Identification of Potential Causal Genes for Neurodegenerative Diseases by Mitochondria-Related Genome-Wide Mendelian Randomization.

Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs.

Causal association and mediating effect of blood biochemical metabolic traits and brain image-derived endophenotypes on Alzheimer's disease.

Background: Recent genetic evidence supports that circulating biochemical and metabolic traits (BMTs) play a causal role in Alzheimer's disease (AD), which might be mediated by changes in brain structure. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between blood BMTs, brain image-derived phenotypes (IDPs) and AD. Methods: Utilizing the genetic variants associated with 760 blood BMTs and 172 brain IDPs as the exposure and the latest AD summary statistics as the outcome, we analyzed the causal relationship between blood BMTs and brain IDPs and AD by using a two-sample Mendelian randomization (MR) method. Additionally, we used two-step/mediation MR to study the mediating effect of brain IDPs between blood BMTs and AD. Results: Twenty-five traits for genetic evidence supporting a causal association with AD were identified, including 12 blood BMTs and 13 brain IDPs. For BMTs, glutamine consistently reduced the risk of AD in 3 datasets. For IDPs, specific alterations of cortical thickness (atrophy in frontal pole and insular lobe, and incrassation in superior parietal lobe) and subcortical volume (atrophy in hippocampus and its subgroups, left accumbens and left choroid plexus, and expansion in cerebral white matter) are vulnerable to AD. In the two-step/mediation MR analysis, superior parietal lobe, right hippocampal fissure and left accumbens were identified to play a potential mediating role among three blood BMTs and AD. Conclusions: The results obtained in our study suggest that 12 circulating BMTs and 13 brain IDPs play a causal role in AD. Importantly, a subset of BMTs exhibit shared genetic architecture and potentially causal relationships with brain structure, which may contribute to the alteration of brain IDPs in AD.

Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for sarcopenia.

BACKGROUND: There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets. METHODS: We integrated druggable genome data, cis-eQTL/cis-pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia-related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for target genes using available databases. RESULTS: MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA-DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up-regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007-0.018, P = 1.2*10-5) and higher grip strength (OR: 0.96, 95% CI: 0.94-0.98, P = 4.2*10-5)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21-0.26, P = 1.8*10-94), higher grip strength (OR: 0.82, 95% CI: 0.75-0.90, P = 2.1*10-5), and faster walking pace (beta: 0.03, 95% CI: 0.02-0.05, P = 8.5*10-6)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06-0.11, P = 6.1*10-13; blood pQTL, beta: 0.05, 95% CI: 0.03-0.07, P = 3.8*10-09)], as well as the down-regulation of HLA-DRA [lower ALM (beta: -0.09, 95% CI: -0.11 to -0.08, P = 5.4*10-36) and lower grip strength (OR: 1.13, 95% CI: 1.07-1.20, P = 1.8*10-5)] and COL15A1 [higher ALM (muscle eQTL, beta: -0.07, 95% CI: -0.10 to -0.04, P = 3.4*10-07; blood pQTL, beta: -0.05, 95% CI: -0.06 to -0.03, P = 1.6*10-07)], decreased the risk of sarcopenia. AURKA in blood (beta: -0.16, 95% CI: -0.22 to -0.09, P = 2.1*10-06) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10-05) tissues showed an inverse relationship with sarcopenia risk. The Phe-MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively. CONCLUSIONS: Our research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA-DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation.

Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction.

