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A Genome-Wide Association Study of Behavioral Disinhibition

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Abstract

We report results from a genome wide association study (GWAS) of five quantitative indicators of behavioral disinhibition: nicotine, alcohol consumption, alcohol dependence, illicit drugs, and non-substance related behavioral disinhibition. The sample, consisting of 7,188 Caucasian individuals clustered in 2,300 nuclear families, was genotyped on over 520,000 SNP markers from Illumina’s Human 660W-Quad Array. Analysis of individual SNP associations revealed only one marker-component phenotype association, between rs1868152 and illicit drugs, with a p value below the standard genome-wide threshold of 5 × 10−8. Because we had analyzed five separate phenotypes, we do not consider this single association to be significant. However, we report 13 SNPs that were associated at p < 10−5 for one phenotype and p < 10−3 for at least two other phenotypes, which are potential candidates for future investigations of variants associated with general behavioral disinhibition. Biometric analysis of the twin and family data yielded estimates of additive heritability for the component phenotypes ranging from 49 to 70 %, GCTA estimates of heritability for the same phenotypes ranged from 8 to 37 %. Consequently, even though the common variants genotyped on the GWAS array appear in aggregate to account for a sizable proportion of heritable effects in multiple indicators of behavioral disinhibition, our data suggest that most of the additive heritability remains “missing”.

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References

  • Agrawal A, Edenberg HJ, Foroud T, Bierut LJ, Dunne G, Hinrichs AL, Dick DM (2006) Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample. Behav Genet 36(5):640–650. doi:10.1007/s10519-006-9069-4

    Article  PubMed  Google Scholar 

  • Allen HL, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Procardis C (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467(7317):832–838

    Article  Google Scholar 

  • Bergen SE, Gardner CO, Kendler KS (2007) Age-related changes in heritability of behavioral phenotypes over adolescence and young adulthood: a meta-analysis. Twin Res Hum Genet 10(3):423–433. doi:10.1375/twin.10.3.423

    Article  PubMed  Google Scholar 

  • Bosker FJ, Hartman CA, Nolte IM, Prins BP, Terpstra P, Posthuma D, Nolen WA (2011) Poor replication of candidate genes for major depressive disorder using genome-wide association data. Mol Psychiatry 16(5):516–532. doi:10.1038/mp.2010.38

    Article  PubMed  Google Scholar 

  • Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678. doi:10.1038/nature05911

    Article  Google Scholar 

  • Collins AL, Kim Y, Sklar P, O’Donovan MC, Sullivan PF, International Schizophrenia Consortium (2012) Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. Psychol Med 42(3):607–616. doi:10.1017/s0033291711001607

    Article  PubMed  Google Scholar 

  • Corley RP, Zeiger JS, Crowley T, Ehringer MA, Hewitt JK, Hopfer CJ, Krauter K (2008) Association of candidate genes with antisocial drug dependence in adolescents. Drug Alcohol Depend 96(1–2):90–98. doi:10.1016/j.drugalcdep.2008.02.004

    Article  PubMed  Google Scholar 

  • Davies G, Tenesa A, Payton A, Yang J, Harris SE, Liewald D, Deary IJ (2011) Genome-wide association studies establish that human intelligence is highly heritable and polygenic. Mol Psychiatry 16(10):996–1005

    Article  PubMed  Google Scholar 

  • Dick DM, Bierut L, Hinrichs A, Fox L, Bucholz KK, Kramer J, Foroud T (2006) The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across developmental stages. Behav Genet 36(4):577–590

    Article  PubMed  Google Scholar 

  • Dick DM, Agrawal A, Wang JC, Hinrichs A, Bertelsen S, Bucholz KK, Bierut LJ (2007) Alcohol dependence with comorbid drug dependence: genetic and phenotypic associations suggest a more severe form of the disorder with stronger genetic contribution to risk. Addiction 102(7):1131–1139

    Article  PubMed  Google Scholar 

  • Dick DM, Aliev F, Wang JC, Grucza RA, Schuckit M, Kuperman S, Goate A (2008) Using dimensional models of externalizing psychopathology to aid in gene identification. Arch Gen Psychiatry 65(3):310–318

    Article  PubMed  Google Scholar 

  • Dick DM, Latendresse SJ, Lansford JE, Budde JP, Goate A, Dodge KA, Bates JE (2009) Role of GABRA2 in trajectories of externalizing behavior across development and evidence of moderation by parental monitoring. Arch Gen Psychiatry 66(6):649–657

    Article  PubMed  Google Scholar 

  • Dick DM, Aliev F, Krueger RF, Edwards A, Agrawal A, Lynskey M, Consortia G (2011) Genome-wide association study of conduct disorder symptomatology. Mol Psychiatry 16(8):800–808. doi:10.1038/mp.2010.73

