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A population-specific HTR2B stop codon predisposes to severe impulsivity

A Corrigendum to this article was published on 16 February 2011


Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency > 1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.

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Figure 1: HTR2B Q20* co-segregates with impulsivity.
Figure 2: HTR2B Q20* blocks protein expression.
Figure 3: Increased impulsivity and novelty seeking in Htr2b −/− mice.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The NCBI accession number for the HTR2B stop codon is rs79874540. For all newly discovered SNPs, NCBI accession numbers are listed in Supplementary Table 4.


  1. Winstanley, C. A., Eagle, D. M. & Robbins, T. W. Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies. Clin. Psychol. Rev. 26, 379–395 (2006)

    Article  Google Scholar 

  2. Eysenck, S. B. & Eysenck, H. J. The place of impulsiveness in a dimensional system of personality description. Br. J. Soc. Clin. Psychol. 16, 57–68 (1977)

    Article  CAS  Google Scholar 

  3. DeJong, J., Virkkunen, M. & Linnoila, M. Factors associated with recidivism in a criminal population. J. Nerv. Ment. Dis. 180, 543–550 (1992)

    Article  CAS  Google Scholar 

  4. Kendler, K. S. et al. The structure of genetic and environmental risk factors for DSM-IV personality disorders. Arch. Gen. Psychiatry 65, 1438–1446 (2008)

    Article  Google Scholar 

  5. Coccaro, E. F., Bergeman, C. S. & McClearn, G. E. Heritability of irritable impulsiveness: a study of twins reared together and apart. Psychiatry Res. 48, 229–242 (1993)

    Article  CAS  Google Scholar 

  6. Brunner, H. G., Nelen, M., Breakefield, X. O., Ropers, H. H. & van Oost, B. A. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262, 578–580 (1993)

    Article  ADS  CAS  Google Scholar 

  7. Sabol, S. Z., Hu, S. & Hamer, D. A functional polymorphism in the monoamine oxidase A gene promoter. Hum. Genet. 103, 273–279 (1998)

    Article  CAS  Google Scholar 

  8. Caspi, A. et al. Role of genotype in the cycle of violence in maltreated children. Science 297, 851–854 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Sjöberg, R. L. et al. A non-additive interaction of a functional MAO-A VNTR and testosterone predicts antisocial behavior. Neuropsychopharmacology 33, 425–430 (2008)

    Article  Google Scholar 

  10. Misener, V. L. et al. Linkage of the dopamine receptor D1 gene to attention deficit/hyperactivity disorder. Mol. Psychiatry 9, 500–509 (2004)

    Article  CAS  Google Scholar 

  11. Faraone, S. V. et al. Molecular genetics of attention deficit/hyperactivity disorder. Biol. Psychiatry 57, 1313–1323 (2005)

    Article  CAS  Google Scholar 

  12. Winstanley, C. A. et al. Double dissociation between serotonergic and dopaminergic modulation of medial prefrontal and orbitofrontal cortex during a test of impulsive choice. Cereb. Cortex 16, 106–114 (2006)

    Article  Google Scholar 

  13. Everitt, B. J. et al. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Phil. Trans. R. Soc. Lond. B 363, 3125–3135 (2008)

    Article  Google Scholar 

  14. Volkow, N. D., Fowler, J. S. & Wang, G. J. Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav. Pharmacol. 13, 355–366 (2002)

    Article  CAS  Google Scholar 

  15. Virkkunen, M. & Linnoila, M. Brain serotonin, type II alcoholism and impulsive violence. J. Stud. Alcohol Suppl. 11163–169 (1993)

  16. Chiavegatto, S. et al. Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase. Proc. Natl Acad. Sci. USA 98, 1277–1281 (2001)

    Article  ADS  CAS  Google Scholar 

  17. Cases, O. et al. Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs. J. Neurosci. 18, 6914–6927 (1998)

    Article  CAS  Google Scholar 

  18. Ducci, F. et al. Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women. Mol. Psychiatry 13, 334–347 (2007)

    Article  Google Scholar 

  19. Roy, A., Hu, X. Z., Janal, M. N. & Goldman, D. Interaction between childhood trauma and serotonin transporter gene variation in suicide. Neuropsychopharmacology 32, 2046–2052 (2007)

    Article  CAS  Google Scholar 

  20. Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003)

    Article  ADS  CAS  Google Scholar 

  21. Ng, S. B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009)

    Article  ADS  CAS  Google Scholar 

  22. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J. A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009)

    Article  ADS  CAS  Google Scholar 

  23. Peltonen, L., Jalanko, A. & Varilo, T. Molecular genetics of the Finnish disease heritage. Hum. Mol. Genet. 8, 1913–1923 (1999)

    Article  CAS  Google Scholar 

  24. Gustavsson, J. P. Swedish universities Scales of Personality (SSP): construction, internal consistency and normative data. Acta Psychiatr. Scand. 102, 217–225 (2000)

    Article  CAS  Google Scholar 

  25. Virkkunen, M. et al. CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers. Arch. Gen. Psychiatry 51, 20–27 (1994)

    Article  CAS  Google Scholar 

  26. Abel, L., Alcais, A. & Mallet, A. Comparison of four sib-pair linkage methods for analyzing sibships with more than two affecteds: interest of the binomial maximum likelihood approach. Genet. Epidemiol. 15, 371–390 (1998)

