Interaction between two independent CNR1 variants increases risk for cocaine dependence in European Americans: a replication study in family-based sample and population-based sample.
- Authors
- Zuo, Lingjun; Kranzler, Henry R; Luo, Xingguang; Yang, Bao-zhu; Weiss, Roger; Brady, Kathleen; Poling, James; Farrer, Lindsay; Gelernter, Joel
- Year
- 2009
- Journal
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
- PMID
- 19052543
- DOI
- 10.1038/npp.2008.206
- PMCID
- PMC2879626
We recently reported that, in a European-American (EA) sample, the interaction between two cannabinoid receptor 1 gene (CNR1) variants significantly increased risk for drug dependence (DD), including cocaine dependence (CD). This study aimed to investigate directly the association between CNR1 and CD in four independent samples. Eight markers across the 45 kb CNR1 region and four large samples, ie, family-based European-American (EA) sample (n=734), case-control EA sample (n=862), family-based African-American (AA) sample (n=834) and case-control AA sample (n=619) were examined in the present study. We investigated the association of these markers with CD and cocaine-induced paranoia (CIP) in the EA family sample first, and then replicated positive results in the other three samples. The interaction between two independent CNR1 variants, ie, the G allele-containing genotypes of rs6454674 (SNP3(G+)), and the T/T genotype of rs806368 (SNP8(T)/T), significantly increased risk for CD in the EA family (P(GEE)=0.015) and EA case-control (P(regression)=0.003) samples. EA subjects with SNP3(G+) and SNP8(T)/T had higher risk to develop CD than those EA subjects with the other genotypes for these two SNPs (LR+ =1.4). The SNP3(G)-SNP8(T)haplotype also showed significant association (P=0.018) with CD in the EA case-control sample. SNP8-containing haplotypes showed significant association with both CD (P(global)=0.007) and CIP (P(global)=0.003) in the EA family sample. In the AA family sample, SNP8(T)/T significantly conferred higher risk for CD (P=0.019). We conclude that two independent CNR1 variants have significant interaction effects on risk for CD in EAs; they may also have effects on risk for CD in AAs.
Pairwise Linkage disequilibrium (LD) of CNR1 markers in Family samplesLD blocks were detected by haploview v3.32 and haplotype blocks were defined by solid spine of LD (Barrett et al., 2005). EAs and AAs represent European Americans and African Americans, respectively; the numbers inside the square are D’×100; the red squares indicate D’=1.
Log10(P) values for the associations of cocaine dependence (CD) with 8 markers in CNR1 in EA family sampleMarkers 1 to 8 represent rs6454674 (SNP3), rs806379 (SNP4), rs806377 (SNP5), rs806371 (SNP6), rs1049353 (SNP7), rs806368 (SNP8), rs806365 (SNP9), and rs2146274 (SNP10), respectively.
Log10(P) values of associations of SNP3 and SNP8 with six different CD subgroups in the EA family sampleCDnoAD, CDnoOD, CDnoMD, CDnoND and CDnoR-SD represent CD without comorbid alcohol dependence, CD without comorbid opioid dependence, CD without comorbid marijuana dependence, CD without comorbid nicotine dependence and CD without comorbid rest type of substance dependence, respectively.
Figure 4a. SNP8^T/T genotype frequency difference between CD cases and controls in different genotype groups of SNP3 in EAs. SNP3^T/T and SNP3^(G/G or G/T) represent T/T genotype and G allele-containing genotype of SNP3, respectivelyFigure 4b. SNP3^(G/G and G/T) genotype frequency difference between CD cases and controls in different genotype groups of SNP8 in EAs. SNP8^(C/C and T/C) and SNP8^T/T represent C allele containing genotype and T/T genotype of SNP8, respectively.
