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Externalizing Behaviors are Associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster

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Abstract

There is strong evidence for shared genetic factors contributing to childhood externalizing disorders and substance abuse. Externalizing disorders often precede early substance experimentation, leading to the idea that individuals inherit a genetic vulnerability to generalized disinhibitory psychopathology. Genetic variation in the CHRNA5/CHRNA3/CHRNB4 gene cluster has been associated with early substance experimentation, nicotine dependence, and other drug behaviors. This study examines whether the CHRNA5/CHRNA3/CHRNB4 locus is correlated also with externalizing behaviors in three independent longitudinally assessed adolescent samples. We developed a common externalizing behavior phenotype from the available measures in the three samples, and tested for association with 10 SNPs in the gene cluster. Significant results were detected in two of the samples, including rs8040868, which remained significant after controlling for smoking quantity. These results expand on previous work focused mainly on drug behaviors, and support the hypothesis that variation in the CHRNA5/CHRNA3/CHRNB4 locus is associated with early externalizing behaviors.

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References

  • Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai YY, Chen WV, Shete S, Spitz MR, Houlston RS (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40(5):616–622

    Article  PubMed  Google Scholar 

  • Anchordoquy HC, McGeary C, Liu L, Krauter KS, Smolen A (2003) Genotyping of three candidate genes after whole-genome preamplification of DNA collected from buccal cells. Behav Genet 33(1):73–78

    Article  PubMed  Google Scholar 

  • Anney RJ, Lasky-Su J, O’Dushlaine C, Kenny E, Neale BM, Mulligan A, Franke B, Zhou K, Chen W, Christiansen H, Arias-Vasquez A, Banaschewski T, Buitelaar J, Ebstein R, Miranda A, Mulas F, Oades RD, Roeyers H, Rothenberger A, Sergeant J, Sonuga-Barke E, Steinhausen H, Asherson P, Faraone SV, Gill M (2008) Conduct disorder and ADHD: evaluation of conduct problems as a categorical and quantitative trait in the international multicentre ADHD genetics study. Am J Med Genet B Neuropsychiatr Genet 147B(8):1369–1378

    Article  PubMed  Google Scholar 

  • Armstrong TD, Costello EJ (2002) Community studies on adolescent substance use, abuse, or dependence and psychiatric comorbidity. J Consult Clin Psychol 70(6):1224–1239

    Article  PubMed  Google Scholar 

  • Baker TB, Weiss RB, Bolt D, von Niederhausern A, Fiore MC, Dunn DM, Piper ME, Matsunami N, Smith SS, Coon H, McMahon WM, Scholand MB, Singh N, Hoidal JR, Kim SY, Leppert MF, Cannon DS (2009) Human neuronal acetylcholine receptor A5–A3–B4 haplotypes are associated with multiple nicotine dependence phenotypes. Nicotine Tob Res 11(7):785–796

    Article  PubMed  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265

    Article  PubMed  Google Scholar 

  • Berrettini W, Yuan X, Tozzi F, Song K, Francks C, Chilcoat H, Waterworth D, Muglia P, Mooser V (2008) alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry 13(4):368–373

    Article  PubMed  Google Scholar 

  • Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366(9481):237–248

    Article  PubMed  Google Scholar 

  • Bierut LJ, Dinwiddie SH, Begleiter H, Crowe RR, Hesselbrock V, Nurnberger JI Jr, Porjesz B, Schuckit MA, Reich T (1998) Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. Arch Gen Psychiatry 55(11):982–988

    Article  PubMed  Google Scholar 

  • Bierut LJ, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau OF, Swan GE, Rutter J, Bertelsen S, Fox L, Fugman D, Goate AM, Hinrichs AL, Konvicka K, Martin NG, Montgomery GW, Saccone NL, Saccone SF, Wang JC, Chase GA, Rice JP, Ballinger DG (2007) Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 16(1):24–35

    Article  PubMed  Google Scholar 

  • Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X, Saccone NL, Saccone SF, Bertelsen S, Fox L, Horton WJ, Breslau N, Budde J, Cloninger CR, Dick DM, Foroud T, Hatsukami D, Hesselbrock V, Johnson EO, Kramer J, Kuperman S, Madden PA, Mayo K, Nurnberger J Jr, Pomerleau O, Porjesz B, Reyes O, Schuckit M, Swan G, Tischfield JA, Edenberg HJ, Rice JP, Goate AM (2008) Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165(9):1163–1171