Novel CHCHD2 mutations causing C-terminal truncation and interrupted CHCHD2 protein stability in Parkinson's disease (PD) patients were previously found. However, there is limited understanding of the underlying mechanism and impact of subsequent CHCHD2 loss-of-function on PD pathogenesis. The current study further identified the crucial motif (aa125-133) responsible for diminished CHCHD2 expression and the molecular interplay within the C1QBP/CHCHD2/CHCHD10 complex to regulate mitochondrial functions. Specifically, CHCHD2 deficiency led to decreased neural cell viability and mitochondrial structural and functional impairments, paralleling the upregulation of autophagy under cellular stresses. Meanwhile, as a binding partner of CHCHD2, C1QBP was found to regulate the stability of CHCHD2 and CHCHD10 proteins to maintain the integrity of the C1QBP/CHCHD2/CHCHD10 complex. Moreover, C1QBP-silenced neural cells displayed severe cell death phenotype along with mitochondrial damage that initiated a significant mitophagy process. Taken together, the evidence obtained from our in vitro and in vivo studies emphasized the critical role of CHCHD2 in regulating mitochondria functions via coordination among CHCHD2, CHCHD10, and C1QBP, suggesting the potential mechanism by which CHCHD2 function loss takes part in the progression of neurodegenerative diseases.

TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.

BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization.

Observational studies have faced challenges in identifying replicable causes for amyotrophic lateral sclerosis (ALS). To address this, we employed an unbiased and data-driven approach to discover and explore potential causal exposures using two-sample Mendelian randomization (MR) analyses. In the phenotype discovery stage, we assessed 3948 environmental exposures from the UK Biobank and utilized ALS summary statistics (Europeans, 20,806 cases, 59,804 controls) as the outcome within a phenome-wide MR pipeline. Through a range of sensitivity analyses, two medication traits were identified to be protective for ALS. In the target exploration stage, we further conducted drug target MR analyses using the latest and trans-ethnic summary data on lipid-related traits and ALS (Europeans, 27,205 cases, 110,881 controls; East Asians, 1234 cases, 2850 controls). Our aim was to explore potential causal drug targets through six lipid-modifying effects. These comprehensive analyses revealed significant findings. Specifically, "cholesterol-lowering medication" and "atorvastatin" survived predefined criteria in the phenotype discovery stage and exhibited a protective effect on ALS. Further in the target exploration stage, we demonstrated that the therapeutic effect of APOB through LDL-lowering was associated with reduced ALS liability in Europeans (OR = 0.835, P = 5.61E - 5). Additionally, the therapeutic effect of APOA1 and LDLR through TC-lowering was associated with reduced ALS liability in East Asians (APOA1, OR = 0.859, P = 5.38E - 4; LDLR, OR = 0.910, P = 2.73E - 5). Overall, we propose potential protective effects of cholesterol-lowering drugs or statins on ALS risk from thousands of exposures. Our research also suggests APOB, APOA1, and LDLR as novel therapeutic targets for ALS and supports their potential protective mechanisms may be mediated by LDL-lowering or TC-lowering effects.

Factors influencing cognitive function in patients with Huntington's disease from China: A cross-sectional clinical study.

BACKGROUND AND AIM: Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. Cognitive decline contributes to the loss of daily activity in manifest HD. We aimed to examine the cognition status in a Chinese HD cohort and explore factors influencing the diverse cognitive domains. METHODS: A total of 205 participants were recruited in the study with the assessment by neuropsychological batteries, including the mini-mental state examination (MMSE), Stroop test, symbol digit modalities test (SDMT), trail making test (TMT), verbal fluency test (VFT), and Hopkins verbal learning test-revised, as well as motor and psychiatric assessment. Pearson correlation and multiple linear regression models were applied to investigate the correlation. RESULTS: Only 41.46% of patients had normal global function first come to our center. There was a significantly difference in MMSE, Stroop test, SDMT, TMT, and VFT across each stage of HD patients (p < .05). Apathy of PBA-s was correlated to MMSE, animal VFT and Stroop-interference tests performance. Severity of motor symptoms, functional capacity, age, and age of motor symptom onset were correlated to all neuropsychological scores, whereas education attainment and diagnostic delay were correlated to most neuropsychological scores except TMT. Severity of motor symptoms, functional capacity, and education attainment showed independent predicting effect (p < .05) in diverse cognitive domains. CONCLUSION: Cognitive impairment was very common in Chinese HD patients at the first visit and worse in the patients in advanced phase. The severity of motor symptoms and functional capacity were correlated to the diverse cognitive domains.

Expanding causal genes for Parkinson's disease via multi-omics analysis.

