Dataset Information

Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence.

ABSTRACT: Several lines of evidence in both human and animal studies suggest that variation in neuropeptide Y (NPY) or its receptor genes (NPY1R, NPY2R and NPY5R) is associated with alcohol dependence as well as alcohol withdrawal symptoms. Additional studies suggest that cocaine may affect NPY expression.A total of 39 single nucleotide polymorphisms (SNPs) were genotyped across NPY and its 3 receptor genes in a sample of 1,923 subjects from 219 multiplex alcoholic families of European American descent recruited as part of the Collaborative Studies on the Genetics of Alcoholism (COGA) study. Family-based association analysis was performed to test the primary hypothesis that variation in these genes is associated with alcohol dependence. Secondary analyses evaluated whether there was an association of these SNPs with symptoms of alcohol withdrawal, cocaine dependence, or comorbid alcohol and cocaine dependence.Although variations in NPY itself were not associated with these phenotypes, variations in 2 NPY-receptor genes were. SNPs in NPY2R provided significant evidence of association with alcohol dependence, alcohol withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence (all p < 0.03). Haplotype analyses strengthened the evidence for these phenotypes (global 0.0004 < p < 0.005). SNPs in NPY5R demonstrated significant association with alcohol withdrawal characterized by seizures (p < 0.05).These results indicate that sequence variations in NPY receptor genes are associated with alcohol dependence, particularly a severe subtype of alcohol dependence characterized by withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence.

SUBMITTER: Wetherill L

PROVIDER: S-EPMC2650441 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence.

Wetherill Leah L Schuckit Marc A MA Hesselbrock Victor V Xuei Xiaoling X Liang Tiebing T Dick Danielle M DM Kramer John J Nurnberger John I JI Tischfield Jay A JA Porjesz Bernice B Edenberg Howard J HJ Foroud Tatiana T

Alcoholism, clinical and experimental research 20080925 12

<h4>Background</h4>Several lines of evidence in both human and animal studies suggest that variation in neuropeptide Y (NPY) or its receptor genes (NPY1R, NPY2R and NPY5R) is associated with alcohol dependence as well as alcohol withdrawal symptoms. Additional studies suggest that cocaine may affect NPY expression.<h4>Methods</h4>A total of 39 single nucleotide polymorphisms (SNPs) were genotyped across NPY and its 3 receptor genes in a sample of 1,923 subjects from 219 multiplex alcoholic famil ...[more]

PMID: 18828811

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Project description:AimSubstance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively). A genome-wide association study of OD and CD related phenotypes reflecting the time between first self-reported use of these substances and a first DSM-IV dependence diagnosis was conducted.MethodsCox proportional hazards regression in a discovery sample of 6,188 African-Americans (AAs) and 6,835 European-Americans (EAs) participants in a genetic study of multiple substance dependence phenotypes were used to test for association between genetic variants and these outcomes. The top findings were tested for replication in two independent cohorts.ResultsIn the discovery sample, three independent regions containing variants associated with time to dependence at P < 5 x 10-8 were identified, one (rs61835088 = 1.03 x 10-8) for cocaine in the combined EA-AA meta-analysis in the gene FAM78B on chromosome 1, and two for opioids in the AA portion of the sample in intergenic regions of chromosomes 4 (rs4860439, P = 1.37 x 10-8) and 9 (rs7032521, P = 3.30 x 10-8). After meta-analysis with data from the replication cohorts, the signal at rs61835088 improved (HR = 0.87, P = 3.71 x 10-9 and an intergenic SNP on chromosome 21 (rs2825295, HR = 1.14, P = 2.57 x 10-8) that missed the significance threshold in the AA discovery sample became genome-wide significant (GWS) for CD.ConclusionsAlthough the two GWS variants are not in genes with obvious links to SUD biology and have modest effect sizes, they are statistically robust and show evidence for association in independent samples. These results may point to novel pathways contributing to disease progression and highlight the utility of related phenotypes to better understand the genetics of SUDs.

Dataset Information

Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence.

Publications

Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence.

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