Further evidence for an association between the gamma-aminobutyric acid receptor A, subunit 4 genes on chromosome 4 and Fagerström Test for Nicotine Dependence.
OBJECTIVE
A previous association analysis identified polymorphisms in gamma-aminobutyric acid receptor A, subunit 4 (GABRA4) and GABRA2 to be associated with nicotine dependence, as assessed by a score of 4 or more on the Fagerström Test for Nicotine Dependence (FTND). In the present report, we extend the previous study by expanding our genotyping efforts significantly for these two genes.


METHODS
In 1049 cases (FTND of 4 or more) and 872 controls (smokers with FTND of 0) from the United States and Australia, we examine the association between 23 GABRA4 and 39 GABRA2 recently genotyped single nucleotide polymorphisms (SNPs) and nicotine dependence using logistic regression-based association analyses using the genomic analysis package PLINK.


RESULTS
Two and 18 additional SNPs in GABRA4 and GABRA2, respectively, were associated with nicotine dependence. The SNPs identified in GABRA4 (P-value = 0.002) were restricted to introns 1 and 2, exon 1 and the 5' end of the gene, while those in GABRA2 localized to the 3' end of the gene and spanned introns 9-3, and were in moderate to high linkage disequilibrium (as measured by r(2)) with each other and with previously studied polymorphisms.


CONCLUSIONS
Our findings demonstrate consistently the role of GABRA4 and GABRA2 in nicotine dependence. However, further research is needed to identify the biological influence of these intronic variations and to isolate functionally relevant polymorphisms neighboring them.
Agrawal
Arpana
A
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. arpana@wustl.edu
Pergadia
Michele L
ML
Balasubramanian
Sumitra
S
Saccone
Scott F
SF
Hinrichs
Anthony L
AL
Saccone
Nancy L
NL
Breslau
Naomi
N
Johnson
Eric O
EO
Hatsukami
Dorothy
D
Martin
Nicholas G
NG
Montgomery
Grant W
GW
Goate
Alison M
AM
Rice
John P
JP
Bierut
Laura J
LJ
Madden
Pamela A F
PA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011963:Receptors, GABA-A / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*
C484841:GABRA2 protein, human; C546260:GABRA4 protein, human; D011963:Receptors, GABA-A