    Article  PubMed  Google Scholar 

  • Breslau N, Fenn N, Peterson EL (1993) Early smoking initiation and nicotine dependence in a cohort of young adults. Drug Alcohol Depend 33(2):129–137

    Article  PubMed  Google Scholar 

  • Bucholz KK, Heath AC, Madden PA (2000) Transitions in drinking in adolescent females: evidence from the Missouri adolescent female twin study. Alcohol Clin Exp Res 24(6):914–923

    Article  PubMed  Google Scholar 

  • Caporaso N, Gu F, Chatterjee N, Sheng-Chih J, Yu K, Yeager M, Chen C, Jacobs K, Wheeler W, Landi MT, Ziegler RG, Hunter DJ, Chanock S, Hankinson S, Kraft P, Bergen AW (2009) Genome-wide and candidate gene association study of cigarette smoking behaviors. PloS one 4(2):e4653

    Article  PubMed  Google Scholar 

  • Chen CY, Anthony JC (2003) Possible age-associated bias in reporting of clinical features of drug dependence: epidemiological evidence on adolescent-onset marijuana use. Addict (Abingdon, England) 98(1):71–82

    Article  Google Scholar 

  • Chen X, Chen J, Williamson VS, An SS, Hettema JM, Aggen SH, Neale MC, Kendler KS (2009) Variants in nicotinic acetylcholine receptors alpha5 and alpha3 increase risks to nicotine dependence. Am J Med Genet B Neuropsychiatr Genet 150B(7):926–933

    Article  PubMed  Google Scholar 

  • DeFries JC, Plomin R, Fulker DW (1994) Nature and nurture during middle childhood. Blackwell, Oxford

    Google Scholar 

  • DeWit DJ, Adlaf EM, Offord DR, Ogborne AC (2000) Age at first alcohol use: a risk factor for the development of alcohol disorders. Am J Psychiatry 157(5):745–750

    Article  PubMed  Google Scholar 

  • Elliott DS, Huizinga D, Menard SW (1989) Multiple problem youth : delinquency substance use and mental health problems. Springer-Verlag, New York

    Google Scholar 

  • Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 57(11):1313–1323

    Article  PubMed  Google Scholar 

  • Flory K, Milich R, Lynam DR, Leukefeld C, Clayton R (2003) Relation between childhood disruptive behavior disorders and substance use and dependence symptoms in young adulthood: individuals with symptoms of attention-deficit/hyperactivity disorder and conduct disorder are uniquely at risk. Psychol Addict Behav 17(2):151–158

    Article  PubMed  Google Scholar 

  • Furberg H, Kim Y, Dackor J, Boerwinkle E, Franceshini N, Ardissino D, Bernardinelli L, Mannucci PM, Mauri F, Merlini PA, Absher D, Assimes TL, Fortmann SP, Iribarren C, Knowles JW, Quertermous T, Ferrucci L, Tanaka T, Bis JC, Furberg CD, Haritunians T, McKnight B, Psaty BM, Taylor KD, Thacker EL, Almgren P, Groop L, Ladenvall C, Boehnke M, Jackson AU, Mohlke KL, Stringham HM, Tuomilehto J, Benjamin EJ, Hwang S, Levy D, Preis SR, Vasan RS, Duan J, Gejman PV, Levinson DF, Sanders AR, Shi J, Lips EH, Mckay JD, Agudo A, Barzan L, Bencko V, Benhamou S, Castellsague X, Canova C, Conway DI, Fabianova E, Foretova L, Janout V, Healy CM, Holcatova I, Kjaerheim K, Lagiou P, Lissowska J, Lowry R, Macfarlane TV, Mates D, Richiardi L, Rudnai P, Szeszenia-Dabrowska J, Zaridze D, Znaor A, Lathrop M, Brennan P, Bandinelli S, Frayling TM, Guralnik JM, Milaneschi Y, Perry JRB, Altshuler D, Elosua R, Kathiresan S, Lucas G, Melander O, O’Donnell CJ, Salomaa V, Schwartz SM, Voight BF, Penninx BW, Smit JH, Vogelzangs N, Boomsma DI, de Geus EJC, Vink JM, Willemsen G, Chanock SJ, Gu F, Hankinson SE, Hunter DJ, Hofman A, Tiemeier H, Uitterlinden AG, van Duijn CM, Walter S, Chasman DI, Everett BM, Pare G, Ridker PM, Li MD, Maes HH, Audrain-McGovern J, Posthuma D, Thornton LM, Lerman C, Kaprio J, Rose JE, Ioannidis JPA, Kraft P, Lin D, Sullivan PF (2010) Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 42(5):441–447