Genome­wide association studies (GWASs) have revealed numerous loci associated with Parkinson's disease (PD). However, some potential causal/risk genes were still not revealed and no etiological therapies are available. To find potential causal genes and explore genetically supported drug targets for PD is urgent. By integrating the expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets from multiple tissues (blood, cerebrospinal fluid (CSF) and brain) and PD GWAS summary statistics, a pipeline combing Mendelian randomization (MR), Steiger filtering analysis, Bayesian colocalization, fine mapping, Protein-protein network and enrichment analysis were applied to identify potential causal genes for PD. As a result, GPNMB displayed a robust causal role for PD at the protein level in the blood, CSF and brain, and transcriptional level in the brain, while the protective role of CD38 (in brain pQTL and eQTL) was also identified. We also found inconsistent roles of DGKQ on PD between protein and mRNA levels. Another 9 proteins (CTSB, ARSA, SEC23IP, CD84, ENTPD1, FCGR2B, BAG3, SNCA, FCGR2A) were associated with the risk for PD based on only a single pQTL after multiple corrections. We also identified some proteins' interactions with known PD causative genes and therapeutic targets. In conclusion, this study suggested GPNMB, CD38, and DGKQ may act in the pathogenesis of PD, but whether the other proteins involved in PD needs more evidence. These findings would help to uncover the genes underlying PD and prioritize targets for future therapeutic interventions.

Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. Currently, there are no effective disease-modifying treatments for AD. Mendelian randomisation (MR) has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for AD and analyse their pathophysiological mechanisms and potential side effects. METHODS: A two-sample MR integrating the identified druggable genes was performed to estimate the causal effects of blood and brain druggable expression quantitative trait loci (eQTLs) on AD. A repeat study was conducted using different blood and brain eQTL data sources to validate the identified genes. Using AD markers with available genome-wide association studies data, we evaluated the causal relationship between established AD markers to explore possible mechanisms. Finally, the potential side effects of the druggable genes for AD treatment were assessed using a phenome-wide MR. RESULTS: Overall, 5883 unique druggable genes were aggregated; 33 unique potential druggable genes for AD were identified in at least one dataset (brain or blood), and 5 were validated in a different dataset. Among them, three prior druggable genes (epoxide hydrolase 2 (EPHX2), SERPINB1 and SIGLEC11) reached significant levels in both blood and brain tissues. EPHX2 may mediate the pathogenesis of AD by affecting the entire hippocampal volume. Further phenome-wide MR analysis revealed no potential side effects of treatments targeting EPHX2, SERPINB1 or SIGLEC11. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting the three druggable genes for AD treatment, which will be useful for prioritising AD drug development.

Identifying novel genes for amyotrophic lateral sclerosis by integrating human brain proteomes with genome-wide association data.

BACKGROUND: Genome-Wide Association Studies (GWAS) have identified numerous risk genes for Amyotrophic Lateral Sclerosis (ALS); however, the mechanisms by which these loci confer ALS risk are uncertain. This study aims to identify novel causal proteins in the brains of patients with ALS using an integrative analytical pipeline. METHODS: Using the datasets of Protein Quantitative Trait Loci (pQTL) (NpQTL1 = 376, NpQTL2 = 152), expression QTL (eQTL) (N = 452), and the largest ALS GWAS (NALS=27,205, NControls = 110,881), we performed a systematic analytical pipeline including Proteome-Wide Association Study (PWAS), Mendelian Randomization (MR), Bayesian colocalization, and Transcriptome-Wide Association Study (TWAS) to identify novel causal proteins for ALS in the brain. RESULTS: Using PWAS, we found that the altered protein abundance of 12 genes in the brain was associated with ALS. Three genes (SCFD1, SARM1 and CAMLG) were identified as lead causal genes for ALS with solid evidence (False discovery rate < 0.05, in MR analysis; PPH4 > 80% for Bayesian colocalization). Specifically, an increased abundance of SCFD1 and CAMLG led to an increased risk of ALS, whereas a higher abundance of SARM1 led to a decreased risk of developing ALS. TWAS showed that SCFD1 and CAMLG were related to ALS at the transcriptional level. CONCLUSIONS: SCFD1, CAMLG, and SARM1 exhibited robust associations and causality with ALS. The study findings provide novel clues for identifying potential therapeutic targets in ALS. Further studies are required to explore the mechanisms underlying the identified genes.

