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Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence

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Abstract

Common SNPs in nicotinic acetylcholine receptor genes (CHRN genes) have been associated with drug behaviors and personality traits, but the influence of rare genetic variants is not well characterized. The goal of this project was to identify novel rare variants in CHRN genes in the Center for Antisocial Drug Dependence (CADD) and Genetics of Antisocial Drug Dependence (GADD) samples and to determine if low frequency variants are associated with antisocial drug dependence. Two samples of 114 and 200 individuals were selected using a case/control design including the tails of the phenotypic distribution of antisocial drug dependence. The capture, sequencing, and analysis of all variants in 16 CHRN genes (CHRNA1-7, 9, 10, CHRNB1-4, CHRND, CHRNG, CHRNE) were performed independently for each subject in each sample. Sequencing reads were aligned to the human reference sequence using BWA prior to variant calling with the Genome Analysis ToolKit (GATK). Low frequency variants (minor allele frequency < 0.05) were analyzed using SKAT-O and C-alpha to examine the distribution of rare variants among cases and controls. In our larger sample, the region containing the CHRNA6/CHRNB3 gene cluster was significantly associated with disease status using both SKAT-O and C-alpha (unadjusted p values <0.05). More low frequency variants in the CHRNA6/CHRNB3 gene region were observed in cases compared to controls. These data support a role for genetic variants in CHRN genes and antisocial drug behaviors.

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References

  • Ajay SS, Parker SCJ, Abaan HO, Fajardo KVF, Margulies EH (2011) Accurate and comprehensive sequencing of personal genomes. Genome Res 21:1498–1505

    Article  PubMed  PubMed Central  Google Scholar 

  • Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73–120

    Article  PubMed  PubMed Central  Google Scholar 

  • Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X, Saccone NL, Saccone SF, Bertelsen S, Fox L et al (2008) Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165:1163–1171

    Article  PubMed  PubMed Central  Google Scholar 

  • Bruschweiler-Li L, Fuentes Medel YF, Scofield MD, Trang EBT, Binke SA, Gardner PD (2010) Temporally- and spatially-regulated transcriptional activity of the nicotinic acetylcholine receptor beta4 subunit gene promoter. Neuroscience 166:864–877

    Article  PubMed  PubMed Central  Google Scholar 

  • Button TMM, Hewitt JK, Rhee SH, Young SE, Corley RP, Stallings MC (2006) Examination of the causes of covariation between conduct disorder symptoms and vulnerability to drug dependence. Twin Res Hum Genet 9:38–45

    Article  PubMed  Google Scholar 

  • Coon H, Piasecki TM, Cook EH, Dunn D, Mermelstein RJ, Weiss RB, Cannon DS (2014) Association of the CHRNA4 neuronal nicotinic receptor subunit gene with frequency of binge drinking in young adults. Alcohol Clin Exp Res 38:930–937

    Article  PubMed  PubMed Central  Google Scholar 

  • Corley RP, Zeiger JS, Crowley T, Ehringer MA, Hewitt JK, Hopfer CJ, Lessem J, McQueen MB, Rhee SH, Smolen A et al (2008) Association of candidate genes with antisocial drug dependence in adolescents. Drug Alcohol Depend 96:90–98

    Article  PubMed  PubMed Central  Google Scholar 

  • Criado JR, Gizer IR, Edenberg HJ, Ehlers CL (2014) CHRNA5 and CHRNA3 variants and level of neuroticism in young adult Mexican American men and women. Twin Res Hum Genet 17:80–88

    Article  PubMed  PubMed Central  Google Scholar 

  • Cui WY, Wang S, Yang J, Yi SG, Yoon D, Kim Y-J, Payne TJ, Ma JZ, Park T, Li MD (2013) Significant association of CHRNB3 variants with nicotine dependence in multiple ethnic populations. Mol Psychiatry 18:1149–1151

    Article  PubMed  Google Scholar 

  • Culverhouse RC, Johnson EO, Breslau N, Hatsukami DK, Sadler B, Brooks AI, Hesselbrock VM, Schuckit MA, Tischfield JA, Goate AM et al (2014) Multiple distinct CHRNB3–CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans. Addiction 109:814–822

