Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland 20852, USA.
Nature. 2010 Dec 23;468(7327):1061-6. doi: 10.1038/nature09629.
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.
冲动性，描述的是一种没有远见的行动，是几种精神疾病、自杀倾向和暴力行为的重要特征。冲动性的复杂起源阻碍了对影响它的基因和与之相关的疾病的识别。在这里，我们在一个创始人群体中对冲动的个体进行了外显子靶向测序，针对属于血清素和多巴胺领域的 14 个基因。鉴定出 HTR2B 中的一个终止密码子，它在芬兰人中很常见（次要等位基因频率 > 1%）但却是芬兰人独有的。评估了该基因在人脑内的表达情况，以及终止密码子的分子功能，该密码子与冲动性为特征的精神疾病有关，在人群和基于家族的分析中都存在。Htr2b 的敲除增加了小鼠的冲动行为，表明具有预测性。我们的研究表明，使用创始人群体识别和追踪复杂行为表型中稀有等位基因的影响具有潜力，并表明 HTR2B 在冲动性中起作用。
