco

rSA19 11 17452815 D11S902 Stallings Polysubstance

11 19245375 D11S2368 Long et al. Alcohol

SA11 11 26648926 WIAF-2046 Uhl et al. Two Polysubstance

11 29083355 WIAF-1949 Uhl et al. Polysubstance

(continued on next page)

144 G.R. Uhl / Neuropharmacology 47 Supplement No. 1 (2004) 140–147

Table 1 (continued )

SA# Ch MV34 WIAF/SSLP Reference Samples Substance

SA12 12 122337633 WIAF-3624 Uhl et al. Two Polysubstance
12 122599343 WIAF-364 Uhl et al. Polysubstance

rSA13 13 90538821 WIAF-4520 Uhl et al. Three Polysubstance

13 nr 91,900,000 D13S762 Reich et al. Alcohol

rSA14 13 109100000 D13S895 Long et al. Three Alcohol

13 110743433 D13S285 Long et al. Alcohol
13 111559844 WIAF-2555 Uhl et al. Polysubstance

rSA20 17 69098093 D17S2059 Straub et al. Two Tobacco

17 73158564 D17S1535 Long et al. Alcohol

rSA15 X 150639232 DXS8061 Straub et al. Three Tobacco

X 151048287 WIAF-1743 Uhl et al. Polysubstance
SA# is the designation for each chromosomal area, as indicated in the text.
Chr is the chromosomal location.
WIAF/SSLP is the single nucleotide polymorphism (SNP) or simple sequence length polymorphism (SSLP).
MV34 chromosomal positions in bp for the markers based on coordinates calculated or inferred from the NCBI ‘‘Mapviewer’’program, version 34.3.
Reference is the reference for the study whose nominally positive results are displayed.
Samples refer to the number of independent samples for which positive data is displayed.
Substance indicates the primary substance reported to be abused by probands, although many subjects in all samples are polysubstance abusers.