    Article  PubMed  PubMed Central  Google Scholar 

  • DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M et al (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498

    Article  PubMed  PubMed Central  Google Scholar 

  • Derringer J, Corley RP, Haberstick BC, Young SE, Demmitt BA, Howrigan DP, Kirkpatrick RM, Iacono WG, McGue M, Keller MC et al (2015) Genome-wide association study of behavioral disinhibition in a selected adolescent sample. Behav Genet 45:375–381

    Article  PubMed  PubMed Central  Google Scholar 

  • Ehringer MA, Clegg HV, Collins AC, Corley RP, Crowley T, Hewitt JK, Hopfer CJ, Krauter K, Lessem J, Rhee SH et al (2007) Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine. Am J Med Genet B Neuropsychiatr Genet 144B:596–604

    Article  PubMed  Google Scholar 

  • Ehringer MA, McQueen MB, Hoft NR, Saccone NL, Stitzel JA, Wang JC, Bierut LJ (2010) Association of CHRN genes with “dizziness” to tobacco. Am J Med Genet B Neuropsychiatr Genet 153B:600–609

    PubMed  PubMed Central  Google Scholar 

  • Elkins IJ, McGue M, Iacono WG (2007) Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Arch Gen Psychiatry 64:1145–1152

    Article  PubMed  Google Scholar 

  • Flora AV, Zambrano CA, Gallego X, Miyamoto JH, Johnson KA, Cowan KA, Stitzel JA, Ehringer MA (2013) Functional characterization of SNPs in CHRNA3/B4 intergenic region associated with drug behaviors. Brain Res 1529:1–15

    Article  PubMed  Google Scholar 

  • Gallego X, Cox RJ, Laughlin JR, Stitzel JA, Ehringer MA (2013) Alternative CHRNB4 3’-UTRs mediate the allelic effects of SNP rs1948 on gene expression. PLoS One 8:e63699

    Article  PubMed  PubMed Central  Google Scholar 

  • Goldstein RB, Compton WM, Pulay AJ, Ruan WJ, Pickering RP, Stinson FS, Grant BF (2007) Antisocial behavioral syndromes and DSM-IV drug use disorders in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Drug Alcohol Depend 90:145–158

    Article  PubMed  PubMed Central  Google Scholar 

  • Gotti C, Zoli M, Clementi F (2006) Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci 27:482–491

    Article  PubMed  Google Scholar 

  • Gotti C, Clementi F, Fornari A, Gaimarri A, Guiducci S, Manfredi I, Moretti M, Pedrazzi P, Pucci L, Zoli M (2009) Structural and functional diversity of native brain neuronal nicotinic receptors. Biochem Pharmacol 78:703–711

    Article  PubMed  Google Scholar 

  • Grady SR, Salminen O, Laverty DC, Whiteaker P, McIntosh JM, Collins AC, Marks MJ (2007) The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum. Biochem Pharmacol 74:1235–1246

    Article  PubMed  PubMed Central  Google Scholar 

  • Grazioplene RG, Deyoung CG, Rogosch FA, Cicchetti D (2013) A novel differential susceptibility gene: CHRNA4 and moderation of the effect of maltreatment on child personality. J Child Psychol Psychiatry 54:872–880

    Article  PubMed  Google Scholar 

  • Greenbaum L, Kanyas K, Karni O, Merbl Y, Olender T, Horowitz A, Yakir A, Lancet D, Ben-Asher E, Lerer B (2006) Why do young women smoke? I. Direct and interactive effects of environment, psychological characteristics and nicotinic cholinergic receptor genes. Mol Psychiatry 11(312–322):223

    Article  Google Scholar 

  • Grucza RA, Wang JC, Stitzel JA, Hinrichs AL, Saccone SF, Saccone NL, Bucholz KK, Cloninger CR, Neuman RJ, Budde JP et al (2008) A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biol Psychiatry 64:922–929