    Article  Google Scholar 

  • Grant BF, Dawson DA (1998) Age of onset of drug use and its association with DSM-IV drug abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse 10(2):163–173

    Article  PubMed  Google Scholar 

  • Greenbaum L, Lerer B (2009) Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions. Mol psychiatry 14(10):912–945

    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(3):312–322 (223)

    Article  PubMed  Google Scholar 

  • Grove WM, Eckert ED, Heston L, Bouchard TJ Jr, Segal N, Lykken DT (1990) Heritability of substance abuse and antisocial behavior: a study of monozygotic twins reared apart. Biol Psychiatry 27(12):1293–1304

    Article  PubMed  Google Scholar 

  • Grucza RA, Bierut LJ (2006) Co-occurring risk factors for alcohol dependence and habitual smoking: update on findings from the Collaborative Study on the Genetics of Alcoholism. Alcohol Res Health 29(3):172–178

    PubMed  Google Scholar 

  • Grucza RA, Wang JC, Stitzel JA, Hinrichs AL, Saccone SF, Saccone NL, Bucholz KK, Cloninger CR, Neuman RJ, Budde JP, Fox L, Bertelsen S, Kramer J, Hesselbrock V, Tischfield J, Nurnberger JI Jr, Almasy L, Porjesz B, Kuperman S, Schuckit MA, Edenberg HJ, Rice JP, Goate AM, Bierut LJ (2008) A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biol Psychiatry 64(11):922–929

    Article  PubMed  Google Scholar 

  • Han C, McGue MK, Iacono WG (1999) Lifetime tobacco, alcohol and other substance use in adolescent Minnesota twins: univariate and multivariate behavioral genetic analyses. Addict 94(7):981–993

    Article  Google Scholar 

  • Harris KM, Halpern CT, Smolen A, Haberstick BC (2006) The National Longitudinal Study of Adolescent Health (Add Health) twin data. Twin Res Hum Genet 9(6):988–997

    Article  PubMed  Google Scholar 

  • Hicks BM, Krueger RF, Iacono WG, McGue M, Patrick CJ (2004) Family transmission and heritability of externalizing disorders: a twin-family study. Arch Gen Psychiatry 61(9):922–928

    Article  PubMed  Google Scholar 

  • Hingson RW, Heeren T, Winter MR (2006) Age at drinking onset and alcohol dependence: age at onset, duration, and severity. Arch Pediatr Adolesc Med 160(7):739–746

    Article  PubMed  Google Scholar 

  • Hoft NR, Corley RP, McQueen MB, Schlaepfer IR, Huizinga D, Ehringer MA (2009) Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample. Neuropsychopharmacology 34(3):698–706

    Article  PubMed  Google Scholar 

  • Hopfer CJ, Stallings MC, Hewitt JK (2001) Common genetic and environmental vulnerability for alcohol and tobacco use in a volunteer sample of older female twins. J Stud Alcohol 62(6):717–723

    PubMed  Google Scholar 

  • Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chen C, Goodman G, Field JK, Liloglou T, Xinarianos G, Cassidy A, McLaughlin J, Liu G, Narod S, Krokan HE, Skorpen F, Elvestad MB, Hveem K, Vatten L, Linseisen J, Clavel-Chapelon F, Vineis P, Bueno-de-Mesquita HB, Lund E, Martinez C, Bingham S, Rasmuson T, Hainaut P, Riboli E, Ahrens W, Benhamou S, Lagiou P, Trichopoulos D, Holcatova I, Merletti F, Kjaerheim K, Agudo A, Macfarlane G, Talamini R, Simonato L, Lowry R, Conway DI, Znaor A, Healy C, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008) A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452(7187):633–637