Risk factors of amyotrophic lateral sclerosis: a global meta-summary.

Background: The etiology of amyotrophic lateral sclerosis (ALS) remains largely unknown. This study aimed to summarize the relationship between ALS and its genetic and non-genetic risk factors. Method: A search of relevant literature from PubMed, Embase, and Cochrane Database from inception to December 2022 was performed. Random-effects or fixed-effects models were performed by Stata MP 15.0 to pool multivariate or adjusted ratios (OR). PROSPERO registration number: CRD42022301549. Results: 230 eligible studies were included, of which 67 involved 22 non-genetic factors, and 163 involved genetic factors. Four aspects of non-genetic factors, including lifestyle, environmental and occupational exposures, pre-existing diseases/comorbidity and medical exposures, and others, were analyzed. Exposure to heavy metals (OR = 1.79), pesticides (OR = 1.46), solvents (OR = 1.37), previous head trauma (OR = 1.37), military service (OR = 1.29), stroke (OR = 1.26), magnetic field (OR = 1.22) and hypertension (OR = 1.04) are significant risk factors, but use of antidiabetics (OR = 0.52), high BMI (OR = 0.60 for obese and overweight vs. normal and underweight), living in urban (OR = 0.70), diabetes mellitus (OR = 0.83), and kidney disease (OR = 0.84) decrease the risk for ALS. In addition, eight common ALS-related genes were evaluated, the mutation frequencies of these genes were ranked from highest to lowest as SOD1 (2.2%), C9orf72 (2.1%), ATXN2 (1.7%), FUS (1.7%), TARDBP (0.8%), VCP (0.6%), UBQLN2(0.6%) and SQSTM1 (0.6%) in all the ALS patients. Conclusions: Our findings suggested that effective intervention for risk exposure and timely modification of lifestyle might prevent the occurrence of ALS. Genetic mutations are important risk factors for ALS and it is essential to detect genetic mutations correctly and scientifically. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=301549, identifier: CRD42022301549.

Protective effect of antihypertensive drugs on the risk of Parkinson's disease lacks causal evidence from mendelian randomization.

Background: Evidence from observational studies concerning the causal role of blood pressure (BP) and antihypertensive medications (AHM) on Parkinson's disease (PD) remains inconclusive. A two-sample Mendelian randomization (MR) study was performed to evaluate the unconfounded association of genetic proxies for BP and first-line AHMs with PD. Methods: Instrumental variables (IV) from the genome-wide association study (GWAS) for BP traits were used to proxy systolic BP (SBP), diastolic BP, and pulse pressure. SBP-associated variants either located within encoding regions or associated with the expression of AHM targets were selected and then scaled to proxy therapeutic inhibition of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, calcium channel blockers, and thiazides. Positive control analyses on coronary heart disease (CHD) and stroke were conducted to validate the IV selection. Summary data from GWAS for PD risk and PD age at onset (AAO) were used as outcomes. Results: In positive control analyses, genetically determined BP traits and AHMs closely mimicked the observed causal effect on CHD and stroke, confirming the validity of IV selection methodology. In primary analyses, although genetic proxies identified by "encoding region-based method" for ß-blockers were suggestively associated with a delayed PD AAO (Beta: 0.115; 95% CI: 0.021, 0.208; p = 1.63E-2; per 10-mmHg lower), sensitivity analyses failed to support this association. Additionally, MR analyses found little evidence that genetically predicted BP traits, overall AHM, or other AHMs affected PD risk or AAO. Conclusion: Our data suggest that BP and commonly prescribed AHMs may not have a prominent role in PD etiology.

