title: A population-specific HTR2B stop codon predisposes to severe impulsivity.
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.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland 20852, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Bevilacqua
authors.forename: Stéphane
authors.initials: S
authors.lastname: Doly
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.forename: Qiaoping
authors.initials: Q
authors.lastname: Yuan
authors.forename: Roope
authors.initials: R
authors.lastname: Tikkanen
authors.forename: Tiina
authors.initials: T
authors.lastname: Paunio
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Juho
authors.initials: J
authors.lastname: Wedenoja
authors.forename: Luc
authors.initials: L
authors.lastname: Maroteaux
authors.forename: Silvina
authors.initials: S
authors.lastname: Diaz
authors.forename: Arnaud
authors.initials: A
authors.lastname: Belmer
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.forename: Liliana
authors.initials: L
authors.lastname: Dell'osso
authors.forename: Jaana
authors.initials: J
authors.lastname: Suvisaari
authors.forename: Emil
authors.initials: E
authors.lastname: Coccaro
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rose
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Matti
authors.initials: M
authors.lastname: Virkkunen
authors.forename: David
authors.initials: D
authors.lastname: Goldman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D005387:Finland; D018703:Founder Effect; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D005838:Genotype; D006801:Humans; D007175:Impulsive Behavior / Q000235:genetics*; D008297:Male; D001523:Mental Disorders / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics* / Q000378:metabolism*; D013739:Testosterone / Q000097:blood / Q000134:cerebrospinal fluid
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D013739:Testosterone