    Article  PubMed  Google Scholar 

  • Iacono WG, Malone SM, McGue M (2008) Behavioral disinhibition and the development of early-onset addiction: common and specific influences. Annu Rev Clin Psychol 4:325–348

    Article  PubMed  Google Scholar 

  • Joslyn G, Brush G, Robertson M, Smith TL, Kalmijn J, Schuckit M, White RL (2008) Chromosome 15q25.1 genetic markers associated with level of response to alcohol in humans. Proc Natl Acad Sci U S A 105(51):20368–20373

    Article  PubMed  Google Scholar 

  • Kendler KS, Jacobson KC, Prescott CA, Neale MC (2003) Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am J psychiatry 160(4):687–695

    Article  PubMed  Google Scholar 

  • Keskitalo K, Broms U, Heliovaara M, Ripatti S, Surakka I, Perola M, Pitkaniemi J, Peltonen L, Aromaa A, Kaprio J (2009) Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15. Hum Mol Genet 18(20):4007–4012

    Article  PubMed  Google Scholar 

  • Koopmans JR, Slutske WS, Heath AC, Neale MC, Boomsma DI (1999) The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins. Behav Genet 29(6):383–393

    Article  PubMed  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(3):411–424

    Article  PubMed  Google Scholar 

  • Laird NM, Lange C (2006) Family-based designs in the age of large-scale gene-association studies. Nat Rev Genet 7(5):385–394

    Article  PubMed  Google Scholar 

  • Laird NM, Horvath S, Xu X (2000) Implementing a unified approach to family-based tests of association. Genet Epidemiol 19 Suppl 1S36-42

  • Lange C, Silverman EK, Xu X, Weiss ST, Laird NM (2003) A multivariate family-based association test using generalized estimating equations: FBAT-GEE. Biostatistics 4(2):195–206

    Article  PubMed  Google Scholar 

  • Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM (2004) PBAT: tools for family-based association studies. Am J Hum Genet 74(2):367–369

    Article  PubMed  Google Scholar 

  • Lasky-Su J, Lange C, Biederman J, Tsuang M, Doyle AE, Smoller JW, Laird N, Faraone S (2008) Family-based association analysis of a statistically derived quantitative traits for ADHD reveal an association in DRD4 with inattentive symptoms in ADHD individuals. Am J Med Genet B Neuropsychiatr Genet 147B(1):100–106

    Article  PubMed  Google Scholar 

  • Le Marchand L, Derby KS, Murphy SE, Hecht SS, Hatsukami D, Carmella SG, Tiirikainen M, Wang H (2008) Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine. Cancer Res 68(22):9137–9140

    Article  PubMed  Google Scholar 

  • Li MD, Xu Q, Lou XY, Payne TJ, Niu T, Ma JZ (2009) Association and interaction analysis of variants in CHRNA5/CHRNA3/CHRNB4 gene cluster with nicotine dependence in African and European Americans. Am J Med Genet B Neuropsychiatr Genet 153B(3):745–756

    Google Scholar 

  • Liu JZ, Tozzi F, Waterworth DM, Pillai SG, Muglia P, Middleton L, Berrettini W, Knouff CW, Yuan X, Waeber G, Vollenweider P, Preisig M, Wareham NJ, Zhao JH, Loos RJ, Barroso I, Khaw KT, Grundy S, Barter P, Mahley R, Kesaniemi A, McPherson R, Vincent JB, Strauss J, Kennedy JL, Farmer A, McGuffin P, Day R, Matthews K, Bakke P, Gulsvik A, Lucae S, Ising M, Brueckl T, Horstmann S, Wichmann HE, Rawal R, Dahmen N, Lamina C, Polasek O, Zgaga L, Huffman J, Campbell S, Kooner J, Chambers JC, Burnett MS, Devaney JM, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Epstein S, Wilson JF, Wild SH, Campbell H, Vitart V, Reilly MP, Li M, Qu L, Wilensky R, Matthai W, Hakonarson HH, Rader DJ, Franke A, Wittig M, Schafer A, Uda M, Terracciano A, Xiao X, Busonero F, Scheet P, Schlessinger D, St Clair D, Rujescu D, Abecasis GR, Grabe HJ, Teumer A, Volzke H, Petersmann A, John U, Rudan I, Hayward C, Wright AF, Kolcic I, Wright BJ, Thompson JR, Balmforth AJ, Hall AS, Samani NJ, Anderson CA, Ahmad T, Mathew CG, Parkes M, Satsangi J, Caulfield M, Munroe PB, Farrall M, Dominiczak A, Worthington J, Thomson W, Eyre S, Barton A, Mooser V, Francks C, Marchini J (2010) Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 42(5):436–440

