Mendelian randomization evidence based on European ancestry for the causal effects of leukocyte telomere length on prostate cancer.

BACKGROUND: Several lines of evidence suggest that leukocyte telomere length (LTL) can affect the development of prostate cancer (PC). METHODS: Here, we employed single nucleoside polymorphisms (SNPs) as instrumental variables (IVs) for LTL (n = 472,174) and conducted Mendelian randomization analysis to estimate their causal impact on PCs (79,148 patients/61,106 controls and 6311 patients/88,902 controls). RESULTS: Every 1-s.d extension of LTL increased the risk of PCs by 34%. Additionally, the analysis of candidate mediators between LTL and PCs via two-step Mendelian randomization revealed that among the 23 candidates, Alzheimer's disease, liver iron content, sex hormone binding global levels, naive CD4-CD8-T cell% T cell, and circulating leptin levels played substantial mediating roles. There is no robust evidence to support the reverse causal relationship between LTL and the selected mediators of PCs. Adjusting for the former four mediators, rather than adjusting for circulating leptin levels, decreased the impact of LTL on PCs. CONCLUSION: This study provides potential intervention measures for preventing LTL-induced PCs.

Comprehensive analysis of T-cell regulatory factors and tumor immune microenvironment in stomach adenocarcinoma.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide and is associated with high morbidity and mortality rates. However, the specific biomarkers used to predict the postoperative prognosis of patients with gastric cancer remain unknown. Recent research has shown that the tumor microenvironment (TME) has an increasingly positive effect on anti-tumor activity. This study aims to build signatures to study the effect of certain genes on gastric cancer. METHODS: Expression profiles of 37 T cell-related genes and their TME characteristics were comprehensively analyzed. A risk signature was constructed and validated based on the screened T cell-related genes, and the roles of hub genes in GC were experimentally validated. RESULTS: A novel T cell-related gene signature was constructed based on CD5, ABCA8, SERPINE2, ESM1, SERPINA5, and NMU. The high-risk group indicated lower overall survival (OS), poorer immune efficacy, and higher drug resistance, with SERPINE2 promoting GC cell proliferation, according to experiments. SERPINE2 and CXCL12 were significantly correlated, indicating poor OS via the Youjiang cohort. CONCLUSIONS: This study identified T cell-related genes in patients with stomach adenocarcinoma (STAD) for prognosis estimation and proposed potential immunotherapeutic targets for STAD.

Effects of exogenous steroid hormones on growth, body color, and gonadal development in the Opsariichthys bidens.

To investigate the effects of exogenous steroid hormones on growth, body color, and gonadal development in the Opsariichthys bidens (O. bidens), synthetic methyltestosterone (MT) and 17ß-estradiol (E2) were used for 28 days' treatment of 4-month-old O. bidens before the breeding season. Our results suggested that MT had a significant growth-promoting effect (P < 0.05), whereas E2 played an inhibitory role. On the body surface, the females in the MT group showed gray stripes, and the fish in other groups showed no obvious stripes. The males with MT treatment displayed brighter blue-green stripes compared to the CK and E2 groups. The histological analysis showed that the MT significantly promoted testes development in males, blocked oocyte development, and caused massive apoptosis in females, whereas the E2 group promoted ovarian development and inhibited testes development. Based on qRT-PCR analysis, in females, the expression of igf-1, dmrt1, and cyp19a1a genes revealed that E2 treatment resulted in down-regulation of igf-1 expression and up-regulation of cyp19a1a expression. In males, igf-1 and dmrt1 were significantly up-regulated after MT treatment, and E2 treatment led to down-regulation of igf-1. Therefore, this study demonstrates that MT and E2 play an important role in reversing the morphological sex characteristics of females and males.

Application of three-dimensional reconstruction technology in dentistry: a narrative review.