    Article  PubMed  PubMed Central  Google Scholar 

  • Haller G, Druley T, Vallania FL, Mitra RD, Li P, Akk G, Steinbach JH, Breslau N, Johnson E, Hatsukami D et al (2012) Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence. Hum Mol Genet 21:647–655

    Article  PubMed  Google Scholar 

  • Haller G, Kapoor M, Budde J, Xuei X, Edenberg H, Nurnberger J, Kramer J, Brooks A, Tischfield J, Almasy L et al (2014) Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence. Hum Mol Genet 23:810–819

    Article  PubMed  Google Scholar 

  • Hällfors J, Loukola A, Pitkäniemi J, Broms U, Männistö S, Salomaa V, Heliövaara M, Lehtimäki T, Raitakari O, Madden PA et al (2013) Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study. Int J Mol Epidemiol Genet 4:109–119

    PubMed  PubMed Central  Google Scholar 

  • Hoft NR, Corley RP, McQueen MB, Schlaepfer IR, Huizinga D, Ehringer MA (2009a) Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample. Neuropsychopharmacology 34:698–706

    Article  PubMed  Google Scholar 

  • Hoft NR, Corley RP, McQueen MB, Huizinga D, Menard S, Ehringer MA (2009b) SNPs in CHRNA6 and CHRNB3 are associated with alcohol consumption in a nationally representative sample. Genes Brain Behav. 8:631–637

    Article  PubMed  PubMed Central  Google Scholar 

  • Kamens HM, Corley RP, McQueen MB, Stallings MC, Hopfer CJ, Crowley TJ, Brown SA, Hewitt JK, Ehringer MA (2013) Nominal association with CHRNA4 variants and nicotine dependence. Genes Brain Behav 12:297–304

    Article  PubMed  Google Scholar 

  • Kamens HM, Miyamoto J, Powers MS, Ro K, Soto M, Cox R, Stitzel JA, Ehringer MA (2015) The β3 subunit of the nicotinic acetylcholine receptor: modulation of gene expression and nicotine consumption. Neuropharmacology 99:639–649

    Article  PubMed  Google Scholar 

  • Kendler K, Prescott C, Myers J, Neale MC (2003) THe structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch Gen Psychiatry 60:929–937

    Article  PubMed  Google Scholar 

  • Keskitalo-Vuokko K, Pitkäniemi J, Broms U, Heliövaara M, Aromaa A, Perola M, Ripatti S, Salminen O, Salomaa V, Loukola A et al (2011) Associations of nicotine intake measures with CHRN genes in Finnish smokers. Nicotine Tob Res 13:686–690

    Article  PubMed  PubMed Central  Google Scholar 

  • Krueger RF, Hicks BM, Patrick CJ, Carlson SR, Iacono WG, McGue M (2002) Etiologic connections among substance dependence, antisocial behavior, and personality: modeling the externalizing spectrum. J Abnorm Psychol 111:411–424

    Article  PubMed  Google Scholar 

  • Landgren S, Engel JA, Andersson ME, Gonzalez-Quintela A, Campos J, Nilsson S, Zetterberg H, Blennow K, Jerlhag E (2009) Association of nAChR gene haplotypes with heavy alcohol use and body mass. Brain Res 1305(Suppl):S72–S79

    Article  PubMed  Google Scholar 

  • Landgren S, Berglund K, Jerlhag E, Fahlke C, Balldin J, Berggren U, Zetterberg H, Blennow K, Engel JA (2011) Reward-related genes and personality traits in alcohol-dependent individuals: a pilot case control study. Neuropsychobiology 64:38–46

    Article  PubMed  Google Scholar 

  • Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, Nickerson DA, NHLBI GO Exome Sequencing Project—ESP Lung Project Team, Christiani, DC, Wurfel MM, Lin X (2012) Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet 91:224–237

  • Lee S, Wu MC, Lin X (2012) Optimal tests for rare variant effects in sequencing association studies. Biostat Oxf Engl 13:762–775

    Article  Google Scholar 

  • Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760

    Article  PubMed  PubMed Central  Google Scholar 

  • Lou X-Y, Ma JZ, Payne TJ, Beuten J, Crew KM, Li MD (2006) Gene-based analysis suggests association of the nicotinic acetylcholine receptor beta1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence. Hum Genet 120:381–389