or associated with human addiction vulnerability from
at least two different populations. Twenty chromo-
somal regions that now provide the ‘‘reproducible sub-
stance abuse vulnerability’’ regions (rSA1-20) that are
listed here. Identifying these regions is an ongoing task.
It is nevertheless gratifying that more recent studies
have provided confirmation of several previously nomi-
nated loci. It is also gratifying that several previously
identified nominally positive markers are now posi-
tioned closer to each other as the precision of the geno-
mic backbone on which they have been localized has
improved.
Initial results from 11,500 SNP arrays appear to but-
tress and extend these results. SNPs that lie in several of
the previously defined rSA regions again display abuser-
control differences anticipated if allelic variants
that alter substance abuse vulnerability lie on blocks of
restricted haplotype diversity that are marked by the
SNPs that we have employed in both initial and follow-
up studies (Q.-R. Liu, GRU et al., in preparation).
4. Caveats and limitations:
The low likelihood that all of the convergence
observed to date is based on chance does not exclude
the likelihood of some false-positive results (Romero
et al., 2002; Glazier et al., 2002). Simulation studies
indicated that the chance that at least one, two, three
or four of the 15 initially defined rSA regions were
identified by chance were 0.78, 0.42, 0.17, 0.06, and
0.01, respectively (Uhl et al., 2002).
It is also likely that there are many false-negative
regions in current data No single study performed to
date has power sufficient to detect all of the allelic var-
iants that contribute to addiction, especially if there is
a polygenic underlying genetic architecture and signifi-
cant genetic heterogeneity. The rSA regions in Table 1
are thus likely to represent an incomplete list of only
those allelic variants that provide enough influence on
abuse of so many different substances in so many
populations that they can be jointly detected in each of
several studies that have used different methodologies
and/or different clinical samples.
Data from candidate gene association studies also
provide evidence for likely false-negative results from
genome scanning studies. Our work and work from a
number of other laboratories have identified allelic var-
iants of the catechol-O-methyl transferase (COMT)
gene that are present in different frequencies in some,
though not all, abuser vs. control populations studied
(Smith et al., 1992; Persico et al., 1996; Vandenbergh
et al., 1997, 2000). The COMT gene is located between
18.30 and 18.33 Mb on chromosome 22. However,
there are no nominally positive association signals at
flanking chromosome SNP markers located at 17,356,651,
17,506,879, 19,773,582, 19,773,965, 20,306,803, 20,379,948
or 20,924,091 bp. Conceivably, the ca. 2 Mb gap in
the markers employed resulted in this apparent false-
negative result, although it does not explain the fail-
ure of linkage-based genome scanning studies. Higher
marker densities will help to improve the power of
association-based genome scanning, and reduce false-
negative results of this sort.
 G.R. Uhl / Neuropharmacology 47 Supplement No. 1 (2004) 140–147
5. Example: candidate addiction vulnerability and
memory-associated locus identified by positional
cloning and as a drug-regulated gene
As we identify the specific genetic haplotypes
that confer human individual differences in addiction
vulnerability and develop animal models of these varia-
tions, we can also seek variations in other addiction-
associated phenotypes that might be conferred by some
of these same allelic variants. We can seek effects of
modeling these allelic variations in animals which can
provide better experimental control over both environ-
mental and genetic background variables.
An example of this sort of progression comes from
our studies of the human gene locus for NrCAM. We
identified NrCAM and specific NrCAM 50 haplotypes
through positional cloning (Ishiguro, Uhl et al. in prep-
aration). We focused on this gene since we had pre-
viously discovered that its expression levels are
regulated by morphine administration. We also ident-
ified NrCAM expression in both dopaminergic neurons
that modulate reward and memory-related brain areas
including striatum and hippocampus.
We have been able to test conditioned place pre-
ferences in NrCAM knockout mice that were originally
developed by Grumet, Sakarai and colleagues (Grumet,
1997). Mouse conditioned place preference for drugs is
almost invariably a good predictor of human abuse
liability. Interestingly, NrCAM knockout mice failed to
develop significant preferences for the place where they
received morphine injections (Ishiguro, Uhl et al. in
preparation). Also intriguingly, other studies of
NrCAM knockouts have identified selective deficits in
several, but not all, memory tasks. Taken together,
these data suggest that we have identified NrCAM
haplotypes that are involved in human addiction vul-
nerability as well as effects of NrCAM deletion in both
mouse models of human addiction vulnerability and
mouse models of memory.
6. Working hypotheses concerning the genetic
architecture of substance abuse based on current,
convergent molecular genetic data
Assembling the markers now linked to or associated
with vulnerability to substance abuse in at least one
published study now provides a brighter and sharper