    Article  PubMed  Google Scholar 

  • Drgon T, D’Addario C, Uhl GR (2006) Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions. Am J Med Genet B Neuropsychiatr Genet 141B(8):854–860. doi:10.1002/ajmg.b.30349

    Article  PubMed  Google Scholar 

  • Furberg H, Kim Y, Dackor J, Boerwinkle E, Franceschini N, Ardissino D, Sullivan PF (2010) Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 42(5):441–447. doi:10.1038/ng.571

    Article  Google Scholar 

  • Gorenstein EE, Newman JP (1980) Disinhibitory psychopathology: a new perspective and model for research. Psychol Rev 87(3):301–315. doi:10.1037/0033-295x.87.3.301

    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 

  • Hicks BM, Schalet BD, Malone SM, Iacono WG, McGue M (2011) Psychometric and genetic architecture of substance use disorder and behavioral disinhibition measures for gene association studies. Behav Genet 41(4):459–475. doi:10.1007/s10519-010-9417-2

    Article  PubMed  Google Scholar 

  • Hodgkinson CA, Yuan QP, Xu K, Shen PH, Heinz E, Lobos EA, Goldman D (2008) Addictions biology: haplotype-based analysis for 130 candidate genes on a single array. Alcohol Alcohol 43(5):505–515. doi:10.1093/alcalc/agn032

    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 

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

    Article  PubMed  Google Scholar 

  • Kendler KS, Kalsi G, Holmans PA, Sanders AR, Aggen SH, Dick DM, Gejman PV (2011) Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. Alcohol Clin Exp Res 35(5):963–975

    Article  PubMed  Google Scholar 

  • Kohli MA, Lucae S, Saemann PG, Schmidt MV, Demirkan A, Hek K, Binder EB (2011) The neuronal transporter gene SLC6A15 confers risk to major depression. Neuron 70(2):252–265. doi:10.1016/j.neuron.2011.04.005

    Article  PubMed  Google Scholar 

  • Krueger RF (1999) The structure of common mental disorders. Arch Gen Psychiatry 56:921–926

    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 

  • Krystal JH, Staley J, Mason G, Petrakis IL, Kaufman J, Harris RA, Lappalainen J (2006) Gamma-aminobutyric acid type A receptors and alcoholism: intoxication, dependence, vulnerability, and treatment. Arch Gen Psychiatry 63(9):957–968

    Article  PubMed  Google Scholar 

  • Lee SH, DeCandia TR, Ripke S, Yang J, Sullivan PF, Goddard ME, Mol Genetics S (2012) Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 44(3):247–250. doi:10.1038/ng.1108

    Article  PubMed  Google Scholar 

  • Li X, Basu S, Miller MB, Iacono WG, McGue M (2011) A rapid generalized least squares model for a genome-wide quantitative trait association analysis in families. Hum Hered 71(1):67–82

    Article  PubMed  Google Scholar 

  • Liu JZ, McRae AF, Nyholt DR, Medland SE, Wray NR, Brown KM, Investigators A (2010) A versatile gene-based test for genome-wide association studies. Am J Hum Genet 87(1):139–145. doi:10.1016/j.ajhg.2010.06.009

    Article  PubMed  Google Scholar 

  • Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461(7265):747–753

    Article  PubMed  Google Scholar 

  • Miller MB, Basu S, Cunningham JM, Eskin E, Malone SM, Oetting WS, McGue M (2012) The minnesota center for twin and family research genome-wide association study. Twin Res Hum Genet 15(6):767–774

    Article  PubMed  Google Scholar 

  • Mobascher A, Rujescu D, Mittelstrass K, Giegling I, Lamina C, Nitz B, Winterer G (2010) Association of a variant in the muscarinic acetylcholine receptor 2 gene (CHRM2) with nicotine addiction. Am J Med Genet B Neuropsychiatr Genet 153B(2):684–690. doi:10.1002/ajmg.b.31011

    PubMed  Google Scholar 

  • Neale MC, Boker SM, Xie G, Maes HH (1999) Mx: statistical modeling, 5th edn. Department of Psychiatry, Richmond

    Google Scholar 

  • Panagiotou OA, Ioannidis JP, Genome-Wide Significance (2012) What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations. Int J Epidemiol 41(1):273–286. doi:10.1093/ije/dyr178

    Article  PubMed  Google Scholar 

  • Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38(8):904–909

    Article  PubMed  Google Scholar 

  • Quay HC (1997) Inhibition and attention deficit hyperactivity disorder. J Abnorm Child Psychol 25(1):7–13. doi:10.1023/a:1025799122529

    Article  PubMed  Google Scholar 

  • Reynolds B, Fields S (2012) Delay discounting by adolescents experimenting with cigarette smoking. Addiction 107(2):417–424. doi:10.1111/j.1360-0443.2011.03644.x