    Article  PubMed  Google Scholar 

  • McGue M, Iacono WG (2005) The association of early adolescent problem behavior with adult psychopathology. Am J psychiatry 162(6):1118–1124

    Article  PubMed  Google Scholar 

  • McGue M, Iacono WG (2008) The adolescent origins of substance use disorders. Int J Methods Psychiatr Res. 17 Suppl 1S30-38

  • McGue M, Iacono WG, Legrand LN, Malone S, Elkins I (2001) Origins and consequences of age at first drink. I. Associations with substance-use disorders, disinhibitory behavior and psychopathology, and P3 amplitude. Alcohol Clin Exp Res 25(8):1156–1165

    Article  PubMed  Google Scholar 

  • Merikangas KR, Stolar M, Stevens DE, Goulet J, Preisig MA, Fenton B, Zhang H, O’Malley SS, Rounsaville BJ (1998) Familial transmission of substance use disorders. Arch Gen Psychiatry 55(11):973–979

    Article  PubMed  Google Scholar 

  • Moffitt TE, Caspi A, Harrington H, Milne BJ (2002) Males on the life-course-persistent and adolescence-limited antisocial pathways: follow-up at age 26 years. Dev Psychopathol 14(1):179–207

    Article  PubMed  Google Scholar 

  • Nadder TS, Rutter M, Silberg JL, Maes HH, Eaves LJ (2002) Genetic effects on the variation and covariation of attention deficit-hyperactivity disorder (ADHD) and oppositional-defiant disorder/conduct disorder (Odd/CD) symptomatologies across informant and occasion of measurement. Psychol Med 32(1):39–53

    Article  PubMed  Google Scholar 

  • Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74(4):765–769

    Article  PubMed  Google Scholar 

  • Pickens RW, Svikis DS, McGue M, LaBuda MC (1995) Common genetic mechanisms in alcohol, drug, and mental disorder comorbidity. Drug Alcohol Depend 39(2):129–138

    Article  PubMed  Google Scholar 

  • Prescott CA, Kendler KS (1999) Age at first drink and risk for alcoholism: a noncausal association. Alcohol Clin Exp Res 23(1):101–107

    PubMed  Google Scholar 

  • Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460(7256):748–752

    PubMed  Google Scholar 

  • Rose JE (2007) Multiple brain pathways and receptors underlying tobacco addiction. Biochem Pharmacol 74(8):1263–1270

    Article  PubMed  Google Scholar 

  • Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau O, Swan GE, Goate AM, Rutter J, Bertelsen S, Fox L, Fugman D, Martin NG, Montgomery GW, Wang JC, Ballinger DG, Rice JP, Bierut LJ (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 16(1):36–49

    Article  PubMed  Google Scholar 

  • Saccone NL, Wang JC, Breslau N, Johnson EO, Hatsukami D, Saccone SF, Grucza RA, Sun L, Duan W, Budde J, Culverhouse RC, Fox L, Hinrichs AL, Steinbach JH, Wu M, Rice JP, Goate AM, Bierut LJ (2009a) The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African–Americans and in European–Americans. Cancer Res 69(17):6848–6856

    Article  PubMed  Google Scholar 

  • Saccone NL, Saccone SF, Hinrichs AL, Stitzel JA, Duan W, Pergadia ML, Agrawal A, Breslau N, Grucza RA, Hatsukami D, Johnson EO, Madden PA, Swan GE, Wang JC, Goate AM, Rice JP, Bierut LJ (2009b) 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(4):453–466

