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.

Fig.1. HTR2B *20 co-segregates with impulsivity

Co-segregation of HTR2B *20 with ASPD and AUD in eight informative families.

Fig. 2. HTR2B *20 blocks protein expression

a) cDNA and b) protein locations of HTR2B Q20*. c) Variable stop codon-mediated RNA decay determined by cDNA sequencing of twelve *20 heterozygotes. d) *20-mediated blockade of 5-HT2B protein expression in Western blots (validated with three anti-5-HT2B antibodies – described in Methods). The 5-HT2B protein ratio was 1.93: 1 in fourteen Q20/Q20 homozygotes (mean 1.78, SD 2.24) compared to 14 Q20/*20 heterozygotes (mean 0.92, SD 1.14) (p = 0.03) (Methods).

Fig.3. Increased impulsivity and novelty seeking in Htr2b^−/− mice

a) Increased locomotor response of Htr2b^−/− mice to environmental novelty and b) to dopamine D1 receptor agonists. c) Increased number of contacts of Htr2b^−/− mice with a novel object. d) Increased delay-discounting of Htr2b^−/− mice. e) Reduced hyponeophagia in 18-hr starved Htr2b^−/− mice. f) Male Htr2b^−/− mice have three-fold higher plasma testosterone levels as compared to control mice. * p<.05, ** p<.01, *** p<.001.

Fig.3. Increased impulsivity and novelty seeking in Htr2b^−/− mice

a) Increased locomotor response of Htr2b^−/− mice to environmental novelty and b) to dopamine D1 receptor agonists. c) Increased number of contacts of Htr2b^−/− mice with a novel object. d) Increased delay-discounting of Htr2b^−/− mice. e) Reduced hyponeophagia in 18-hr starved Htr2b^−/− mice. f) Male Htr2b^−/− mice have three-fold higher plasma testosterone levels as compared to control mice. * p<.05, ** p<.01, *** p<.001.