Signature of miRNAs derived from the circulating exosomes of patients with amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder (NDS) with unclear pathophysiology and few therapeutic options. Mutations in SOD1 and C9orf72 are the most common in Asian and Caucasian patients with ALS, respectively. Aberrant (microRNAs) miRNAs found in patients with gene-mutated ALS may be involved in the pathogenesis of gene-specific ALS and sporadic ALS (SALS). The aim of this study was to screen for differentially expressed miRNAs from exosomes in patients with ALS and healthy controls (HCs) and to construct a miRNA-based diagnostic model to classify patients and HCs. Methods: We compared circulating exosome-derived miRNAs of patients with ALS and HCs using the following two cohorts: a discovery cohort (three patients with SOD1-mutated ALS, three patients with C9orf72-mutated ALS, and three HCs) analyzed by microarray and a validation cohort (16 patients with gene-mutated ALS, 65 patients with SALS, and 61 HCs) confirmed by RT-qPCR. The support vector machine (SVM) model was used to help diagnose ALS using five differentially expressed miRNAs between SALS and HCs. Results: A total of 64 differentially expressed miRNAs in patients with SOD1-mutated ALS and 128 differentially expressed miRNAs in patients with C9orf72-mutated ALS were obtained by microarray compared to HCs. Of these, 11 overlapping dysregulated miRNAs were identified in both groups. Among the 14 top-hit candidate miRNAs validated by RT-qPCR, hsa-miR-34a-3p was specifically downregulated in patients with SOD1-mutated ALS, while hsa-miR-1306-3p was downregulated in ALS patients with both SOD1 and C9orf72 mutations. In addition, hsa-miR-199a-3p and hsa-miR-30b-5p were upregulated significantly in patients with SALS, while hsa-miR-501-3p, hsa-miR-103a-2-5p, and hsa-miR-181d-5p had a trend to be upregulated. The SVM diagnostic model used five miRNAs as features to distinguish ALS from HCs in our cohort with an area under receiver operating characteristic curve (AUC) of 0.80. Conclusion: Our study identified aberrant miRNAs from exosomes of SALS and ALS patients with SOD1/C9orf72 mutations and provided additional evidence that aberrant miRNAs were involved in the pathogenesis of ALS regardless of the presence or absence of the gene mutation. The machine learning algorithm had high accuracy in predicting the diagnosis of ALS, shedding light on the foundation for the clinical application of blood tests in the diagnosis of ALS, and revealing the pathological mechanisms of the disease.

MiR-30e-3p inhibits gastric cancer development by negatively regulating THO complex 2 and PI3K/AKT/mTOR signaling.

BACKGROUND: Gastric cancer (GC) is a common type of digestive cancer with high morbidity and mortality rates worldwide. Considerable effort has been expended in understanding the mechanism of GC development and metastasis. The current study therefore explores the involvement of microRNAs in the regulation of GC progression. AIM: To explore the expression and function of miR-30e-3p in GC development. METHODS: MiR-30e-3p was found to be downregulated in GC, with low levels thereof predicting poor outcomes among patients with GC. Functionally, we revealed that miR-30e-3p suppressed cell growth and metastatic behaviors of GC cells. Bioinformatics analysis predicted that THO complex 2 (THOC2) was a direct target of miR-30e-3p, and the interaction between miR-30e-3p and THOC2 was further validated by a luciferase reporter assay. RESULTS: Our findings revealed that knockdown of THOC2 inhibited the growth and metastatic behaviors of GC cells. After investigating signaling pathways involved in miR-30e-3p regulation, we found that the miR-30e-3p/THOC2 axis regulated the PI3K/AKT/mTOR pathway in GC. CONCLUSION: Our findings suggest the novel functional axis miR-30e-3p/THOC2 is involved in GC development and progression. The miR-30e-3p/THOC2 axis could be utilized to develop new therapies against GC.

LncRNA GAS5 Suppresses Colorectal Cancer Progress by Target miR-21/LIFR Axis.