    Article  PubMed  Google Scholar 

  • Saccone NL, Culverhouse RC, Schwantes-An TH, Cannon DS, Chen X, Cichon S, Giegling I, Han S, Han Y, Keskitalo-Vuokko K, Kong X, Landi MT, Ma JZ, Short SE, Stephens SH, Stevens VL, Sun L, Wang Y, Wenzlaff AS, Aggen SH, Breslau N, Broderick P, Chatterjee N, Chen J, Heath AC, Heliovaara M, Hoft NR, Hunter DJ, Jensen MK, Martin NG, Montgomery GW, Niu T, Payne TJ, Peltonen L, Pergadia ML, Rice JP, Sherva R, Spitz MR, Sun J, Wang JC, Weiss RB, Wheeler W, Witt SH, Yang BZ, Caporaso NE, Ehringer MA, Eisen T, Gapstur SM, Gelernter J, Houlston R, Kaprio J, Kendler KS, Kraft P, Leppert MF, Li MD, Madden PA, Nothen MM, Pillai S, Rietschel M, Rujescu D, Schwartz A, Amos CI, Bierut LJ (2010) Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS Genet 6(8)

  • Sakai JT, Boardman JD, Gelhorn HL, Smolen A, Corley RP, Huizinga D, Menard S, Hewitt JK, Stallings MC (2010) Using trajectory analyses to refine phenotype for genetic association: conduct problems and the serotonin transporter (5HTTLPR). Psychiatr genet 20(5):199–206

    Article  PubMed  Google Scholar 

  • Sasaki H, Hikosaka Y, Okuda K, Kawano O, Yukiue H, Yano M, Fujii Y (2009) CHRNA5 Gene D398N polymorphism in Japanese lung adenocarcinoma. J Surg Res 162(1):75–78

    Article  PubMed  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(11):1039–1046

    Article  PubMed  Google Scholar 

  • Schwartz AG, Cote ML, Wenzlaff AS, Land S, Amos CI (2009) Racial differences in the association between SNPs on 15q25.1, smoking behavior, and risk of non-small cell lung cancer. J Thorac Oncol 4(10):1195–1201

    Article  PubMed  Google Scholar 

  • Sherva R, Wilhelmsen K, Pomerleau CS, Chasse SA, Rice JP, Snedecor SM, Bierut LJ, Neuman RJ, Pomerleau OF (2008) Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with ‘pleasurable buzz’ during early experimentation with smoking. Addic (Abingdon, England) 103(9):1544–1552

    Article  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(9):1921–1931

    Article  PubMed  Google Scholar 

  • Spitz MR, Amos CI, Dong Q, Lin J, Wu X (2008) The CHRNA5–A3 region on chromosome 15q24–25.1 is a risk factor both for nicotine dependence and for lung cancer. J Natl Cancer Inst 100(21):1552–1556

    Article  PubMed  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(3):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, Crowley TJ (2005) A genome-wide search for quantitative trait Loci that influence antisocial drug dependence in adolescence. Arch Gen Psychiatry 62(9):1042–1051

    Article  PubMed  Google Scholar 

  • Stevens VL, Bierut LJ, Talbot JT, Wang JC, Sun J, Hinrichs AL, Thun MJ, Goate A, Calle EE (2008) Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiol Biomarkers Prev 17(12):3517–3525

    Article  PubMed  Google Scholar 

  • Stinson FS, Grant BF, Dawson DA, Ruan WJ, Huang B, Saha T (2005) Comorbidity between DSM-IV alcohol and specific drug use disorders in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Drug Alcohol Depend 80(1):105–116

    Article  PubMed  Google Scholar 

  • Swan GE, Carmelli D, Cardon LR (1996) The consumption of tobacco, alcohol, and coffee in Caucasian male twins: a multivariate genetic analysis. J Subst Abuse 8(1):19–31

    Article  PubMed  Google Scholar 

  • Tarter RE, Kirisci L, Mezzich A, Cornelius JR, Pajer K, Vanyukov M, Gardner W, Blackson T, Clark D (2003) Neurobehavioral disinhibition in childhood predicts early age at onset of substance use disorder. Am J psychiatry 160(6):1078–1085

