Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper for Review
Appendix 6.14.1
Selected Recent Investigations into the Genetic
Basis of Alcoholism
By Warren Kaplan, Ph.D, JD, MPH
14 September 2004
Please send comments to:
Warren Kaplan: wak22@comcast.net
Dr Richard Laing: laingr@who.int
6.14-1
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
Authors
Year
Chromosome/Gene/Allele/SNP
Investigated
Outcome/Findings
Edenberg, H.J., D.M. 2004 GABA(A) receptors (chromosome
Dick, X. Xuei, H. Tian,
4p)
L. Almassy, L.O.
Bauer, et al.
A three-SNP haplotype in the region
of GABA receptor A2 was associated
with alcoholism (p<.0001). 31 single
nucleotide changes in the gene for
the receptor showed significant
association with alcoholism.
Limosin, F., J.Y. Loze, 2003
F. Rouillon, J. Ades, P.
Gorwood
Dopamine D1 receptor gene
polymorphism
Results suggest a limited association
between the dopamine D1 receptor
gene polymorphism and sensationseeking score among alcoholdependent men, but not women.
2003
Dopamine D1 receptor
(investigated in rats)
Dopamine D1 receptor plays a
salient role in selectively modulating
alcohol-motivated behaviors.
2001
ALDH2, CYP2E1, ADH2, ADH3
Association study fndings suggest
that certain ethanol metabolizing
enzymes protects against
alcoholism, however development
of cirrhosis not associated.
Chromosome 1, 2, 6, and 16
A gene or genes on chromosome 1
may affect susceptibility to
alcoholism and depression (which
may be alcohol induced)
ALDH2, CYP2E1
Findings strongly suggest that the
ALDH2 genotype is strongly
associated with alcohol drinking
behavior, but the CYP2E1 genotype
is not.
Alcohol Clin Exp Res.
2003 Aug;27(8):1226-8.
Eiler, W.L., R.
Seyoum, K.L. Foster,
C. Mailey, H.L. June.
Synapse. 2003
Apr;48(1):45-56.
Lee, H.C., H.S. Lee,
S.H. Jung, S.Y. Yi,
H.K. Jung, J.H. Yoon,
and C.Y. Kim
J Korean Med Sci. 2001
Dec;16(6):745-50.
Nurnberger, J.I., T.
2001
Foroud, L. Flury, J. Su,
E.T. Meyer,
K. Hu, R. Crowe, et al.
Am J Psychiatry. 2001
May;158(5):718-24
Okamoto. K., Y.
Murawaki, A. Yuasa,
and H. Kawasaki.
2001
Alcohol Clin Exp Res.
2001 Jun;25(6
Suppl):19S-23S.
Loh, E.W., I. Smith, R. 2000 GABAA receptors (chromosome
Murray, M.
5q33)
McLaughlin, S.
McNulty, and D. Ball
Mol Psychiatry. 2000
Jul;5(4):452
Lichtermann, D., D.
2000
Hranilovic, M. Trixler,
P. Franke, B. Jernej,
C.D. Delmo, M.
Knapp, S.G. Schwab,
W. Maier, D.B.
Wildenauer
5-HT serotonin transporter gene
(chromosome 17q11.2)
6.14-2
Findings showed associations
between alcohol dependence with
novel genetic markers at the
GABAA alpha2 receptor gene
(p=0.015) and the GABAA beta 6
receptor gene (p=0.013).
The study findings suggest allelic
association between a variant in the
promoter region of the serotonin
transporter gene and the risk for
alcohol dependence (p<0.006).
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
Am J Psychiatry. 2000
Dec;157(12):2045-7.
Thiele, T.E., B. Willis,
J. Stadler, J.G.
Reynolds, I.L.
Bernstein, G.S.
McKnight
2000
cAMP-dependent protein kinase
(PKA) RIIalpha subunit
(investigated in mice)
Study findings demonstrate that the
subunit of PKA has a role in
regulating voluntary alcohol
consumption (p<0.005) and
sensitivity to the intoxicating effects
of alcohol (p<0.05).
1999
5-HTT, 5-HT2A, 5-HT2C,
And GABAA receptor Ü6
(chromosome 5q33)
Findings show significant
relationships to low-level response
to alcohol and alcoholism to the 5HTTLPR serotonin transporter
variant (p-0.04) and the GABAA
receptor Ü6 (p=0.02). No evidence
found for 5-HT polymorphisms
(p=0.24, 0.55 and 0.95).
Genome scan using 291 markers
Analyses provided the strongest
suggestions of linkage with
susceptibility loci for alcohol
dependence on chromosomes 1 and
7, and more modest evidence for a
locus on chromosome 2. There was
also suggestive evidence for a
protective locus on chromosome 4q
near the alcohol dehydrogenase
genes .
CYP2E1
Findings suggest that the CYP2E1
regulatory polymorphism not only
enhances CYP2E1 metabolic activity,
but it is sufficiently common to
impact susceptibility to CYP2E1related diseases in at least two
ethnic groups (p<0.01).
J Neurosci. 2000 May
15;20(10):RC75
Schuckit, M.A., C.
Mazzanti, T.L. Smith,
U. Ahmed, M. Radel,
N. Iwata, & D.
Goldman
Biol Psychiatry. 1999
Mar 1;45(5):647-51.
Reich, T., H.J.
1998
Edenberg, A. Goate,
J.T. Williams, J.P. Rice,
P. Van Eerdewegh, T.
Foroud, et al.
Am J Med Genet. 1998
May 8;81(3):207-15
McCarver, D.G., R.
Byun, R.N. Hines, M.
Hichme, and W.
Wegenek.
1998
Toxicol Appl
Pharmacol. 1998
Sep;152(1):276-81.
Noble, E.P., X. Zhang, 1998
Dopamine D2 receptor and
T. Ritchie, B.R.
GABAA receptor alpha3 subunit
Lawford, S.C. Grosser,
genes
R.M. Young & R.S.
Sparkes
Psychiatry Res. 1998
Nov 16;81(2):133-47.
6.14-3
Variants of the D2 dopamine
receptor (p<0.00002) and GABA(A)
receptor alpha3 subunit (p<0.03)
genes independently contribute to
the risk for alcoholism. When the
variants are combined, the risk for
alcoholism is even greater.