2006 - 2007 Publications > Genetics of drug abuse and addiction vulnerability

Genetics of drug abuse and addiction vulnerability

To clarify the structure of genetic and environmental risk factors for symptoms of dependence on cannabis, cocaine, alcohol, caffeine, and nicotine, Kendler et al (2007) performed a structured clinical interview of 4865 members of male-male and female-female pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. It was reported that the pattern of genetic and environmental risk factors for psychoactive substance dependence was similar in males and females. Genetic risk for dependence on common psychoactive substances could be explained by two factors: predisposing to illicit and licit drug dependence. Furthermore, a large proportion of the genetic influences on nicotine and particularly caffeine dependence appear to be specific to those substances. Arch Gen Psychiatry. 2007 Nov;64(11):1313-20.

To evaluate the familial risk mechanism for substance use disorders (SUD), Wilens et al (2007) examined the expression of both SUD and juvenile bipolar disorder (BPD) in families of youth with BPD. Bipolar disorder and SUD are prevalent in the first-degree relatives of adolescents with BPD. Adults with BPD were more likely to manifest SUD with preliminary evidence of BPD and SUD co-segregation. Biol Psychiatry. 2007 Jul 15;62(2):129-34. Epub 2007 May 3.

The single-nucleotide polymorphisms (SNPs) spanning OPRD1 were studied by Zhang et al (2007) in human subjects with substance dependence. Specific haplotype GCAACT, which harbors G80T G-allele and C921T C-allele, was significantly associated with alcohol dependence (AD), cocaine dependence (CD) and opioid dependence (OD) in Americans of European lineage. Logistic regression analyses, with sex and age being considered, demonstrated that this haplotype had a risk effect on AD and especially on OD. Mol Psychiatry. 2008 May;13(5):531-43.

Covault et al (2007) observed two large haplotype blocks in the GABRG1 (the GABA(A) receptor gamma-1 subunit) -GABRA2 (the GABA(A) alpha-2 subunit) intergenic interval with a region of increased recombination midway between the two genes in a study of control and alcohol dependent subjects. Markers in the two haplotype blocks were in moderate linkage disequilibrium. Compared with markers in the GABRA2 haplotype block, markers in the 5' GABRG1 haplotype showed greater allelic, genotypic and haplotypic association with alcohol dependence (AD) in European Americans. Genetic elements in the GABRG1 haplotype block contribute to AD risk in an additive manner, whereas those in the GABRA2 haplotype block may act in a dominant manner. Neuropsychopharmacology. 2008 Mar;33(4):837-48.

Luo et al (2007) examined the relationship between 7 alcohol dehydrogenase (ADH) genes, previously reported to be associated with alcohol dependence (AD), and drug dependence (DD). ADH5 and ADH6 genotypes, and diplotypes at ADH1A, ADH1B, ADH1C and ADH7, were associated with DD in European-Americans and/or African-Americans. Allelic association of these loci with DD provides new insight into the mechanism of genetic risk for DD and helps to explain the high rate of co-morbidity between AD and DD. Hum Mol Genet. 2007 Feb 15;16(4):380-90.

Dick et al (2007) provided specific genetic evidence that alcohol dependence with comorbid drug dependence represents a particularly severe form of the disorder, with higher genetic contribution to vulnerability. While testing for heterogeneity in the association between the muscarinic acetylcholine M2 receptor gene (CHRM2) and alcohol dependence among the subgroups of alcohol-dependent individuals with and without comorbid drug dependence, they reported association between CHRM2 and alcohol dependence in the subgroup of individuals with comorbid drug dependence solely. There was no evidence of association with CHRM2 among the alcohol-dependent individuals without drug dependence. Subsequent phenotypic analyses suggested that the subgroup of alcohol-dependent individuals with comorbid drug dependence differ on a number of other phenotypic characteristics, including several measures of the severity of their alcohol problems, personality traits and comorbid psychiatric disorders. Addiction. 2007 Jul;102(7):1131-9

A sample of 148 European-American males was assessed prospectively at ages from 10-12 to 18-19 years and genotyped for the monoamine oxidase A (MAOA) variable number tandem repeat by Vanyukov et al (2007). The MAOA polymorphism's association with the risk for substance use disorders was detected. Psychiatr Genet. 2007 Dec;17(6):323-32.

Ishiguro et al (2007) reported SLC4A7 gene, a member of the bicarbonate co-transporter family that is expressed in tissues including brain and kidney, as a novel candidate in the contribution to vulnerability to addictions. Addiction. 2007 Aug;102(8):1320-5

Liu et al 2006 using a 639,401 SNP whole genome association identified 89 genes likely to contain variants that contribute to addiction vulnerability in each of four different samples. Many of the 89 genes identified are cellular adhesion molecules such as semaphorin 3a, contactins, and cadherins. One of the 5 genes identified by Beirut et al with multiple positive SNPs in their study was identified by multiple positive SNPs in multiple samples in this study.  Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141(8):918-25  

Ishiguruo et al 2006 fine mapped a locus on Chromosome 7 for drug addiction that identified NrCAM haplotypes a being associated with substance abuse vulnerability.  Ishiguruo et al  report that expression of NrCAM is regulated by drugs of abuse; shows allele specific gene expression in post-mortem tissue; and the knockout of NrCAM  reduces conditioned place preference to opiates and psychostimulants Neuropsychopharmacology. 2006 Mar;31(3):572-84 

Drgon et al 2006, based on analysis of the COGA sample for alcoholism and the NIDA Baltimore sample for substance abuse in European American and African Americans for SNPs on chromosome 4p12, reports a modest role for GABRA2 variants in addiction vulnerabilities Am J Med   B Neuropsychiatr Genet. 2006 Dec 5;141(8):854-60

Flanagan et al 2006 shows that the fatty acid amide hydrolase 385 A/A (P129T) variant is associated with street drug use and problem drug use.  Hum Genet. 2006 Nov;120(4):581-8.

Luo et al 2007 provides the first report that ADH5 and ADH6 genotypes, and diplotypes at ADH1A, ADH1B, ADH1C and ADH7 are associated with drug dependence in European-Americans and/or African-Americans.  This finding may explain the high co-morbidity between alcohol and drug dependence.  Hum Mol Genet. 2007 Feb 15;16(4):380-90