CNR1 variation modulates risk for drug and alcohol dependence.
BACKGROUND
Human cannabinoid receptor 1 (CB1), which is encoded by the CNR1 gene, may play a role in the development of substance dependence (SD). Following initial reports of association of CNR1 with SD, we studied multiple markers at this locus in a large case-control sample.


METHODS
Ten CNR1 markers and 38 ancestry-informative markers were genotyped in 451 healthy control subjects and 550 SD (AD and/or DD) patients (including European Americans [EAs] and African Americans [AAs]). Common confounding effects on association analysis of population stratification and admixture, age, and sex were controlled for using regression analysis. Disease risk and protective alleles were fine-mapped using a linkage disequilibrium measure (delta).


RESULTS
In EAs, risk for each SD subtype significantly increased with the number of "G" alleles at rs6454674 (single nucleotide polymorphisms [SNP]3). SNP3;G(+) (the genotypes containing a G allele) and SNP8;T/T genotypes had significant interaction effects (p = .0003 for comorbid DD and AD, .0002 for DD, and .007 for AD). SNP3 and SNP8 together exerted stronger genetic effects on SD than either did individually. The peak delta values among all the markers were seen for SNP3 and SNP8 (rs806368).


CONCLUSIONS
We demonstrate that CNR1 variation and interactive effects play important roles in risk for both DD and AD.
Zuo
Lingjun
L
Department of Psychiatry, Yale University School of Medicine, 950 Campbell Avenue, New Haven, CT 06516, USA.
Kranzler
Henry R
HR
Luo
Xingguang
X
Covault
Jonathan
J
Gelernter
Joel
J
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D015897:Comorbidity; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics*; D012044:Regression Analysis; D012307:Risk Factors; D019966:Substance-Related Disorders / Q000453:epidemiology / Q000235:genetics*; D044465:White People / Q000235:genetics
D005819:Genetic Markers; D043884:Receptor, Cannabinoid, CB1