    Article  PubMed  Google Scholar 

  • Lubke GH, Stephens SH, Lessem JM, Hewitt JK, Ehringer MA (2012) The CHRNA5/A3/B4 gene cluster and tobacco, alcohol, cannabis, inhalants and other substance use initiation: replication and new findings using mixture analyses. Behav Genet 42:636–646

    Article  PubMed  PubMed Central  Google Scholar 

  • McClure-Begley TD, Papke RL, Stone KL, Stokes C, Levy AD, Gelernter J, Xie P, Lindstrom J, Picciotto MR (2014) Rare human nicotinic acetylcholine receptor α4 subunit (CHRNA4) variants affect expression and function of high-affinity nicotinic acetylcholine receptors. J Pharmacol Exp Ther 348:410–420

    Article  PubMed  PubMed Central  Google Scholar 

  • McDonough J, Deneris E (1997) beta43’: an enhancer displaying neural-restricted activity is located in the 3’-untranslated exon of the rat nicotinic acetylcholine receptor beta4 gene. J Neurosci 17:2273–2283

    PubMed  Google Scholar 

  • McDonough J, Francis N, Miller T, Deneris ES (2000) Regulation of transcription in the neuronal nicotinic receptor subunit gene cluster by a neuron-selective enhancer and ETS domain factors. J Biol Chem 275:28962–28970

    Article  PubMed  Google Scholar 

  • McGue M, Iacono WG (2008) The adolescent origins of substance use disorders. Int J Methods Psychiatr Res 17(Suppl 1):S30–S38

    Article  PubMed  PubMed Central  Google Scholar 

  • McGue M, Iacono WG, Krueger R (2006) The association of early adolescent problem behavior and adult psychopathology: a multivariate behavioral genetic perspective. Behav Genet 36:591–602

    Article  PubMed  PubMed Central  Google Scholar 

  • McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M et al (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303

    Article  PubMed  PubMed Central  Google Scholar 

  • Neale BM, Rivas MA, Voight BF, Altshuler D, Devlin B, Orho-Melander M, Kathiresan S, Purcell SM, Roeder K, Daly MJ (2011) Testing for an unusual distribution of rare variants. PLoS Genet 7:e1001322

    Article  PubMed  PubMed Central  Google Scholar 

  • Papke RL (2014) Merging old and new perspectives on nicotinic acetylcholine receptors. Biochem Pharmacol 89:1–11

    Article  PubMed  PubMed Central  Google Scholar 

  • Pedneault M, Labbe A, Roy-Gagnon M-H, Low NC, Dugas E, Engert JC, O’Loughlin J (2014) The association between CHRN genetic variants and dizziness at first inhalation of cigarette smoke. Addict Behav 39:316–320

    Article  PubMed  Google Scholar 

  • Philibert RA, Todorov A, Andersen A, Hollenbeck N, Gunter T, Heath A, Madden P (2009) Examination of the nicotine dependence (NICSNP) consortium findings in the Iowa adoption studies population. Nicotine Tob Res 11:286–292

    Article  PubMed  PubMed Central  Google Scholar 

  • Rhea S-A, Gross AA, Haberstick BC, Corley RP (2006) Colorado Twin Registry. Twin Res Hum Genet 9:941–949

    Article  PubMed  Google Scholar 

  • Rice JP, Hartz SM, Agrawal A, Almasy L, Bennett S, Breslau N, Bucholz KK, Doheny KF, Edenberg HJ, Goate AM et al (2012) CHRNB3 is more strongly associated with Fagerström test for cigarette dependence-based nicotine dependence than cigarettes per day: phenotype definition changes genome-wide association studies results. Addict Abingdon Engl 107:2019–2028

    Article  Google Scholar 

  • Robins LN, Cottler L, Bucholz KK, Compton WM, North CS, Rourke KM (2000) Diagnostic Interview Schedule for the DSM-IV (DIS-IV). Washington University School of Medicine, St. Louis

