Background and hypothesis Psychiatric disorders impose a huge health and economic burden on modern society. However, there is currently no proven completely effective treatment available, partly owing to the inefficiency of drug target identification and validation. We aim to identify therapeutic targets relevant to psychiatric disorders by conducting Mendelian randomization (MR) analysis. Study design We performed genome-wide MR analysis by integrating expression quantitative trait loci (eQTL) of 4479 actionable genes that encode druggable proteins and genetic summary statistics from genome-wide association studies of psychiatric disorders. After conducting colocalization analysis on the brain MR findings, we employed protein quantitative trait loci (pQTL) data as genetic proposed instruments for intersecting the colocalized genes to provide further genetic evidence. Study results By performing MR and colocalization analysis with eQTL genetic instruments, we obtained 31 promising drug targets for psychiatric disorders, including 21 significant genes for schizophrenia, 7 for bipolar disorder, 2 for depression, 1 for attention deficit and hyperactivity (ADHD) and none for autism spectrum disorder. Combining MR results using pQTL genetic instruments, we finally proposed 8 drug-targeting genes supported by the strongest MR evidence, including gene ACE, BTN3A3, HAPLN4, MAPK3 and NEK4 for schizophrenia, gene NEK4 and HAPLN4 for bipolar disorder, and gene TIE1 for ADHD. Conclusions Our findings with genetic support were more likely to be to succeed in clinical trials. In addition, our study prioritizes approved drug targets for the development of new therapies and provides critical drug reuse opportunities for psychiatric disorders.

Objective: Polo-like kinase 1 (PLK1) modulates leukemia cell apoptosis, proliferation, and cell cycle arrest in the progression of acute lymphoblastic leukemia (ALL). This study intended to investigate the dysregulation of PLK1 and its association with induction therapy response and prognosis in pediatric ALL patients. Materials and Methods: Bone marrow mononuclear cell samples were collected from 90 pediatric ALL patients at baseline and on the 15th day of induction therapy (D15), as well as from 20 controls after enrollment, for the detection of PLK1 by reverse transcription-quantitative polymerase chain reaction. Results: PLK1 was increased in pediatric ALL patients compared with controls (P<0.001). In pediatric ALL patients, PLK1 decreased from baseline to D15 (P<0.001). Lower PLK1 at baseline was associated with a good prednisone response (P=0.002), while decreased PLK1 at D15 was related to good prednisone response (P=0.001), better bone marrow response (P=0.025), and favorable risk stratification (P=0.014). In addition, reduced PLK1 at baseline was linked with better event-free survival (EFS) (P=0.046), and decreased PLK1 at D15 was related to prolonged EFS (P=0.027) and overall survival (OS) (P=0.047). Moreover, PLK1 decline ≥25% was linked to favorable EFS (P=0.015) and OS (P=0.008). Further multivariate Cox proportional regression analysis revealed that PLK1 decline ≥25% was independently linked with prolonged EFS (hazard ratio (HR)=0.324, P=0.024) and OS (HR=0.211, P=0.019). Conclusion: The reduction of PLK1 after induction therapy reflects a good treatment response and correlates with a favorable survival profile in pediatric ALL patients.

Background: Cutis laxa is a connective tissue disease caused by abnormal synthesis or secretion of skin elastic fibers, leading to skin flabby and sagging in various body parts. It can be divided into congenital cutis laxa and acquired cutis laxa, and inherited cutis laxa syndromes is more common in clinic. Methods: In this study, we reported a case of a Han-Chinese male newborn with ATP6V0A2 gene variant leading to cutis laxa. The proband was identified by whole-exome sequencing to determine the novel variant, and their parents were verified by sanger sequencing. Bioinformatics analysis and minigene assay were used to verify the effect of this variant on splicing function. Results: The main manifestations of the proband are skin laxity, abnormal facial features, and enlargement of the anterior fontanelle. Whole-exome sequencing showed that the newborn carried a non-canonical splicing-site variant c.117+5G>T，p. (?) in ATP6V0A2 gene. Sanger sequencing showed that both parents of the proband carried the heterozygous variant. The results of bioinformatics analysis and minigene assay displayed that the variant site affected the splicing function of pre-mRNA of ATP6V0A2 gene. Conclusions: In this study, it was identified that ATP6V0A2 gene c. 117+5G>T may be the cause of the disease. Few non-canonical splicing variants of ATP6V0A2 gene were reported in the past, and this variant expands the variants spectrum of the gene. The functional study of minigene assay plays a certain role in improving the evidence level of splicing variants, which lays a foundation for prenatal counseling and follow-up gene therapy.

Background Cutis laxa is a connective tissue disease caused by abnormal synthesis or secretion of skin elastic fibers, leading to skin flabby and sagging in various body parts. It can be divided into congenital cutis laxa and acquired cutis laxa, and inherited cutis laxa syndromes is more common in clinic. Methods In this study, we reported a case of a Han-Chinese male baby with ATP6V0A2 gene variant leading to cutis laxa. The proband was identified by whole-exome sequencing to determine the new variant, and their parents were verified by sanger sequencing. Bioinformatics analysis and minigene assay were used to verify the effect of this variant on splicing function. Results The main manifestations of the proband are skin laxity, abnormal facial features, and enlargement of the anterior fontanelle. Whole-exome sequencing showed that the baby carried a non-canonical splicing-site variant c.117 + 5G > T, p. (?) in ATP6V0A2 gene. Sanger sequencing showed that both parents of the proband carried the heterozygous variant. The results of bioinformatics analysis and minigene assay displayed that the variant site affected the splicing function of pre-mRNA of ATP6V0A2 gene. Conclusions In this study, it was identified that ATP6V0A2 gene c. 117 + 5G > T may be the cause of the disease. Few non-canonical splicing variants of ATP6V0A2 gene were reported in the past, and this variant expands the variants spectrum of the gene. The functional study of minigene assay plays a certain role in improving the evidence level of splicing variants, which lays a foundation for prenatal counseling and follow-up gene therapy.