    Article  PubMed  Google Scholar 

  • Taylor J, Iacono WG, McGue M (2000) Evidence for a genetic etiology of early-onset delinquency. J Abnorm Psychol 109(4):634–643

    Article  PubMed  Google Scholar 

  • Thapar A, Harrington R, McGuffin P (2001) Examining the comorbidity of ADHD-related behaviours and conduct problems using a twin study design. Br J Psychiatry 179:224–229

    Article  PubMed  Google Scholar 

  • Thapar A, O’Donovan M, Owen MJ (2005) The genetics of attention deficit hyperactivity disorder. Human molecular genetics 14 Spec No. 2R275-282

  • Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP, Manolescu A, Thorleifsson G, Stefansson H, Ingason A, Stacey SN, Bergthorsson JT, Thorlacius S, Gudmundsson J, Jonsson T, Jakobsdottir M, Saemundsdottir J, Olafsdottir O, Gudmundsson LJ, Bjornsdottir G, Kristjansson K, Skuladottir H, Isaksson HJ, Gudbjartsson T, Jones GT, Mueller T, Gottsater A, Flex A, Aben KK, de Vegt F, Mulders PF, Isla D, Vidal MJ, Asin L, Saez B, Murillo L, Blondal T, Kolbeinsson H, Stefansson JG, Hansdottir I, Runarsdottir V, Pola R, Lindblad B, van Rij AM, Dieplinger B, Haltmayer M, Mayordomo JI, Kiemeney LA, Matthiasson SE, Oskarsson H, Tyrfingsson T, Gudbjartsson DF, Gulcher JR, Jonsson S, Thorsteinsdottir U, Kong A, Stefansson K (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452(7187):638–642

    Article  PubMed  Google Scholar 

  • Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F, Sulem P, Rafnar T, Esko T, Walter S, Gieger C, Rawal R, Mangino M, Prokopenko I, Magi R, Keskitalo K, Gudjonsdottir IH, Gretarsdottir S, Stefansson H, Thompson JR, Aulchenko YS, Nelis M, Aben KK, den Heijer M, Dirksen A, Ashraf H, Soranzo N, Valdes AM, Steves C, Uitterlinden AG, Hofman A, Tonjes A, Kovacs P, Hottenga JJ, Willemsen G, Vogelzangs N, Doring A, Dahmen N, Nitz B, Pergadia ML, Saez B, De Diego V, Lezcano V, Garcia-Prats MD, Ripatti S, Perola M, Kettunen J, Hartikainen AL, Pouta A, Laitinen J, Isohanni M, Huei-Yi S, Allen M, Krestyaninova M, Hall AS, Jones GT, van Rij AM, Mueller T, Dieplinger B, Haltmayer M, Jonsson S, Matthiasson SE, Oskarsson H, Tyrfingsson T, Kiemeney LA, Mayordomo JI, Lindholt JS, Pedersen JH, Franklin WA, Wolf H, Montgomery GW, Heath AC, Martin NG, Madden PA, Giegling I, Rujescu D, Jarvelin MR, Salomaa V, Stumvoll M, Spector TD, Wichmann HE, Metspalu A, Samani NJ, Penninx BW, Oostra BA, Boomsma DI, Tiemeier H, van Duijn CM, Kaprio J, Gulcher JR, McCarthy MI, Peltonen L, Thorsteinsdottir U, Stefansson K (2010) Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 42(5):448–453

    Article  PubMed  Google Scholar 

  • True WR, Xian H, Scherrer JF, Madden PA, Bucholz KK, Heath AC, Eisen SA, Lyons MJ, Goldberg J, Tsuang M (1999) Common genetic vulnerability for nicotine and alcohol dependence in men. Arch Gen Psychiatry 56(7):655–661

    Article  PubMed  Google Scholar 

  • Tsuang MT, Lyons MJ, Eisen SA, Goldberg J, True W, Lin N, Meyer JM, Toomey R, Faraone SV, Eaves L (1996) Genetic influences on DSM-III-R drug abuse and dependence: a study of 3, 372 twin pairs. Am J Med Genet 67(5):473–477