    Article  CAS  Google Scholar 

  27. Kim, S. J. et al. Mutation screening of human 5-HT2B receptor gene in early-onset obsessive-compulsive disorder. Mol. Cell. Probes 14, 47–52 (2000)

    Article  Google Scholar 

  28. Lin, Z., Walther, D., Yu, X. Y., Drgon, T. & Uhl, G. R. The human serotonin receptor 2B: coding region polymorphisms and association with vulnerability to illegal drug abuse. Pharmacogenetics 14, 805–811 (2004)

    Article  CAS  Google Scholar 

  29. Doly, S. et al. Serotonin 5-HT2B receptors are required for 3,4 methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro. J. Neurosci. 28, 2933–2940 (2008)

    Article  CAS  Google Scholar 

  30. Launay, J. M., Schneider, B., Loric, S., Da Prada, M. & Kellermann, O. Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells. FASEB J. 20, 1843–1854 (2006)

    Article  CAS  Google Scholar 

  31. Blanpain, C. et al. Serotonin 5-HT2B receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc. Res. 60, 518–528 (2003)

    Article  CAS  Google Scholar 

  32. Hawton, K. & van Heeringen, K. Suicide. Lancet 373, 1372–1381 (2009)

    Article  Google Scholar 

  33. Rutter, M., Caspi, A. & Moffitt, T. E. Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies. J. Child Psychol. Psychiatry 44, 1092–1115 (2003)

    Article  Google Scholar 

  34. Chiavegatto, S., Quadros, I. M., Ambar, G. & Miczek, K. A. Individual vulnerability to escalated aggressive behavior by a low dose of alcohol: decreased serotonin receptor mRNA in the prefrontal cortex of male mice. Genes Brain Behav. 9, 110–119 (2010)

    Article  CAS  Google Scholar 

  35. Jaffré, F. et al. Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy. Circ. Res. 104, 113–123 (2009)

    Article  Google Scholar 

  36. Belin, D., Mar, A. C., Dalley, J. W., Robbins, T. W. & Everitt, B. J. High impulsivity predicts the switch to compulsive cocaine-taking. Science 320, 1352–1355 (2008)

    Article  ADS  CAS  Google Scholar 

  37. Linnoila, M. et al. Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior. Life Sci. 33, 2609–2614 (1983)

    Article  CAS  Google Scholar 

  38. Brown, G. L. et al. Aggression in humans correlates with cerebrospinal fluid amine metabolites. Psychol. Res. 1, 131–139 (1979)

    CAS  Google Scholar 

  39. Hodgkinson, C. A. et al. Addictions biology: haplotype-based analysis for 130 candidate genes on a single array. Alcohol Alcohol. 43, 505–515 (2008)

    Article  CAS  Google Scholar 

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This study is dedicated to the memory of L.P. and M. Linnoila. We thank L. Akhtar for assistance with tissue culture, C. Marietta for assistance with measurement of receptor protein levels, V. Srivastava and G. Yamini for discussions, and P.-H. Shen for contributions to ancestry analyses. M. Eggert and L. Brown assisted with clinical ascertainment and assessment of the University of Helsinki sample. We thank M. Linnoila for his contributions to the collection of the University of Helsinki sample. E. Kempas assisted with genotyping. J.-M. Launay measured plasma testosterone levels in Htr2b−/− mice. We also thank A. Tuulio-Henriksson, E. Vuoksimaa, A. Häppölä and L. Arala. This work was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH and the Academy of Finland Centre of Excellence in Complex Disease Genetics. The FinnTwin12 and FinnTwin16 studies were supported by the National Institute on Alcohol Abuse and Alcoholism (AA-12502 and AA-09203 to R.J.R.), and by the Academy of Finland (100499, 205585 and 118555 to J.K.). The studies on Htr2b−/− mice were supported by the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie, and by grants from the Fondation de France, the Fondation pour la Recherche Médicale, the French Ministry of Research (Agence Nationale pour la Recherche), and the European Union. L.M.’s team is an “Equipe Fondation pour la Recherche Médicale”. S. Diaz is supported by a fellowship from IBRO and Region Ile de France DIM STEM.

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Authors and Affiliations



L.B. and D.G. drafted and revised the manuscript, conceptualized the study, and performed molecular, clinical and statistical analyses. L.M., S. Doly, S. Diaz and A.B. performed behavioural analyses in mice and statistical analyses. J.K. performed clinical and statistical analyses. Q.Y. performed statistical analyses. R.T., M.V. and J.S. performed clinical analyses. T.P. directed molecular analyses. J.W. performed molecular analyses. C.A.H and Z.Z. helped direct molecular analyses. L.P. helped direct clinical analyses. C.A.H., Z.Z., J.K., T.P., J.S., M.V. and E.C. revised the manuscript. D.G., L.M., J.K., C.A.H., L.P., L.D., E.C., R.J.R. and M.V. also helped with organization and support.

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Correspondence to David Goldman.

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The authors declare no competing financial interests.

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The file contains Supplementary Methods, Supplementary Data, Supplementary Figures 1-13 with legends and Supplementary Tables 1-12. The file also contains additional references. (PDF 1892 kb)

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Bevilacqua, L., Doly, S., Kaprio, J. et al. A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature 468, 1061–1066 (2010).

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