@article{481d3c12af784a098a1fcd8b52776f96,
title = "Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent",
abstract = "We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p = 0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285 G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype-specific.",
author = "Winham, {Stacey J.} and Preuss, {Ulrich W.} and Geske, {Jennifer R.} and Peter Zill and Heit, {John A.} and Georgy Bakalkin and Biernacka, {Joanna M.} and Karpyak, {Victor M.}",
note = "Funding Information: This study was supported by grants from the St. Marys Hospital Sponsorship Award (VMK), Samuel C. Johnson Genomics of Addiction Program (VMK, JMB), NIH/NIAAA P20 AA17830Z (VMK, JMB), NIH K12 HD65987 (SJW), and the Swedish Council for Working Life and Social Research, Swedish Science Research Council and Swedish Research Council FORMAS(GB). Controls were recruited and genotyped as part of the GWAS of Venous Thrombosis study (NIH/NHGRI grant HG04735, PI J.A. Heit). We thank the Mayo Clinic Cancer Center for the use of the Genotyping Core, which provided genotyping services. Mayo Clinic Cancer Center is supported in part by an NCI Cancer Center Support Grant 5P30 CA15083-37. This project was supported by Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The datasets used for the eQTL analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http:// www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000417.v2.p1. Submission of this data (phs000417.v2.p1) to dbGaP was provided by Drs. Barbara Lipska and Joel Kleinman. Collection of the data was through a collaborative study sponsored by the NIMH Intramural Research Program. Initial report on this dataset is from Colantuoni, et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature, (2011).",
year = "2015",
month = oct,
day = "27",
doi = "10.1038/srep15670",
language = "English (US)",
volume = "5",
journal = "Scientific reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
}