    Article  PubMed  Google Scholar 

  • Uhl GR (2004) Molecular genetics of substance abuse vulnerability: remarkable recent convergence of genome scan results. Ann N Y Acad Sci 1025:1–13

    Article  PubMed  Google Scholar 

  • Uhl GR, Drgon T, Johnson C, Li CY, Contoreggi C, Hess J, Naiman D, Liu QR (2008) Molecular genetics of addiction and related heritable phenotypes: genome-wide association approaches identify “connectivity constellation” and drug target genes with pleiotropic effects. Ann N Y Acad of Sci 1141:318–381

    Article  Google Scholar 

  • van den Bree MB, Johnson EO, Neale MC, Pickens RW (1998) Genetic and environmental influences on drug use and abuse/dependence in male and female twins. Drug Alcohol Depend 52(3):231–241

    Article  PubMed  Google Scholar 

  • Vierikko E, Pulkkinen L, Kaprio J, Rose RJ (2004) Genetic and environmental influences on the relationship between aggression and hyperactivity-impulsivity as rated by teachers and parents. Twin Res 7(3):261–274

    PubMed  Google Scholar 

  • Wang JC, Grucza R, Cruchaga C, Hinrichs AL, Bertelsen S, Budde JP, Fox L, Goldstein E, Reyes O, Saccone N, Saccone S, Xuei X, Bucholz K, Kuperman S, Nurnberger J Jr, Rice JP, Schuckit M, Tischfield J, Hesselbrock V, Porjesz B, Edenberg HJ, Bierut LJ, Goate AM (2009a) Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Mol psychiatry 14(5):501–510

    Article  PubMed  Google Scholar 

  • Wang JC, Cruchaga C, Saccone NL, Bertelsen S, Liu P, Budde JP, Duan W, Fox L, Grucza RA, Kern J, Mayo K, Reyes O, Rice J, Saccone SF, Spiegel N, Steinbach JH, Stitzel JA, Anderson MW, You M, Stevens VL, Bierut LJ, Goate AM (2009b) Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. Hum Mol Genet 18(16):3125–3135

    Article  PubMed  Google Scholar 

  • Weinberg NZ, Rahdert E, Colliver JD, Glantz MD (1998) Adolescent substance abuse: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 37(3):252–261

    Article  PubMed  Google Scholar 

  • Weiss RB, Baker TB, Cannon DS, von Niederhausern A, Dunn DM, Matsunami N, Singh NA, Baird L, Coon H, McMahon WM, Piper ME, Fiore MC, Scholand MB, Connett JE, Kanner RE, Gahring LC, Rogers SW, Hoidal JR, Leppert MF (2008) A candidate gene approach identifies the CHRNA5–A3–B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet 4(7):e1000125

    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(5):684–695

    Article  PubMed  Google Scholar 

  • Young SE, Rhee SH, Stallings MC, Corley RP, Hewitt JK (2006) Genetic and environmental vulnerabilities underlying adolescent substance use and problem use: general or specific? Behav Genet 36(4):603–615

    Article  PubMed  Google Scholar 

  • Zheng S, Ma X, Buffler PA, Smith MT, Wiencke JK (2001) Whole genome amplification increases the efficiency and validity of buccal cell genotyping in pediatric populations. Cancer Epidemiol Biomarkers Prev 10(6):697–700

    PubMed  Google Scholar 

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Acknowledgments

This work was supported by NIH grants K01 AA015336 (MAE), R01 AA017889 (MAE), R01 DA021913 (CJH), P60 DA011015 (JKH), R01 AA011949, and T32 DA017637 (JKH). This research uses data from Add Health, a program project directed by Kathleen Mullan Harris and designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris at the University of North Carolina at Chapel Hill, and funded by grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 23 other federal agencies and foundations. Special acknowledgment is due Ronald R. Rindfuss and Barbara Entwisle for assistance in the original design. Information on how to obtain the Add Health data files is available on the Add Health website (http://www.cpc.unc.edu/addhealth). No direct support was received from grant P01-HD31921 for this analysis.

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Stephens, S.H., Hoft, N.R., Schlaepfer, I.R. et al. Externalizing Behaviors are Associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster. Behav Genet 42, 402–414 (2012). https://doi.org/10.1007/s10519-011-9514-x

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