    Google Scholar 

  • Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PAF, Breslau N, Johnson EO, Hatsukami D, Pomerleau O et al (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 16:36–49

    Article  PubMed  Google Scholar 

  • Saccone NL, Saccone SF, Hinrichs AL, Stitzel JA, Duan W, Pergadia ML, Agrawal A, Breslau N, Grucza RA, Hatsukami D et al (2009) Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet 150B:453–466

    Article  PubMed  PubMed Central  Google Scholar 

  • Saccone NL, Schwantes-An T-H, Wang JC, Grucza RA, Breslau N, Hatsukami D, Johnson EO, Rice JP, Goate AM, Bierut LJ (2010) Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans. Genes Brain Behav 9:741–750

    Article  PubMed  PubMed Central  Google Scholar 

  • Sadler B, Haller G, Agrawal A, Culverhouse R, Bucholz K, Brooks A, Tischfield J, Johnson EO, Edenberg H, Schuckit M et al (2014) Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: evidence for pleiotropy. Sci Rep 4:4497

    Article  PubMed  PubMed Central  Google Scholar 

  • Schlaepfer IR, Hoft NR, Collins AC, Corley RP, Hewitt JK, Hopfer CJ, Lessem JM, McQueen MB, Rhee SH, Ehringer MA (2008) The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biol Psychiatry 63:1039–1046

    Article  PubMed  Google Scholar 

  • Schork AJ, Thompson WK, Pham P, Torkamani A, Roddey JC, Sullivan PF, Kelsoe JR, O’Donovan MC, Furberg H, Tobacco and Genetics Consortium et al (2013) All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs. PLoS Genet. 9:e1003449

    Article  PubMed  PubMed Central  Google Scholar 

  • Schubiner H, Tzelepis A, Milberger S, Lockhart N, Kruger M, Kelley BJ, Schoener EP (2000) Prevalence of attention-deficit/hyperactivity disorder and conduct disorder among substance abusers. J Clin Psychiatry 61:244–251

    Article  PubMed  Google Scholar 

  • Scofield MD, Tapper AR, Gardner PD (2010) A transcriptional regulatory element critical for CHRNB4 promoter activity in vivo. Neuroscience 170:1056–1064

    Article  PubMed  PubMed Central  Google Scholar 

  • Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME (2000) NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry 39:28–38

    Article  PubMed  Google Scholar 

  • Sherva R, Kranzler HR, Yu Y, Logue MW, Poling J, Arias AJ, Anton RF, Oslin D, Farrer LA, Gelernter J (2010) Variation in nicotinic acetylcholine receptor genes is associated with multiple substance dependence phenotypes. Neuropsychopharmacology 35:1921–1931

    Article  PubMed  PubMed Central  Google Scholar 

  • Stallings MC, Corley RP, Hewitt JK, Krauter KS, Lessem JM, Mikulich SK, Rhee SH, Smolen A, Young SE, Crowley TJ (2003) A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence. Drug Alcohol Depend 70:295–307

    Article  PubMed  Google Scholar 

  • Stallings MC, Corley RP, Dennehey B, Hewitt JK, Krauter KS, Lessem JM, Mikulich-Gilbertson SK, Rhee SH, Smolen A, Young SE et al (2005) A genome-wide search for quantitative trait Loci that influence antisocial drug dependence in adolescence. Arch Gen Psychiatry 62:1042–1051

    Article  PubMed  Google Scholar 

  • Stephens SH, Hoft NR, Schlaepfer IR, Young SE, Corley RC, McQueen MB, Hopfer C, Crowley T, Stallings M, Hewitt J et al (2012) Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster. Behav Genet 42:402–414

    Article  PubMed  Google Scholar 

  • Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F, Sulem P, Rafnar T, Esko T, Walter S et al (2010) Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 42:448–453

    Article  PubMed  PubMed Central  Google Scholar 

  • Vrieze SI, Feng S, Miller MB, Hicks BM, Pankratz N, Abecasis GR, Iacono WG, McGue M (2014) Rare nonsynonymous exonic variants in addiction and behavioral disinhibition. Biol Psychiatry 75:783–789

