Family-based association analyses of alcohol dependence phenotypes across DRD2 and neighboring gene ANKK1.
BACKGROUND
There is an extensive and inconsistent literature on the association of the dopamine D2 receptor gene (DRD2) with alcohol dependence. Conflicting results have been attributed to differences in the severity of the alcohol dependence phenotype across studies, failure to exclude related disorders from comparison groups, and artifacts of population-stratification. Recently the genetic polymorphism most widely analyzed in DRD2, Taq1A, has been discovered to reside in a neighboring gene, ankyrin repeat and kinase domain containing 1 (ANKK1), located 10 kb downstream from DRD2.


METHODS
To more carefully characterize evidence for association across this region, we genotyped 26 single nucleotide polymorphisms (SNPs) spanning DRD2 and ANKK1 in a sample of 219 Caucasian families (n = 1,923) from the Collaborative Study on the Genetics of Alcoholism (COGA), making this the most extensive analysis to date of association between this region and alcohol dependence. We used family-based analyses robust to population-stratification, and we made use of rich phenotypic data to analyze alcohol dependence and subtypes hypothesized in the literature to be more directly influenced by DRD2.


RESULTS
We found that the evidence for association is strongest in the 5' linkage disequilibrium block of ANKK1 (that does not contain Taq1A), with weak evidence of association with a small number of SNPs in DRD2. The association in ANKK1 is strongest among the subsets of alcoholics with medical complications and with antisocial personality disorder.


CONCLUSIONS
More extensive genotyping across DRD2 and ANKK1 suggests that the association with alcohol dependence observed in this region may be due to genetic variants in the ANKK1 gene. ANKK1 is involved in signal transduction pathways and is a plausible biological candidate for involvement in addictive disorders.
Dick
Danielle M
DM
Washington University in St Louis, St Louis, Missouri, USA. ddick@vcu.edu
Wang
Jen C
JC
Plunkett
Jevon
J
Aliev
Fazil
F
Hinrichs
Anthony
A
Bertelsen
Sarah
S
Budde
John P
JP
Goldstein
Elianna L
EL
Kaplan
Daniel
D
Edenberg
Howard J
HJ
Nurnberger
John
J
Hesselbrock
Victor
V
Schuckit
Marc
M
Kuperman
Sam
S
Tischfield
Jay
J
Porjesz
Bernice
B
Begleiter
Henri
H
Bierut
Laura Jean
LJ
Goate
Alison
A
D000437:Alcoholism / Q000235:genetics* / Q000503:physiopathology; D004198:Disease Susceptibility; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D044465:White People / Q000235:genetics
D017448:Receptors, Dopamine D2; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases