A Novel Interaction between Tryptophan Hydroxylase 2 (TPH2) Gene Polymorphism (rs4570625) and BDNF Val66Met Predicts a High-Risk Emotional Phenotype in Healthy Subjects

Abstract

Poor inhibitory processing of negative emotional content is central to many psychiatric disorders, including depression and anxiety. Moreover, increasing evidence suggests that core aspects of emotion-inhibitory processing are largely inherited and as such may represent a key intermediate or risk-related phenotype for common affective diseases (e.g., unipolar depressive, anxiety disorders). The current study employed a candidate-gene approach in order to most effectively examine this complex behavioral phenotype. We examined the novel interaction between BDNF (Val66Met) and TPH2 (rs4570625) polymorphisms and their influence on behavioral inhibition of negative emotion in two independent investigations of healthy adults. BDNF Met carriers consistently report greater symptoms of affective disease and display corresponding behavioral rigidity, while TPH2 T carriers display poor inhibitory processing. These genotypes are traditionally perceived as ‘risk’ genotypes when compared to their respective major Val and G homozygous genotypes, but evidence is mixed. Recent studies in humans and mutant mouse models suggest biological epistasis between BDNF and genes involved in serotonin regulation. Moreover, polymorphisms in the TPH2 gene may have greater influence on serotonergic function than other more commonly studied polymorphisms (e.g., 5-HTTLPR). We observed consistent evidence across two different emotion-inhibition paradigms, one with high internal validity (Study 1, n = 119) and one with high ecological validity (Study 2, n = 115) that the combination of Val/Val and G/G genotypes was clearly associated with impaired inhibition of negative emotional content. This was followed by individuals carrying the BDNF—Met allele (including Met/Val and Met/Met) when combined with the TPH2—T allele (including T/G and T/T combinations). The consistency of these results across tasks and studies suggests that these two groups may be particularly vulnerable to the most common psychiatric disorders and should be targets for future clinical investigation.

The Role of Irisin in Alzheimer’s Disease

“…Several studies have demonstrated that the administration of BDNF in patients with AD ameliorates AD pathology [ 98 , 99 ]. Recent studies have demonstrated that the irisin-BDNF axis could strengthen learning and memory function [ 82 , 100 , 101 ] and improve mood disorders and anxiety [ 102 , 103 , 104 ]. FNDC5/irisin contributes to the boosting of reward-related learning and motivation by enhancing the production of BDNF [ 82 ].…”

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

“…Levels of serotonin in the central nervous system (CNS) depend on the activity of tryptophan hydroxylase 2, the rate-limiting enzyme of the synthesis of serotonin. The −703 G/ T polymorphism of the TPH2 gene (rs4570625) has been associated with amygdalar responsiveness (Brown et al, 2005;Canli et al, 2005), risk of affective disorder (Gao et al, 2012), and with behavioural inhibition (Latsko et al, 2016). This genotype is associated with functional connectivity (Tao et al, 2018) and white matter integrity (Ping et al, 2019) in the brain.…”

Therapy of obesity by sibutramin: polymorphisms of TPH2 and GNB3 genes and decrease of body weight

“…Полиморфизм G703T (rs4570625) расположен в промоторной области гена TPH2. Предполагается, что функциональный эффект полиморфизма TPH2 rs4570625 может заключаться в изменении ДНК-белковых взаимодействий и транскрипции гена TPH2; что приведет к снижению уровня серотонина [6,7]. В проведенных ранее исследованиях были показаны влияние полиморфизма гена TPH2 на развитие большого депрессивного расстройства (БДР), суицидального поведения, обсессивно-компульсивного расстройства, а также его связь с синдромом дефицита внимания и гиперактивности (СДВГ) [8][9][10][11].…”