Orexin/hypocretin receptor gene (HCRTR1) variation is associated with aggressive behaviour

Abstract

Highlights• Orexins are involved in the regulation of stress response • The HCRTR1 rs2271933 G>A genotype was associated with aggressiveness • A/A homozygotes were more aggressive and relapsed to drunk driving • A-allele carriers were more frequently involved in traffic accidents• The genotype effect is sensitive to stressful life events AbstractOrexins, alternatively called hypocretins, are neuropeptides with crucial role in maintaining wakefulness. The orexin system is thought to mediate a coordinated defense response but thus far investigated from the flight, but never fight, response perspective. An HCRTR1 gene variant (rs2271933 G > A) leading to amino acid substitution (Ile408Val) has been associated with migraine and mood disorders. We genotyped, and assessed aggressive behaviour in both birth cohorts (n=655 and 583) of the Estonian Children Personality Behaviour and Health Study (ECPBHS). Measures of aggressiveness were collected at age 25 or 33 and data on stressful life events (SLE-s) at age 15. Violations of traffic law were monitored in the samples of the Estonian Psychobiological Study of Traffic Behaviour. In both birth cohorts of the ECPBHS, the HCRTR1 the A/A homozygotes reported higher aggression in both Buss-Perry Aggression Questionnaire and the Life History of Aggression Interview. With either measure of aggressiveness, the HCRTR1 genotype effect was dependent on experience of SLE, the highest level of aggressiveness increase by environment being found in female A/A homozygotes. The HCRTR1 A/A homozygotes scored higher in the ANGER facet of the Affective Neuroscience Personality Scale, while such an effect on FEAR was found only in females. Male HCRTR1 A/A homozygotes were more likely to relapse into drunk driving of a passenger car, and in two independent samples the A-allele carriers were causing traffic accidents more often. Conclusively, self-report, interview, and traffic record data converge indicating that the HCRTR1 Ile408Val genotype is associated with aggressiveness and breach of law.This article is part of the Special Issue entitled "Current status of the neurobiology of aggression and impulsivity".

Reward sensitivity, affective neuroscience personality, symptoms of attention-deficit/hyperactivity disorder, andTPH2-703G/T (rs4570625) genotype

“…The Reward Openness and Insatiability Scale (ROIS) that is used in this manuscript to measure reward sensitivity was constructed post hoc making use of previously collected information on personality. Three experienced behavioural scientists independently extracted items thought to reflect reward sensitivity from the Estonian versions of International Personality Item Pool NEO (IPIP) (Goldberg, 1999;Mõttus et al, 2006), Barratt Impulsiveness Scale (BIS-11;Patton et al, 1995;Akkermann et al, 2010), the brief version of the ANPS (Davis et al, 2003;Harro et al, 2019), Spielberger State-Trait Anxiety Inventory (STAI; Spielberger et al, 1983;Akkermann et al, 2010), and Adaptive and Maladaptive Impulsivity Scale (AMIS) (Paaver et al, 2006;Tomson-Johanson et al, 2020). The extracted items were discussed, and an initial pool of items was formed with consensus.…”

“…We used the adaptation (Harro et al, 2019) of the short version of the ANPS (Davis et al, 2003) that is a self-report instrument constructed bottom up to correspond to the activity in neural circuits underlying basic emotive systems as defined in animal research (Panksepp, 1998;Davis and Panksepp, 2011). It comprises scales termed ANGER, FEAR, SADNESS, SEEKING, CARE, and PLAY, each measured with six items, each on a 5-point scale.…”

Variants of the Aggression-Related RBFOX1 Gene in a Population Representative Birth Cohort Study: Aggressiveness, Personality, and Alcohol Use Disorder

“…Nevertheless, when performing subgroup analyses by ethnicity, age of participants, sample characteristics, and outcome measures, significant associations emerge (6). Several variants in a number of candidate genes have been found strongly associated with aggression measures in the ECPBHS sample [see (29,33) and references therein]. It should hence be concluded that in this specific population of which the ECPBHS sample is highly representative, other genes than RBFOX1 play a role in aggressiveness.…”

“…ECPBHS is population representative, while 79.1% of subjects of the randomized regional sample participated in the original sampling. Details on follow-ups have been described elsewhere [e.g., (29)], and the number of participants in the presented analyses is given below. The study was approved by the Ethics Review Committee on Human Research of the University of Tartu.…”

Association of orexin/hypocretin receptor gene (HCRTR1) with reward sensitivity, and interaction with gender

“…Orexin release modulates the expression and extinction of fear memories (Flores et al, 2015) and the orexin neurons are activated in acute response to a variety of stressors; however, their role in chronic stress appears complex (Sargin, 2019), leading to the hypothesis that the role for orexins in neurotransmission is promoted during aversive conditions that elicit high arousal (Berridge et al, 2010). We have recently found evidence for a role of orexins in the other side of the flight/fight response, aggressiveness, by association of the HCRTR1 gene encoding the orexin OX1 receptor (Harro et al, 2019). The HCRTR1 gene variant (rs2271933, G1222A) in exon 7 that leads to amino acid substitution (Ile408Val) (Meerabux et al, 2005) was linked to aggressive behaviour or breach of law in four independent population samples by use of self-reports, interviews, and databases.…”