• A Corrigendum to this article was published on 16 February 2011

Abstract

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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Accessions

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.

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Acknowledgements

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.

Author information

Author notes

    • Leena Peltonen

    Deceased.

Affiliations

  1. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland 20852, USA

    • Laura Bevilacqua
    • , Qiaoping Yuan
    • , Zhifeng Zhou
    • , Colin A. Hodgkinson
    •  & David Goldman
  2. INSERM UMR-S 839 and Université Pierre et Marie Curie, Institut du Fer à Moulin, Paris 75654, France

    • Stéphane Doly
    • , Luc Maroteaux
    • , Silvina Diaz
    •  & Arnaud Belmer
  3. Department of Public Health, University of Helsinki, Helsinki FI-00014, Finland

    • Jaakko Kaprio
  4. Institute for Molecular Medicine, Helsinki FI-00014, Finland

    • Jaakko Kaprio
  5. Unit for Child and Adolescent Psychiatry, National Institute for Health and Welfare, Helsinki FI-00271, Finland

    • Jaakko Kaprio
  6. Institute of Clinical Medicine, Department of Psychiatry, University of Helsinki, Helsinki FI-00014, Finland

    • Roope Tikkanen
    •  & Matti Virkkunen
  7. Department of Psychiatry, Helsinki University Central Hospital, Helsinki FI-00014, Finland

    • Tiina Paunio
    •  & Jaana Suvisaari
  8. Department of Medical Genetics, University of Helsinki, Helsinki FI-00014, Finland

    • Juho Wedenoja
  9. Institute for Molecular Medicine Finland FIMM, University of Helsinki and National Institute for Health and Welfare, Helsinki FI-00014, Finland

    • Juho Wedenoja
  10. Department of Psychiatry, University of Pisa, Pisa 56100, Italy

    • Liliana Dell’Osso
  11. Department of Psychiatry, The Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637, USA

    • Emil Coccaro
  12. Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA

    • Richard J. Rose
  13. Kellokoski Psychiatric Hospital, Kellokoski FI-04500, Finland

    • Matti Virkkunen

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David Goldman.

Supplementary information

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  1. 1.

    Supplementary Information

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

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DOI

https://doi.org/10.1038/nature09629

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