A population-specific HTR2B stop codon predisposes to severe impulsivity

Nature. 2010 Dec 23;468(7327):1061-6. doi: 10.1038/nature09629.

Laura Bevilacqua ¹, Stéphane Doly, Jaakko Kaprio, Qiaoping Yuan, Roope Tikkanen, Tiina Paunio, Zhifeng Zhou, Juho Wedenoja, Luc Maroteaux, Silvina Diaz, Arnaud Belmer, Colin A Hodgkinson, Liliana Dell'osso, Jaana Suvisaari, Emil Coccaro, Richard J Rose, Leena Peltonen, Matti Virkkunen, David Goldman

Affiliations

Affiliation

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

PMID: 21179162 DOI: 10.1038/nature09629

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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