picture of the molecular genetics of substance abuse.
The data support polygenic inheritance for substance
abuse vulnerability. They also support the idea that
common allelic variants that are likely to contribute to
vulnerability to abuse of several substances exist in
humans from several racial/ethnic groups.
Although common allelic variants could thus play
significant roles in vulnerabilities to abuse of multiple
145
substances, each allelic variant could provide a distinc-
tive pattern of influences. Each could manifest effects
on different aspects of addiction vulnerability and/or
on vulnerability to the other traits and behavioral dis-
orders that often co-occur with substance disorders.
Alleles altering the metabolism of a drug, for example,
might produce a straightforward shift in the dose-effect
relationships for that drug without substantially alter-
ing brain chemistries or vulnerabilities to comorbid
conditions. Additional studies will be able to better
identify the ways in which each allelic variant changes
specific features of addiction vulnerability. Such studies
can also help us better understand the ways in which
genetic and environmental influences could interact and
add to our understanding of addictions.
7. Potential impact
We have recently described the large size of the com-
plex genetic contributions to addictions in US society
(Uhl and Grow, 2004). This sizable impact continues to
motivate us to identify allelic variants that contribute
to addiction vulnerability, even though we are increas-
ingly certain that no single allelic variant is likely to
contribute any large fraction of this vulnerability in
individuals from several different populations. Know-
ing which addiction-vulnerability allelic variants are
present in vulnerable individuals should improve tar-
geting of large addiction treatment and prevention
expenditures. Individual and societal suffering could be
substantially relieved by better understanding the com-
plex human processes of human addiction through
careful application of complex human genetic approa-
ches.
Acknowledgments
I am grateful for the help with personal studies cited
here from Qing-Rong Liu, Daniel Naiman, Judith
Hess, Bruce O’Hara, Antonio Persico, Donna Walther,
Fely Carillo, Brenda Campb Linda Kahler, Fred
Snyder, Carlo Contoreggi, Larry Rodriguez, Robert
Grow, David Gorelick, Zhicheng Lin, Andrew Shapiro
and Leslie Cope and financial support from NIDA-
IRP.
References
Begleiter, H., 2002. Neurophysiological endophenotypes in the search
for genes for alcoholism. ACNP.
Carmelli, D., Swan, G.E., et al., 2002. Quantitative genetic modeling
of regional brain volumes and cognitive performance in older
male twins. Biol. Psychol. 61 (1-2), 139–155.
146 G.R. Uhl / Neuropharmacology 47 Supplement No. 1 (2004) 140–147
Carter, J.A., Herbst, J.H., et al., 2001. Short-term stability of
NEO-PI-R personality trait scores in opioid-dependent out-
patients. Psychol. Addict. Behav. 15 (3), 255–260.
Cloninger, C.R., Svrakic, D.M., Przybeck, T.R., 1993. A psychobio-
logical model of temperament and character. Arch. Gen.
Psychiatry 50 (12), 975–990.
Costa, P.T., Widiger, T.A., 1998. Personality disorders and the five-
factor model of personality. American Psychological Association,
Washington, DC.
Fein, G., Di Sclafani, V., et al., 2002a. Cortical gray matter loss in
treatment—naive alcohol dependent individuals. Alcohol Clin.
Exp. Res. 26 (4), 558–564.
Fein, G., Di Sclafani, V., et al., 2002b. Prefrontal cortical volume
reduction associated with frontal cortex function deficit in 6-week
abstinent crack-cocaine dependent men. Drug Alcohol Depend.
68 (1), 87–93.
Foroud, T., Edenberg, H.J., et al., 2000. Alcoholism susceptibility
loci: confirmation studies in a replicate sample and further map-
ping. Alcohol Clin. Exp. Res. 24 (7), 933–945.
Gelernter, 2002. A genome scan for nicotine addiction in panic dis-
order clinic atendees. American Society for Human Genetics
satellite.
Geschwind, D.H., Miller, B.L., DeCarli, C., Carmelli, D., 2002. Heri-
tability of lobar brain volumes in twins supports genetic models
of cerebral laterality and handedness. Proc. Natl. Acad. Sci. USA
99, 3176–3181.
Glazier, A.M., Nadeau, J.H., et al., 2002. Finding genes that underlie
complex traits. Science 298 (5602), 2345–2349.
Grumet, M., 1997. Nr-CAM: a cell adhesion molecule with ligand
and receptor functions. Cell Tissue Res. 290 (2), 423–428,
(November).
Jang, K.L., Livesley, W.J., et al., 1996. Heritability of the big five
personality dimensions and their facets: a twin study. J. Pers. 64
(3), 577–591.
Kendler, K.S., Prescott, C.A., 1998. Cocaine use, abuse and depen-
dence in a population-based sample of female twins. Br. J.
Psychiatry 173, 345–350.
Kendler, K.S., Prescott, C.A., et al., 1997. Temperance board regis-
tration for alcohol abuse in a national sample of Swedish male
twins, born 1902 to 1949. Arch. Gen. Psychiatry 54 (2), 178–184.
Kendler, K.S., Karkowski, L.M., et al., 1999. Genetic and environ-
mental risk factors in the aetiology of illicit drug initiation and
subsequent misuse in women. Br. J. Psychiatry 175, 351–356.
Kendler, K.S., Thornton, L.M., et al., 2000. Tobacco consumption
in Swedish twins reared apart and reared together. Arch. Gen.
Psychiatry 57 (9), 886–892.
Long, J.C., Knowler, W.C., et al., 1998. Evidence for genetic linkage
to alcohol dependence on chromosomes 4 and 11 from an auto-
some-wide scan in an American Indian population. Am. J. Med.