| Name | Type |
|---|---|
| 2-arachidonoylglycerol | drug |
| AA | cohort |
| AA case-control sample local | cohort |
| AA family sample local | cohort |
| AA_family_sample local | cohort |
| (AAT)n polymorphism local | variant |
| addiction | phenotype |
| adolescent Caucasian sample local | cohort |
| African American | cohort |
| African Caribbean local | cohort |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| alcohol withdrawal delirium local | phenotype |
| allele | cohort |
| Alzheimer's disease | phenotype |
| amygdala | anatomy |
| anandamide | drug |
| basal ganglia | anatomy |
| blood | drug |
| cannabis dependence | phenotype |
| Cannabis dependence without nicotine dependence local | phenotype |
| cannabis use | phenotype |
| case-control sample | cohort |
| cases | cohort |
| CB1 binding local | phenotype |
| CB1 knockout mice local | cohort |
| CB1 protein local | drug |
| CB1 receptor | drug |
| CD | phenotype |
| CD cases local | phenotype |
| CDnoAD local | phenotype |
| CDnoMD local | phenotype |
| CDnoOD local | phenotype |
| CDnoR-SD local | phenotype |
| CD vulnerability local | phenotype |
| cerebellum | anatomy |
| CIP | phenotype |
| CIP cases local | phenotype |
| Cnr1 | gene |
| CNR1 SNP3 G+ local | variant |
| CNR1 SNP3 G+ / SNP8 T/T interaction local | variant |
| CNR1 SNP8 T/T local | variant |
| CNR1 SNPs local | variant |
| cocaine | phenotype |
| Cocaine dependence without alcohol dependence local | phenotype |
| Cocaine dependence without marijuana dependence local | phenotype |
| Cocaine dependence without nicotine dependence local | phenotype |
| Cocaine dependence without opioid dependence local | phenotype |
| Cocaine dependence without other substance dependence local | phenotype |
| cocaine-induced LTD local | phenotype |
| cocaine-induced paranoia | phenotype |
| Cocaine induced paranoia local | phenotype |
| cocaine relapse | phenotype |
| controls | cohort |
| Crohn's disease | phenotype |
| D2-like receptor local | gene |
| DBH | gene |
| DD | phenotype |
| delta-9-tetrahydrocannabinol | drug |
| drug dependence | phenotype |
| drug-seeking behavior | phenotype |
| EA | cohort |
| EA case-control sample local | cohort |
| EA controls | cohort |
| EA family-based association tests local | cohort |
| EA family sample local | cohort |
| EAs | cohort |
| EA sample | cohort |
| European American family sample local | cohort |
| European ancestry | cohort |
| family based cohort local | cohort |
| family-based sample | cohort |
| family samples local | cohort |
| FBAT local | drug |
| genetic variants | cohort |
| genomic DNA | drug |
| German population | cohort |
| GT haplotype local | locus |
| GT haplotype local | variant |
| haplotype | variant |
| healthy controls | cohort |
| hippocampus | anatomy |
| HU210 local | drug |
| Immortalized cell line local | drug |
| independent samples | cohort |
| Major anxiety disorder local | phenotype |
| major depressive disorder | phenotype |
| male African Caribbean sample local | cohort |
| marijuana dependence | phenotype |
| McLean Hospital of Harvard Medical School local | cohort |
| Medical University of South Carolina | cohort |
| methamphetamine | drug |
| methamphetamine dependence | phenotype |
| midbrain | anatomy |
| midbrain DA neurons local | anatomy |
| mood disorders | phenotype |
| motivation to seek cocaine local | phenotype |
| neocortex | anatomy |
| nicotine | drug |
| nicotine dependence | phenotype |
| nucleus accumbens | anatomy |
| OD | phenotype |
| opioid | drug |
| opioid dependence | phenotype |
| other substances | phenotype |
| Pedcheck | drug |
| pedigrees | cohort |
| phenotype | phenotype |
| polysubstance abuse | phenotype |
| PowerMarker local | drug |
| prefrontal cortex | anatomy |
| psychosis | phenotype |
| Regular smoking dependence local | phenotype |
| Relapse to heavy cocaine use local | phenotype |
| risk SNP local | variant |
| rs1049353 local | variant |
| rs2023239 | variant |
| rs2146274 local | variant |
| rs6454674 local | variant |
| rs806368 local | variant |
| rs806371 local | variant |
| rs806380 local | variant |
| saliva | drug |
| schizophrenia | phenotype |
| SLC6A3 | gene |
| SNP | cohort |
| SNP 10 local | variant |
| SNP10 local | variant |
| SNP 3 local | variant |
| SNP3^G local | variant |
| SNP3^G+ local | variant |
| SNP3_Gplus local | variant |
| SNP 4 local | variant |
| SNP 5 local | variant |
| SNP 6 local | variant |
| SNP6 local | variant |
| SNP 7 local | variant |
| SNP7 local | variant |
| SNP 8 local | variant |
| SNP8 local | variant |
| SNP8-containing haplotype local | variant |
| SNP8-SNP3 interaction local | variant |
| SNP8^T/T local | variant |
| SNP8_TT local | variant |
| SNP 9 local | variant |
| SNP9 local | variant |
| SR141716 | drug |
| striatum | anatomy |
| substance abuse | phenotype |
| substance use | phenotype |
| TAG haplotype local | variant |
| Taqman technique local | drug |
| University of Connecticut Health Center | cohort |
| ventral tegmental area | anatomy |
| wild-type mice | cohort |
| Yale University School of Medicine | cohort |
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