The tachykinin receptor 3 is associated with alcohol and cocaine dependence.

BACKGROUND A broad region on chromosome 4q was previously linked to the phenotype of alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample. A strong positional candidate gene was identified within this region: tachykinin receptor 3 gene (TACR3), which encodes tachykinin receptor 3 (NK3R), the receptor for the tachykinin 3 (neurokinin B) peptide. Pharmacological studies have provided evidence that the administration of NK3R agonists attenuates the intake of alcohol and NK3R can also mediate the acute and chronic behavioral effects of cocaine. METHODS Thirty SNPs were genotyped throughout TACR3. Family based association analysis was performed in 219 European American families to detect an association with alcohol dependence. Subsequent analyses were performed to evaluate the evidence of association with other definitions of alcohol dependence as well as cocaine dependence. RESULTS Seven of the 9 SNPs in the 3' region of TACR3 provided significant evidence of association with alcohol dependence (p <or= 0.05). Further analyses suggest that the evidence of association is strongest among those subjects with more severe alcohol dependence (defined by ICD-10) and those with co-morbid cocaine dependence. Haplotype analyses further strengthen the evidence of association in the 3' region of the gene. CONCLUSIONS These results indicate that sequence variations in TACR3 contribute to the variation in more severe alcohol dependent individuals and those who are also cocaine dependent.

[1]  L. Bierut,et al.  Lack of association of alcohol dependence and habitual smoking with catechol-O-methyltransferase. , 2007, Alcoholism, clinical and experimental research.

[2]  L. Bierut,et al.  Alcohol dependence with comorbid drug dependence: genetic and phenotypic associations suggest a more severe form of the disorder with stronger genetic contribution to risk. , 2007, Addiction.

[3]  J. Nurnberger,et al.  Association of Alcohol Craving With α‐Synuclein (SNCA) , 2007 .

[4]  J. Nurnberger,et al.  Association of alcohol craving with alpha-synuclein (SNCA). , 2007, Alcoholism, clinical and experimental research.

[5]  G. Jocham,et al.  Interaction of the tachykinin NK3 receptor agonist senktide with behavioral effects of cocaine in marmosets (Callithrix penicillata) , 2006, Peptides.

[6]  G. Jocham,et al.  Neurokinin3 receptor antagonism attenuates cocaine's behavioural activating effects yet potentiates its dopamine‐enhancing action in the nucleus accumbens core , 2006, The European journal of neuroscience.

[7]  G. Jocham,et al.  The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys. , 2006, European journal of pharmacology.

[8]  L. Bierut,et al.  Association of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysis. , 2006, Human molecular genetics.

[9]  N. Dahmen,et al.  Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis , 2006, Psychiatric genetics.

[10]  J. Gelernter,et al.  ADH4 gene variation is associated with alcohol and drug dependence: results from family controlled and population-structured association studies , 2005, Pharmacogenetics and genomics.

[11]  S. Gabriel,et al.  Efficiency and power in genetic association studies , 2005, Nature Genetics.

[12]  H. Blumberg,et al.  CHRM2 gene predisposes to alcohol dependence, drug dependence and affective disorders: results from an extended case-control structured association study. , 2005, Human molecular genetics.

[13]  N. Page New challenges in the study of the mammalian tachykinins , 2005, Peptides.

[14]  G. Breen,et al.  Association of genetic variants in alcohol dehydrogenase 4 with alcohol dependence in Brazilian patients. , 2005, The American journal of psychiatry.

[15]  J. Krystal,et al.  Association Between Alcoholism and γ‐Amino Butyric Acid α2 Receptor Subtype in a Russian Population , 2005 .

[16]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[17]  J. Krystal,et al.  Association between alcoholism and gamma-amino butyric acid alpha2 receptor subtype in a Russian population. , 2005, Alcoholism, clinical and experimental research.

[18]  L. Bierut,et al.  Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. , 2004, Human molecular genetics.

[19]  V. Hesselbrock,et al.  Allelic and haplotypic association of GABRA2 with alcohol dependence , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[20]  B. Grant,et al.  The 12-Month Prevalence and Trends in DSM–IV Alcohol Abuse and Dependence , 2004, Drug and alcohol dependence.

[21]  Tatiana Foroud,et al.  Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. , 2004, American journal of human genetics.

[22]  F. Dudbridge Pedigree disequilibrium tests for multilocus haplotypes , 2003, Genetic epidemiology.

[23]  E R Martin,et al.  Letter to the Editor Correcting for a Potential Bias in the Pedigree Disequilibrium Test , 2022 .

[24]  M. Massi,et al.  The psychopharmacology of tachykinin NK-3 receptors in laboratory animals , 2000, Peptides.

[25]  Daniel L. Koller,et al.  Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping. , 2000, Alcoholism, clinical and experimental research.

[26]  E. Martin,et al.  A test for linkage and association in general pedigrees: the pedigree disequilibrium test. , 2000, American journal of human genetics.

[27]  J Blangero,et al.  Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. II. Alcoholism and event-related potentials. , 1999, American journal of human genetics.

[28]  M. Hesselbrock,et al.  A validity study of the SSAGA--a comparison with the SCAN. , 1999, Addiction.

[29]  J R O'Connell,et al.  PedCheck: a program for identification of genotype incompatibilities in linkage analysis. , 1998, American journal of human genetics.

[30]  J. Rice,et al.  Genome-wide search for genes affecting the risk for alcohol dependence. , 1998, American journal of medical genetics.

[31]  L. Bierut,et al.  Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men , 1997, Psychological Medicine.

[32]  C. Polidori,et al.  Subcutaneous injections of the tachykinin senktide reduce alcohol intake in alcohol-preferring rats , 1995, Peptides.

[33]  R. Ciccocioppo,et al.  Selective agonists at NK3 tachykinin receptors inhibit alcohol intake in Sardinian alcohol-preferring rats , 1994, Brain Research Bulletin.

[34]  J. Nurnberger,et al.  A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA. , 1994, Journal of studies on alcohol.

[35]  R. Kessler,et al.  A twin-family study of alcoholism in women. , 1994, The American journal of psychiatry.

[36]  M. Boehnke,et al.  Allele frequency estimation from data on relatives. , 1991, American journal of human genetics.

[37]  D. Lykken,et al.  Heterogeneity in the inheritance of alcoholism. A study of male and female twins. , 1991, Archives of general psychiatry.

[38]  C. Robert Cloninger,et al.  Inheritance of alcohol abuse. Cross-fostering analysis of adopted men. , 1981, Archives of general psychiatry.

[39]  R. Cadoret,et al.  Development of alcoholism in adoptees raised apart from alcoholic biologic relatives. , 1980, Archives of general psychiatry.

[40]  D. W. Goodwin,et al.  The cause of alcoholism and why it runs in families. , 1979, The British journal of addiction to alcohol and other drugs.

[41]  J. Feighner,et al.  Diagnostic criteria for use in psychiatric research. , 1972, Archives of general psychiatry.