Genet. 81 (3), 216–221.
Persico, A.M., Bird, G., et al., 1996. D2 dopamine receptor gene
TaqI A1 and B1 restriction fragment length polymorphisms:
enhanced frequencies in psychostimulant-preferring polysubstance
abusers. Biol. Psychiatry 40 (8), 776–784.
Pickens, R.W., Svikis, D.S., et al., 1991. Heterogeneity in the inherit-
ance of alcoholism. A study of male and female twins. Arch. Gen.
Psychiatry 48 (1), 19–28.
Reich, D.E., Lander, E.S., 2001. On the allelic spectrum of human
disease. Trends Genet. 17 (9), 502–510.
Regier, D.A., Farmer, M.E., et al., 1990. Comorbidity of mental
disorders with alcohol and other drug abuse. Results from the
Epidemiologic Catchment Area (ECA) Study. JAMA 264 (19),
2511–2518.
Reich, T., Edenberg, H.J., et al., 1998. Genome-wide search for genes
affecting the risk for alcohol dependence. Am. J. Med. Genet. 81
(3), 207–215.
Romero, R., Kuivaniemi, H., et al., 2002. The design, execution, and
interpretation of genetic association studies to decipher complex
diseases. Am. J. Obstet. Gynecol. 187 (5), 1299–1312.
Rowland, A.S., Lesesne, C.A., et al., 2002. The epidemiology of
attention-deficit/hyperactivity disorder (ADHD): a public health
view. Ment. Retard Dev. Disabil. Res. Rev. 8 (3), 162–170.
Schuckit, M.A., Smith, T.L., Kalmijn, J., Tsuang, J., Hesselbrock,
V., Bucholz, K., 2000. Response to alcohol in daughters of alco-
holics: a pilot study and a comparison with sons of alcoholics.
Alcohol Alcohol 35 (3), 242–248.
Sim, T., Simon, S.L., et al., 2002. Cognitive deficits among metham-
phetamine users with attention deficit hyperactivity disorder
symptomatology. J. Addict. Dis. 21 (1), 75–89.
Simon, S.L., Domier, C.P., et al., 2002. Cognitive performance of
current methamphetamine and cocaine abusers. J. Addict. Dis. 21
(1), 61–74.
Smith, S.S., O’Hara, B.F., et al., 1992. Genetic vulnerability to drug
abuse. The D2 dopamine receptor Taq I B1 restriction fragment
length polymorphism appears more frequently in polysubstance
abusers. Arch. Gen. Psychiatry 49 (9), 723–727.
Stallings, M.C., Corley, R.P., et al., 2003. A genome-wide search for
QTLs influencing substance dependence vulnerabity in ado-
lescence. Drug Alcohol Depend 70, 295–307.
Straub, R.E., Sullivan, P.F., et al., 1999. Susceptibility genes for
nicotine dependence: a genome scan and followup in an inde-
pendent sample suggest that regions on chromosomes 2, 4, 10, 16,
17 and 18 merit further study. Mol. Psychiatry 4 (2), 129–144.
Sullivan, E.V., Pfefferbaum, A., Swan, G.E., Carmelli, D., 2001.
Heritability of hippocampal size in elderly twin men: equivalent
influence from genes and environment. Hippocampus 11 (6),
754–762.
Swan, G.E., Carmelli, D., 2002. Evidence for genetic mediation
of executive control: a study of aging male twins. J. Gerontol. B
Psychol. Sci. Soc. Sci. 57 (2), 133–143.
True, W.R., Heath, A.C., et al., 1999a. Interrelationship of genetic
and environmental influences on conduct disorder and alcohol
and marijuana dependence symptoms. Am. J. Med. Genet. 88 (4),
391–397.
True, W.R., Xian, H., et al., 1999b. Common genetic vulnerability
for nicotine and alcohol dependence in men. Arch. Gen. Psy-
chiatry 56 (7), 655–661.
Tsuang, M.T., Lyons, M.J., et al., 1996. Genetic influences on DSM-
III-R drug abuse and dependence: a study of 3,372 twin pairs.
Am. J. Med. Genet. 67 (5), 473–477.
Tsuang, M.T., Lyons, M.J., et al., 1998. Co-occurrence of abuse of
different drugs in men: the role of drug-specific and shared vulner-
abilities. Arch. Gen. Psychiatry 55 (11), 967–972.
Tsuang, M.T., Lyons, M.J., et al., 1999. Genetic and environmental
influences on transitions in drug use. Behav. Genet. 29 (6), 473–
479.
Uhl, G.R., 1999. Molecular genetics of substance abuse vulnerability:
a current approach. Neuropsychopharmacology 20 (1), 3–9.
Uhl, G.R., Grow, R.W., 2004. The burden of complex genetics in
brain disorders. Arch. Gen. Psychiatry 61 (3), 223–229.
Uhl, G.R., Elmer, G.I., et al., 1995. Genetic influences in drug abuse.
In: Bloom, F.E., Kupfer, D.J. (Eds.), Psychopharmacology: the
Fourth Generation. Raven Press, New York, pp. 1793–1806.
Uhl, G.R., Liu, Q.R., et al., 2001. Polysubstance abuse-vulnerability
genes: genome scans for association, using 1,004 subjects and
1,494 single-nucleotide polymorphisms. Am. J. Hum. Genet.
69 (6), 1290–1300.
Uhl, G.R., Liu, Q.R., et al., 2002. Substance abuse vulnerability loci:
converging genome scanning data. Trends Genet. 18 (8), 420–425.
Vandenbergh, D.J., Rodriguez, L.A., et al., 1997. High-activity
catechol-O-methyltransferase allele is more prevalent in poly-
substance abusers. Am. J. Med. Genet. 74 (4), 439–442.
 G.R. Uhl / Neuropharmacology 47 Supplement No. 1 (2004) 140–147 147

Vandenbergh, D.J., Rodriguez, L.A., et al., 2000. Long forms of the
dopamine receptor (DRD4) gene VNTR are more prevalent in
substance abusers: no interaction with functional alleles of the
catechol-o-methyltransferase (COMT) gene. Am. J. Med. Genet.
96 (5), 678–683.
Wright, M., Degeus, E., Ando, J., Luciano, M., Posthuma, D., Ono,
Y., Hansell, N., Van Baal, C., Hiraishi, K., Hasegawa, T., Smith,
D., Geffen, G., Geffen, L., Kanba, S., Miyake, A., Martin, N.,
Boomsma, D., 2001. Genetics of cognition: outline of a collabora-
tive twin study. Twin Res. 4 (1), 48–56, (February).
Yamashita, I., Ohmori, T., et al., 1990. Biological study of alcohol
dependence syndrome with reference to ethnic difference: report
of a WHO Collaborative Study. Jpn. J. Psychiatry Neurol. 44 (1),
79–84.