Accordingly this receptor likely is involved in

Accordingly, this receptor likely is
involved in dependence on these
drugs as well (Orser 2006).
The GABA
A
receptor is composed
of five subunits that are encoded by
numerous genes, most of which are
located in clusters. Thus, chromo­
some 4 contains a cluster comprising
the genes GABRA2 , GABRA4 , GABRB1 ,
and GABRG1 ; chromosome 5 contains
GABRA1 , GABRA6 , GABRB2 , and
GABRG2 ; and chromosome 15 contains
GABRA5 , GABRB3 , and GABRG3
(see
http://
entrez?db=gene ).
Interest in the GABA
A
receptor
genes on chromosome 4 grew when
this region consistently was identified
in genome-wide scans looking for
linkage with alcohol dependence
(Long et al. 1998; Williams et al.
1999). Subsequently, COGA investi­
gators systematically evaluated short
DNA segments of known location
(i.e., genetic markers) that were situ­
ated in the GABA
A
receptor gene
cluster on chromosome 4. These
studies found that a significant associ­
ation existed between multiple SNPs
in the GABRA2 gene and alcohol
dependence (Edenberg et al. 2004).
This association has been replicated
in multiple independent samples
(Covault et al. 2004; Fehr et al. 2006;
Lappalainen et al. 2005; Soyka
2007). In addition, the same SNPs in
the GABRA2 gene have been shown to
be associated with drug dependence in
both adults and adolescents (Dick et
4
Rapid acetaldehyde production can lead to acetaldehyde
accumulation in the body, which results in highly unpleas­
ant effects, such as nausea, flushing, and rapid heartbeat,
that may deter people from drinking more alcohol.
5
For example, the medication disulfiram, which inhibits
another enzyme involved in alcohol metabolism called
aldehyde dehydrogenase 2 (ALDH2) and is used for
treatment of alcoholism, has demonstrated a treatment
effect in cocaine dependence (Luo et al. 2007).
Alcohol Research & Health 114

Genetics of AOD Dependence
al. 2006 a ), as well as with the use of
multiple drugs in another independent
sample (Drgon et al. 2006).
Variations in the GABRA2 gene
are associated not only with AOD
dependence but also with certain
electrophysiological characteristics
(i.e., endophenotypes) in the COGA
sample (Edenberg et al. 2004). As
reviewed above, these electrophysio­
logical characteristics are not unique
to alcohol dependence but also are
found in individuals with other forms
of externalizing psychopathology.
This association supports the hypoth­
esis that the GABRA2 gene generally
is involved in AOD use and/or
externalizing problems. Interestingly,
subsequent analyses investigating the
role of GABRA2 in drug dependence
(Agrawal et al. 2006) found that
the association with GABRA2 was
strongest in people with co-morbid
AOD dependence, with no evidence
of association in people who were
only alcohol dependent. This obser­
vation supports the assertion that
co-morbid AOD dependence may
represent a more severe, genetically
influenced form of the disorder.