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.
Similar content being viewed by others
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
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
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
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
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
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265
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
Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366(9481):237–248
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
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
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
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
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
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
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
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
DeFries JC, Plomin R, Fulker DW (1994) Nature and nurture during middle childhood. Blackwell, Oxford
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
Elliott DS, Huizinga D, Menard SW (1989) Multiple problem youth : delinquency substance use and mental health problems. Springer-Verlag, New York
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Laird NM, Lange C (2006) Family-based designs in the age of large-scale gene-association studies. Nat Rev Genet 7(5):385–394
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
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
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
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
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
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
McGue M, Iacono WG (2005) The association of early adolescent problem behavior with adult psychopathology. Am J psychiatry 162(6):1118–1124
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
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
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
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
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
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
Prescott CA, Kendler KS (1999) Age at first drink and risk for alcoholism: a noncausal association. Alcohol Clin Exp Res 23(1):101–107
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
Rose JE (2007) Multiple brain pathways and receptors underlying tobacco addiction. Biochem Pharmacol 74(8):1263–1270
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Taylor J, Iacono WG, McGue M (2000) Evidence for a genetic etiology of early-onset delinquency. J Abnorm Psychol 109(4):634–643
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
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
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
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
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
Uhl GR (2004) Molecular genetics of substance abuse vulnerability: remarkable recent convergence of genome scan results. Ann N Y Acad Sci 1025:1–13
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
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
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
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
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
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
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
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
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
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
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by Tatiana Foroud.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10519-011-9514-x