    Article  PubMed  Google Scholar 

  • Wang GT, Peng B, Leal SM (2014) Variant association tools for quality control and analysis of large-scale sequence and genotyping array data. Am J Hum Genet 94:770–783

    Article  PubMed  PubMed Central  Google Scholar 

  • Wei J, Chu C, Wang Y, Yang Y, Wang Q, Li T, Zhang L, Ma X (2012) Association study of 45 candidate genes in nicotine dependence in Han Chinese. Addict Behav 37:622–626

    Article  PubMed  Google Scholar 

  • Wessel J, McDonald SM, Hinds DA, Stokowski RP, Javitz HS, Kennemer M, Krasnow R, Dirks W, Hardin J, Pitts SJ et al (2010) Resequencing of nicotinic acetylcholine receptor genes and association of common and rare variants with the Fagerström test for nicotine dependence. Neuropsychopharmacology 35:2392–2402

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie P, Kranzler HR, Krauthammer M, Cosgrove KP, Oslin D, Anton RF, Farrer LA, Picciotto MR, Krystal JH, Zhao H et al (2011) Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence. Biol Psychiatry 70:528–536

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu X, Scott MM, Deneris ES (2006) Shared long-range regulatory elements coordinate expression of a gene cluster encoding nicotinic receptor heteromeric subtypes. Mol Cell Biol 26:5636–5649

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang J, Wang S, Yang Z, Hodgkinson CA, Iarikova P, Ma JZ, Payne TJ, Goldman D, Li MD (2015) The contribution of rare and common variants in 30 genes to risk nicotine dependence. Mol Psychiatry 20:1467–1478

    Article  PubMed  Google Scholar 

  • Young SE, Stallings MC, Corley RP, Krauter KS, Hewitt JK (2000) Genetic and environmental influences on behavioral disinhibition. Am J Med Genet 96:684–695

    Article  PubMed  Google Scholar 

  • Zeiger JS, Haberstick BC, Schlaepfer I, Collins AC, Corley RP, Crowley TJ, Hewitt JK, Hopfer CJ, Lessem J, McQueen MB et al (2008) The neuronal nicotinic receptor subunit genes (CHRNA6 and CHRNB3) are associated with subjective responses to tobacco. Hum Mol Genet 17:724–734

    Article  PubMed  Google Scholar 

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Acknowledgments

We acknowledge Ryan Cox and Jill Miyamoto for technical assistance. This work was supported by National Institutes of Health Grants AA019447 (HMK), AA017889 (MAE), DA032555 (CJH), DA035804 (CJH), DA021905 (SAB), DA011015 (JKH), DA012845 (JKH), DA017637 (JKH), DA039838 (PI: Linda Collins). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, USA

    Helen M. Kamens

  2. Institute for Behavioral Genetics, University of Colorado, 447 UCB, Boulder, CO, 80309, USA

    Robin P. Corley, Todd M. Darlington, Michael C. Stallings, John K. Hewitt & Marissa A. Ehringer

  3. BioFrontiers Institute, University of Colorado, Boulder, CO, USA

    Phillip A. Richmond & Robin Dowell

  4. Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA

    Robin Dowell

  5. Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Christian J. Hopfer

  6. Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA

    Michael C. Stallings & John K. Hewitt

  7. Department of Psychology and Psychiatry, University of California San Diego, San Diego, CA, USA

    Sandra A. Brown

  8. Department of Integrative Physiology, University of Colorado, Boulder, CO, USA

    Marissa A. Ehringer

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Helen M. Kamens, Robin P. Corley, Phillip A. Richmond, Todd M. Darlington, Robin Dowell, Christian J. Hopfer, Michael C. Stallings, John K. Hewitt, Sandra A. Brown, and Marissa A. Ehringer declare that they have no conflict of interest.

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The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and 2008. All participants provided informed consent.

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Kamens, H.M., Corley, R.P., Richmond, P.A. et al. Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence. Behav Genet 46, 693–704 (2016). https://doi.org/10.1007/s10519-016-9792-4

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