GAS5 is abnormally high in colorectal cancer tissues, which is a specific expression of lncRNA in colorectal cancer (CRC). Nevertheless, its biological function in CRC has not been elucidated. The abnormal high expression of GAS5 in CRC is the specific expression of lncRNA in CRC. The purpose of our study is to explore the effect of GAS5 on CRC and its mechanism. The expression of GAS5 in 53 paired normal and colorectal cancer tissues and colorectal cancer cell lines was detected by real-time PCR. The biological effects of GAS5, miR-21, and LIFR were measured by functional assays, including wound healing, transwell assays, and in vivo assays. We ensured the carcinogenesis role of GAS5 in CRC in the xenograft nude model. The dual-luciferase reporter assay system and chromatin immunoprecipitation method were used for target evaluation and Western blot for verification. GAS5 was significantly decreased in tumor tissues and CRC cells, and the low expression of CAS5 in CRC promoted tumor metastasis and decreased the survival of patients. GAS5 knockdown increases the cell viability, inhibits apoptosis, and promotes migration. Xenografted tumors in nude mice studies showed that GAS5 knockdown promoted tumor growth and caused worse lesions in colorectal. Furthermore, GAS5 increases the expression level of target gene LIFR to promote the apoptosis of CRC cells by binding to miR-21. Our study revealed that a novel pathway about lncRNA GAS5 inhibited the proliferation and metastasis of CRC cells by targeting miR-21/LIFR which provides a new strategy to treat CRC.

Production of a human iPSC line from an early-onset Parkinson's disease patient with a novel CHCHD2 gene truncated mutation.

CHCHD2 mutations have been reported to cause Parkinson's disease (PD) by a loss of function in mitochondria. Most reported mutations, however, were missense, which was not the perfect model for a study of haploinsufficiency. Here, a truncated mutation, CHCHD2 p.Pro53Alafs*38, was identified in one familial early-onset PD patient. We generated a human-induced pluripotent stem cell (iPSC) line WCHSCUi001-A from this patient. The generated iPSCs resembled human embryonic stem cells, expressed pluripotency markers, exhibited a normal karyotype and could be differentiated into three germ layers in vitro. This line will be valuable for investigating the disease mechanisms and screening candidate drugs.

The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson's disease in ethnic Chinese.

BACKGROUND AND PURPOSE: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese. METHODS: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. RESULTS: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. CONCLUSIONS: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.

Genetic factors for survival in amyotrophic lateral sclerosis: an integrated approach combining a systematic review, pairwise and network meta-analysis.

BACKGROUND: The time of survival in patients with amyotrophic lateral sclerosis (ALS) varies greatly, and the genetic factors that contribute to the survival of ALS are not well studied. There is a lack of a comprehensive study to elucidate the role of genetic factors in the survival of ALS. METHODS: The published studies were systematically searched and obtained from PubMed, EMBASE, and the Cochrane Library without any language restrictions from inception to Oct 27, 2021. A network meta-analysis for ALS causative/risk genes and a systematic review and pairwise meta-analysis for other genetic modifiers were conducted. The PROSPERO registration number: CRD42022311646. RESULTS: A total of 29,764 potentially relevant references were identified, and 71 papers were eligible for analysis based on pre-decided criteria, including 35 articles in network meta-analysis for 9 ALS causative/risk genes, 17 articles in pairwise meta-analysis for four genetic modifiers, and 19 articles described in the systematic review. Variants in three genes, including ATXN2 (HR: 3.6), C9orf72 (HR: 1.6), and FUS (HR:1.8), were associated with short survival of ALS, but such association was not identified in SOD1, TARDBP, TBK1, NEK1, UBQLN2, and CCNF. In addition, UNC13A rs12608932 CC genotype and ZNF521B rs2275294 C allele also caused a shorter survival of ALS; however, APOE ε4 allele and KIFAP3 rs1541160 did not be found to have any effect on the survival of ALS. CONCLUSIONS: Our study summarized and contrasted evidence for prognostic genetic factors in ALS and would help to understand ALS pathogenesis and guide clinical trials and drug development.

Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.