A missense variant in NDUFA6 confers schizophrenia risk by affecting YY1 binding and NAGA expression.

Genome-wide association studies (GWASs) have revealed that genetic variants at the 22q13.2 risk locus were robustly associated with schizophrenia. However, the causal variants at this risk locus and their roles in schizophrenia remain elusive. Here we identify the risk missense variant rs1801311 (located in the 1st exon of NDUFA6 gene) as likely causal for schizophrenia at 22q13.2 by disrupting binding of YY1, TAF1, and POLR2A. We systematically elucidated the regulatory mechanisms of rs1801311 and validated the regulatory effect of this missense variant. Intriguingly, rs1801311 physically interacted with NAGA (encodes the alpha-N-acetylgalactosaminidase, which is mainly involved in regulating metabolisms of glycoproteins and glycolipids in lysosome) and showed the most significant association with NAGA expression in the human brain, with the risk allele (G) associated with higher NAGA expression. Consistent with eQTL analysis, expression analysis showed that NAGA was significantly upregulated in brains of schizophrenia cases compared with controls, further supporting that rs1801311 may confer schizophrenia risk by regulating NAGA expression. Of note, we found that NAGA regulates important neurodevelopmental processes, including proliferation and differentiation of neural stem cells. Transcriptome analysis corroborated that NAGA regulates pathways associated with neuronal differentiation. Finally, we independently confirmed the association between rs1801311 and schizophrenia in a large Chinese cohort. Our study elucidates the regulatory mechanisms of the missense schizophrenia risk variant rs1801311 and provides mechanistic links between risk variant and schizophrenia etiology. In addition, this study also revealed the novel role of coding variants in gene regulation and schizophrenia risk, i.e., genetic variant in coding region of a specific gene may confer disease risk through regulating distal genes (act as regulatory variant for distal genes).

Abnormal functional network of the thalamic subregions in adult patients with obsessive-compulsive disorder.

The thalamus plays an important role in pathological mechanisms underlying obsessive-compulsive disorder (OCD). As the thalamus is a heterogeneous brain region, functional connectivity (FC) between thalamic subregions and other brain regions is worth investigating in OCD. In addition, the relationship between abnormal FC and clinical symptoms is still unclear. In this study, we used resting-state functional magnetic resonance imaging to scan 45 OCD patients and 43 well-matched healthy controls (HCs). Thalamic subregions were defined according to the Human Brainnetome Atlas. The fractional amplitude of low-frequency fluctuations (fALFF) and FC seeding-based connectivity were compared using a two-sample t-test. Correlations between abnormal FC and clinical symptoms were analyzed in OCD patients. Compared with HCs, increased fALFF was found in the bilateral thalamus, and increased FC was observed between the right posterior parietal thalamus (PPtha) and left middle occipital gyrus (LMOG) and between the right occipital thalamus (Otha) and right middle occipital gyrus (RMOG) in OCD patients. In addition, OCD patients had reduced FC between the left sensory thalamus (Stha) and left orbital inferior frontal gyrus, right PPtha and left prefrontal cortex, and between the right Otha and left inferior parietal gyrus (LIPG), respectively. Within the OCD group, the FC between right PPtha-LMOG was correlated with severity of clinical symptoms. These results revealed that the FC between the thalamus and occipital lobe is related to obsessive-compulsive symptoms in OCD patients. This finding provides more accurate information about the involvement of the thalamus in the pathophysiology of OCD.

Antidepressant-like and anti-oxidative efficacy of Campsis grandiflora flower.

OBJECTIVES: Our study aimed to investigate the antidepressant-like effect of ethyl acetate extract of the flowers of Campsis grandiflora (EFCG) in a mice model of chronic unpredictable mild stress (CUMS). METHODS: HPLC-Q-TOF-MS was used to identify the chemical constituents of EFCG. The DPPH assay and ABTS radical-scavenging assay were performed to measure the antioxidant properties. The protective properties of EFCG against H2 O2 -induced oxidative damage were analysed in PC12 cells. The changes of behaviour profiles were investigated by using open-field test, sucrose preference test, forced swimming test (FST) and tail suspension test (TST). Brain tissue samples of mice were collected, and antioxidative measure levels were measured. KEY FINDINGS: The result showed that EFCG had the most active anti-oxidative effect and the protective effect against H2 O2 oxidative injury in PC12 cells. Treatment with the EFCG significantly reduced the depressant-like severity and immobility period as compared with untreated CUMS mice in FST and TST. Moreover, EFCG significantly elevated the contents of superoxide dismutase, Glutathione Peroxidase and decreased the contents of Malonaldehyde (MDA) in mice brain. CONCLUSIONS: Our study found first the antidepressant activity of the EFCG. The results suggested the therapeutic potential of EFCG for depressive disorder.