A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence.
BACKGROUND
A nonsynonymous coding polymorphism, rs16969968, of the CHRNA5 gene that encodes the alpha-5 subunit of the nicotinic acetylcholine receptor (nAChR) has been found to be associated with nicotine dependence. The goal of this study was to examine the association of this variant with cocaine dependence.


METHODS
Genetic association analysis was performed in two independent samples of unrelated case and control subjects: 1) 504 European Americans participating in the Family Study on Cocaine Dependence (FSCD) and 2) 814 European Americans participating in the Collaborative Study on the Genetics of Alcoholism (COGA).


RESULTS
In the FSCD, there was a significant association between the CHRNA5 variant and cocaine dependence (odds ratio = .67 per allele, p = .0045, assuming an additive genetic model), but in the reverse direction compared with that previously observed for nicotine dependence. In multivariate analyses that controlled for the effects of nicotine dependence, both the protective effect for cocaine dependence and the previously documented risk effect for nicotine dependence were statistically significant. The protective effect for cocaine dependence was replicated in the COGA sample. In COGA, effect sizes for habitual smoking, a proxy phenotype for nicotine dependence, were consistent with those observed in FSCD.


CONCLUSIONS
The minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence. The biological plausibility of such a bidirectional association stems from the involvement of nAChRs with both excitatory and inhibitory modulation of dopamine-mediated reward pathways.
Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, Missouri 63110, USA. Rick@tci.wustl.edu
Richard A
RA
Grucza
Jen C
JC
Wang
Jerry A
JA
Stitzel
Anthony L
AL
Hinrichs
Scott F
SF
Saccone
Nancy L
NL
Saccone
Kathleen K
KK
Bucholz
C Robert
CR
Cloninger
Rosalind J
RJ
Neuman
John P
JP
Budde
Louis
L
Fox
Sarah
S
Bertelsen
John
J
Kramer
Victor
V
Hesselbrock
Jay
J
Tischfield
John I
JI
Nurnberger
Laura
L
Almasy
Bernice
B
Porjesz
Samuel
S
Kuperman
Marc A
MA
Schuckit
Howard J
HJ
Edenberg
John P
JP
Rice
Alison M
AM
Goate
Laura J
LJ
Bierut
D000293:Adolescent; D000328:Adult; D000437:Alcoholism / Q000208:ethnology / Q000235:genetics; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D019970:Cocaine-Related Disorders / Q000208:ethnology / Q000235:genetics*; D016001:Confidence Intervals; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016017:Odds Ratio; D011978:Receptors, Nicotinic / Q000235:genetics*; D012307:Risk Factors; D014029:Tobacco Use Disorder / Q000208:ethnology / Q000235:genetics*; D055815:Young Adult
C447158:CHRNA5 protein, human; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic