2006 - 2007 Publications > Genetics of Alcohol Dependence

Genetics of Alcohol Dependence

Lasek et al (2007) reports that Downregulation of mu opioid receptor by RNA interference in the ventral tegmental area reduces ethanol consumption in mice. Genes Brain Behav. 2007 Nov;6(8):728-35

Zuo et al (2007) reported that gene variants in the human canabinoid receptor (CNR1) are associated with risk for drug and alcohol dependence.  The number of G alleles at SNP rs6454674 in CNR1 is associated with risk for substance abuse in European Americans.  A significant interaction between rs6454674 in CNR1 with the T alleles in rs806368 in CNR1 gene was also observed; the occurrence of these alleles in the same individual produced a larger risk than when occurring alone.  
Biol Psychiatry. 2007 Sep 15;62(6):616-26.

Covault et al (2008) reports that Markers in the 5'-Region of GABRG1 are associated with  alcohol dependence and are in linkage disequilibrium with markers in the adjacent GABRA2 gene previously associated with alcohol dependence.  While Covault et al finds a stronger association of alcohol dependence with  GABRG1 5'-upstream markers than with markers in the GABRA2 haplotype block, Covault suggests that the GABRA2 haplotype blocks acts in an additive manner with the GABRG1 haplotype block acts in a dominant manner.  Neuropsychopharmacology. 2008 Mar;33(4):837-48

Previous work has suggested that the A118G allele of the mu opioid receptor predicts the treatment response to naltrexone, an opioid receptor anatagonist.  Gelernter et al (2007) failed to find a treatment response to naloxone predicted by any gene variants in the OPRM1, OPRK1, and OPRD1 gene. Differences in ascertainment or lack of statistical power. may explain the different results.  Time to relapse and rate of relapse at 3 months was predicted by treatment condition, age, and the frequency and amount of drinking before treatment. Alcohol Clin Exp Res. 2007 Apr;31(4):555-63

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.

Haberstack et al (2007) found no association of the dopamine receptor D2 Taq1A polymorphism with any measure of alcohol abuse and dependence in a general population samples of adults with the ability to detect an effect size of 1 percent. J Stud Alcohol Drugs. 2007 May;68(3):362-70.

Ehringer et al (2007)  reports that the initial subjective rewarding effects of both alcohol and nicotine are associated with a SNP (rs2072658) located immediately upstream of CHRNB2.  Both nicotine dependence and alcoholism are highly comorbid disorders.  The overlap may be explained by this polymorphism located in the CHRNB2 gene. Am J Med Genet B Neuropsychiatr Genet. 2007 Jul 5;144B(5):596-604

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

Blednov et al (2007) report that mice lacking fatty acid amide hydrolase prefer alcohol (FAAH), show shorter loss of the righting reflex, and faster recovery of the ataxic effects of alcohol.  At the same time the mice lacking the FAAH did not show any difference from wild type litter mates in  the severity of ethanol-induced acute withdrawal, conditioned taste aversion to alcohol, conditioned place preference, or sensitivity to hypnotic effect of ethanol.  A similar effect was seen with the FAAH inhibitor –URB597. Neuropsychopharmacology. 2007 Jul;32(7):1570-82.

The association of the dopamine receptor 2, DRD2, with alcohol dependence has been inconsistent across studies.  The Taq1 polymorphism that has been widely used in studies to test the association of DRD2 association with alcoholism has been found to lie within a neighboring gene, the ankyrin repeat and kinase domain containing 1 (ANKK1), located 10 kb downstream from DRD2.  Dick et al (2007) genotypes 29 polymorphisms in the ANKK1 gene and  found that the evidence of association was 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 strongest association of ANKK1 with alcoholism by Dick et al (2007) was observed alcoholics with medical complications and with antisocial personality disorder.  Alcohol Clin Exp Res. 2007 Oct;31(10):1645-53 . Consistent with these results Sakai et al (2007) did not find association between the TaqIA polymorphism and early onset alcohol use disorders.  Drug Alcohol Depend. 2007 May 11;88(2-3):130-7

Yang et al (2007) conducted two association studies of Alcohol dependence with 43 single nucleotide polymorphisms mapped to the gene cluster of NCAM1, TTC12, ANKK1 and DRD2 in 1220 European-American subjects using family-based (488 subjects) and case-control (318 cases and 414 controls) designs.  Four regions within this cluster: exon 3 of TTC12, exon 12/intron13 of NCAM1 and exons 2 and 5 of ANKK1 appear to account for the association with alcohol dependence according to Yang et al (2007).  These variants may affect the development of the dopaminergic pathway.  Hum Mol Genet. 2007 Dec 1;16(23):2844-53

Johnson et al (2006) conducted a genome wide association scan for alcohol dependence using 104,268 SNPS.  Johnson et al identified positive SNPs associated with Phospholipid-signaling (DGKB diacylglycerol kinase gene, the ITPR2 inositol 1,4,5-triphosphate receptor, type 2  and the MAP3K7 mitogen-activated protein kinase kinase kinase 7 gene);  ion channels (KCNK2 potassium channel); genes regulating development (ephrin EFNA5 gene, DAB1-disabled homolog 1, DOCK2 dedicator of cytokinesis 2, CSMD1 CUB, and Sushi multiple domains 1, SESTD1 SEC14 and spectrin domains 1, ZNF533 zinc finger protein 533, and the MSH3 mutS homolog 3; cell adhesion molecules) cell adhesion molecules (LRP1B low-density lipoprotein-related protein, cadherin 11 and cadherin 13 genes. The results converge with linkage and association results for alcohol and other addictive phenotypes  Am J Med Genet B x      Neuropsychiatr Genet. 2006 Dec 5;141(8):844-53

Xuei et al 2006 report that gene variants for both the kappa-opioid receptor and its ligand, OPRK1 and PDYN, are associated with the risk for alcohol dependence Mol Psychiatry. 2006 Nov;11(11):1016-24

Agrawal et al 2006 report that the association for alcohol dependence with SNPs in GABRA2 gene only occurs in individuals with co-morbid illicit drug dependence.   No association with GABRA2 is seen in individuals affected with alcoholism only.  Behavior Genetics, 2006 Sept; 36(5): 640-650

Volkow et al 2006 report that high levels of D2 receptor2 are protective against alcoholism in unaffected members of alcoholic families. Because high levels of D2 receptor are positively associated with increased metabolism in frontal regions associated with emotionality and executive function Volkow suggests that high levels D2 receptors protect individuals from alcoholism by increasing inhibitory control by circuits in the orbitofrontal cortex and cingulated gyrus.  Arch Gen Psychiatry. 2006 Sep;63(9):999-1008

Zhang et al 2006 identified intronic variants and two OPRM1 haplotypes blocks that are associated with drug or alcohol dependence in subjects of European Ancestry.  Linkage disequilibrium between A118G and SNPs in the first haplotype block may explain the reason for conflicting findings for the association of A118G with substance dependence Hum Mol Genet. 2006 Mar 15;15(6):807-19

Using diplotype trend analysis, Luo et al reports  that ADH5 genotypes and diplotypes of ADH1A, ADH1B, ADH7, and ALDH2 were associated with AD in European Americans and/or African Americans.  ADH1C diplotypes were significantly associated with drug dependence.  The risk-influencing alleles were fine mapped from among the markers studied and were found to coincide with some well-known functional variants.  Risk for developing alcohol dependence is multigenic and additive.  There is little correlation among the presence of a risk allele with another risk allele.  This is the first demonstration that ADH and ALDH2 gene variants play an important role in European Americans and African Americans as wells as Asians. Am J Hum Genet. 2006 Jun;78(6):973-87.

Luo et al 2006 present strong evidence supporting the hypothesis that ADH4 is a susceptibility gene for alcohol dependence, and presents the first evidence that it is also a susceptibility gene for drug dependence  SNP2 (rs1042363) at exon 9 and the promoter SNP (SNP6: rs1800759) are the genetic markers most closely to the functional risk allele for alcohol and drug dependence in European Americans.  They suggest that alleles have a recessive mode of transmission of the heritable phenotype. Neuropsychopharmacology. 2006 May;31(5):1085-95

Edenberg et al 2006 also demonstrates association between many SNPs and the htSNP haplotype in ADH4 with alcohol dependence.  The region most strongly associated with alcohol dependence ranges from 39.5 kb downstream from the start of  intron 1 to 19.5 kb beyond the 3' end of the of the ADH4 gene. A weaker association for alcohol dependence was found for SNPs in ADH1A and ADH1B.  The ADH1B*3 allele was found to be protective in African Americans. Hum Mol Genet. 2006 May 1;15(9):1539-49

Rothenfluh et al 2006 found that RhoGAP18B encodes several mRNA varieties or isoforms (A, B, C, and D).  Interestingly, the A isoform regulates the locomotor stimulating effects of ethanol, while the C isoform regulates the sedating effects of ethanol.  Furthermore, mutants in RhoGAP18B were also resistant to the intoxicating effects of nicotine and cocaine, revealing a role for RhoGAP18B in regulation of the intoxicating effects of multiple drugs.  Although it is unclear exactly how RhoGAP18B modulates resistance to acute drug exposure, Rothenfluh et al 2006 hypothesize that RhoGAP18B regulates actin cytoskeletal dynamics critical for reorganization of neuronal dendrites and axons which in turn leads to altered synaptic plasticity in response to drug exposure. Cell. 2006 Oct 6;127(1):199-211

Previously, the Buck laboratory mapped two genetic loci on chromosome 11 spanning a 28 cM region that accounts for 9 and 12 percent of the genetic variance for acute acute alcohol and pentobarbital withdrawal convulsions in mice.  Hood et al using haplotype analysis has further narrowed the region to 3cM and reduced the number of candidate genes from 200 to 34 which include four GABA A subunits.  Because DBA/J mice encodes a unique variant of GABAA receptor γ2 subunit and is most susceptible to withdrawal as compared to other mouse strains Hood et al 2006 suggests that variants within the GABAA receptor γ2 subunit explain phenotypic differences in withdrawal to alcohol, benzodiazepine and barbiturate.  Genes Brain Behav. 2006 Feb;5(1):1-10