    Article  PubMed  Google Scholar 

  • Saccone SF, Bierut LJ, Chesler EJ, Kalivas PW, Lerman C, Saccone NL, Rutter JL (2009) Supplementing high-density SNP microarrays for additional coverage of disease-related genes: addiction as a paradigm. PLoS One 4(4):e5225. doi:10.1371/journal.pone.0005225

    Article  PubMed  Google Scholar 

  • Saccone NL, Culverhouse RC, Schwantes-An TH, Cannon DS, Chen XN, Cichon S, 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):e1001053. doi:10.1371/journal.pgen.1001053

    Article  PubMed  Google Scholar 

  • Schol-Gelok S, Janssens A, Tiemeier H, Liu F, Lopez-Leon S, Zorkoltseva IV, van Duijn CM (2010) A genome-wide screen for depression in two independent Dutch populations. Biol Psychiatry 68(2):187–196. doi:10.1016/j.biopsych.2010.01.033

    Article  PubMed  Google Scholar 

  • Schumann G, Coin LJ, Lourdusamy A, Charoen P, Berger KH, Stacey D, Elliott P (2011) Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci USA 108(17):7119–7124. doi:10.1073/pnas.1017288108

    Article  PubMed  Google Scholar 

  • Sher KJ, Bartholow BD, Wood MD (2000) Personality and substance use disorders: a prospective study. J Consult Clin Psychol 68(5):818–829. doi:10.1037//0022-006x.68.5.818

    Article  PubMed  Google Scholar 

  • Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42(11):937–948

    Article  PubMed  Google Scholar 

  • Sullivan PF (2007) Spurious genetic associations. Biol Psychiatry 61(10):1121–1126. doi:10.1016/j.biopsych.2006.11.010

    Article  PubMed  Google Scholar 

  • Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F, Consortium E (2010) Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 42(5):448–453

    Article  PubMed  Google Scholar 

  • Vinkhuyzen AAE, Pedersen NL, Yang J, Lee SH, Magnusson PKE, Iacono WG, Wray NR (2012) Common SNPs explain some of the variation in the personality dimensions of neuroticism and extraversion. Transl Psychiatry 2:e102. doi:10.1038/tp.2012.27

    Article  PubMed  Google Scholar 

  • Visscher PM, Yang JA, Goddard ME (2010) A commentary on common SNPs explain a large proportion of the heritability for human height’ by Yang et al. (2010). Twin Res Hum Genet 13(6):517–524. doi:10.1375/twin.13.6.517

    Article  PubMed  Google Scholar 

  • Visscher PM, Brown MA, McCarthy MI, Yang J (2012) Five years of GWAS discovery. Am J Hum Genet 90(1):7–24. doi:10.1016/j.ajhg.2011.11.029

    Article  PubMed  Google Scholar 

  • Vollebergh WAM, Iedema J, Bijl RV, de Graaf R, Smit F, Ormel J (2001) The structure and stability of common mental disorders: the NEMESIS study. Arch Gen Psychiatry 58(6):597–603

    Article  PubMed  Google Scholar 

  • Vrieze SI, McGue M, Iacono WG (2012) The interplay of genes and adolescent development in substance use disorders: leveraging findings from GWAS meta-analyses to test developmental hypotheses about nicotine consumption. Hum Genet 131(6):791–801. doi:10.1007/s00439-012-1167-1

    Article  PubMed  Google Scholar 

  • Yang JA, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, Visscher PM (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42(7):565–569. doi:10.1038/ng.608

    Article  PubMed  Google Scholar 

  • Yang JA, Lee SH, Goddard ME, Visscher PM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88(1):76–82. doi:10.1016/j.ajhg.2010.11.011

    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 

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Acknowledgments

This research was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886), the National Institute on Drug Abuse (DA05147, DA13240, and DA024417), and the National Institute on Mental Health (MH066140).

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Authors and Affiliations

  1. Minnesota Center for Twin and Family Research, Department of Psychology, University of Minnesota, Elliott Hall, Minneapolis, MN, 55455, USA

    Matt McGue, Michael B. Miller, Steve Malone & William G. Iacono

  2. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA

    Yiwei Zhang & Saonli Basu

  3. Department of Biostatistics, Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    Scott Vrieze

  4. Addiction Research Center, University of Michigan, Ann Arbor, MI, USA

    Brian Hicks

  5. Department of Experimental and Clinical Pharmacology, College of Pharmacy, and the Institute of Human Genetics, University of Minnesota, Minneapolis, MN, USA

    William S. Oetting

  6. Institute of Public Health, University of Southern Denmark, Odense, Denmark

    Matt McGue

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  1. Matt McGue
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Correspondence to Matt McGue.

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McGue, M., Zhang, Y., Miller, M.B. et al. A Genome-Wide Association Study of Behavioral Disinhibition. Behav Genet 43, 363–373 (2013). https://doi.org/10.1007/s10519-013-9606-x

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