TPH-2 Gene Polymorphism in Major Depressive Disorder Patients With Early-Wakening Symptom

Abstract

Background: Sleep disturbances, such as early wakening, are frequently observed in patients with major depressive disorder (MDD). The suprachiasmatic nuclei (SCN), which controls circadian rhythm, is innervated by the raphe nucleus, a region where Tryptophan hydroxylase-2 (TPH-2) gene is primarily expressed. Although TPH-2 is often implicated in the pathophysiology of depression, few studies have applied a genetic and imaging technique to investigate the mechanism of early wakening symptom in MDD. We hypothesized that TPH-2 variants could influence the function of SCN in MDD patients with early wakening symptom.Methods: One hundred and eighty five MDD patients (62 patients without early wakening and 123 patients with early wakening) and 64 healthy controls participated in this study. Blood samples were collected and genotyping of rs4290270, rs4570625, rs11178998, rs7305115, rs41317118, and rs17110747 were performed by next-generation sequencing (NGS) technology. Logistic regression model was employed for genetic data analysis using the PLINK software. Based on the allele type, rs4290270, which was significant in the early wakening MDD group, participants were categorized into two groups (A allele and T carrier). All patients underwent whole brain resting-state functional magnetic resonance imaging (rs-fMRI) scanning and a voxel-wise functional connectivity comparison was performed between the groups.Results: rs4290270 was significantly linked to MDD patients who exhibited early wakening symptom. The functional connectivities of the right SCN with the right fusiform gyrus and right middle frontal gyrus were increased in the T carrier group compared to the A allele group. In addition, the functional connectivities of the left SCN with the right lingual gyrus and left calcarine sulcus were decreased in the T carrier group compared to the A allele group.Conclusion: These findings suggested that the TPH-2 gene variant, rs4290270, affected the circadian regulating function of SCN. The altered functional connectivities, observed between the SCN and right fusiform gyrus, right middle frontal gyrus, the right lingual gyrus and left calcarine sulcus, could highlight the neural mechanism by which SCN induces sleep-related circadian disruption in T carrier MDD patients. Hence, rs4290270 could potentially serve as a reliable biomarker to identify MDD patients with early wakening symptom.

Brain Structural and Functional Alterations Specific to Low Sleep Efficiency in Major Depressive Disorder

“…Liu et al (2018) reported patients with MDD and high insomnia (HAMD sleep subscale score ≥ 4) had increased amplitude of low-frequency fluctuations in the right inferior frontal gyrus/anterior insula when compared with patients with MDD and low insomnia (HAMD sleep subscale score ≤ 3). Tao et al (2018) found that functional connectivity alterations of the suprachiasmatic nuclei were associated with early-wakening symptom (HAMD-6 score = 1 or 2 for waking early in the morning) in MDD. McKinnon et al (2018) suggested that sleep disturbance [the total score of Pittsburgh Sleep Quality Index (PSQI) > 5] in older people with a lifetime history of depression was related to increased functional connectivity in the default mode network.…”

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

“…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. A recent systematic review and meta-analysis concluded that the TPH2 rs4570625 polymorphism is significantly associated with psychiatric disorders such as unipolar depression, bipolar disorder, schizophrenia, and suicide (Ottenhof et al, 2018).…”

Quantitative Identification of Major Depression Based on Resting-State Dynamic Functional Connectivity: A Machine Learning Approach

“…Occipital bending is a powerful biomarker for depression, and patients with occipital bending were reported to have abnormal cortical thickness in the posterior occipital lobe (Fullard et al, 2019). Notably, a recent study revealed that brain regions associated with early awakening and visual processing overlap in patients with MDD (Tao et al, 2018). Thus, impairments in the visual areas may result in disruption of sleep rhythms and symptoms of sleep disturbances generally seen in patients with MDD.…”