BACKGROUND: Three-dimensional(3D) reconstruction technology is a method of transforming real goals into mathematical models consistent with computer logic expressions and has been widely used in dentistry, but the lack of review and summary leads to confusion and misinterpretation of information. The purpose of this review is to provide the first comprehensive link and scientific analysis of 3D reconstruction technology and dentistry to bridge the information bias between these two disciplines. METHODS: The IEEE Xplore and PubMed databases were used for rigorous searches based on specific inclusion and exclusion criteria, supplemented by Google Academic as a complementary tool to retrieve all literature up to February 2023. We conducted a narrative review focusing on the empirical findings of the application of 3D reconstruction technology to dentistry. RESULTS: We classify the technologies applied to dentistry according to their principles and summarize the different characteristics of each category, as well as the different application scenarios determined by these characteristics of each technique. In addition, we indicate their development prospects and worthy research directions in the field of dentistry, from individual techniques to the overall discipline of 3D reconstruction technology, respectively. CONCLUSIONS: Researchers and clinicians should make different decisions on the choice of 3D reconstruction technology based on different objectives. The main trend in the future development of 3D reconstruction technology is the joint application of technology.

Association between gut microbiome and intracerebral hemorrhage based on genome-wide association study data. / 基于GWASæ•°æ®åˆ†æžè‚ é“èŒç¾¤ä¸Žè„‘å‡ºè¡€çš„å ³ç³».

OBJECTIVES: Intracerebral hemorrhage (ICH) has the highest mortality and disability rates among various subtypes of stroke. Previous studies have shown that the gut microbiome (GM) is closely related to the risk factors and pathological basis of ICH. This study aims to explore the causal effect of GM on ICH and the potential mechanisms. METHODS: Genome wide association study (GWAS) data on GM and ICH were obtained from Microbiome Genome and International Stroke Genetics Consortium. Based on the GWAS data, we first performed Mendelian randomization (MR) analysis to evaluate the causal association between GM and ICH. Then, a conditional false discovery rate (cFDR) method was conducted to identify the pleiotropic variants. RESULTS: MR analysis showed that Pasteurellales, Pasteurellaceae, and Haemophilus were negatively correlated with the risk of ICH, whileVerrucomicrobiae, Verrucomicrobiales, Verrucomicrobiaceae, Akkermansia, Holdemanella, and LachnospiraceaeUCG010 were positively correlated with ICH. By applying the cFDR method, 3 pleiotropic loci (rs331083, rs4315115, and rs12553325) were found to be associated with both GM and ICH. CONCLUSIONS: There is a causal association and pleiotropic variants between GM and ICH.

A bioinformatic analysis study of m7G regulator-mediated methylation modification patterns and tumor microenvironment infiltration in glioblastoma.

BACKGROUND: Glioblastoma is one of the most common brain cancers in adults, and is characterized by recurrence and little curative effect. An effective treatment for glioblastoma patients remains elusive worldwide. 7-methylguanosine (m7G) is a common RNA modification, and its role in tumors has become a research hotspot. METHODS: By searching for differentially expressed genes related to m7G, we generated a prognostic signature via cluster analysis and established classification criteria of high and low risk scores. The effectiveness of classification was validated using the Non-negative matrix factorization (NMF) algorithm, and repeatedly verified using training and test groups. The dimension reduction method was used to clearly show the difference and clinical significance of the data. All analyses were performed via R (version 4.1.2). RESULTS: According to the signature that included four genes (TMOD2, CACNG2, PLOD3, and TMSB10), glioblastoma patients were divided into high and low risk score groups. The survival rates between the two groups were significantly different, and the predictive abilities for 1-, 3-, and 5-year survivals were effective. We further established a Nomogram model to further examine the signature,as well as other clinical factors, with remaining significant results. Our signature can act as an independent prognostic factor related to immune-related processes in glioblastoma. CONCLUSIONS: Our research addresses the gap in knowledge in the m7G and glioblastoma research fields. The establishment of a prognostic signature and the extended analysis of the tumor microenvironment, immune correlation, and tumor mutation burden further suggest the important role of m7G in the development and development of this disease. This work will provide support for future research.

Mapping the Minnesota Living with Heart Failure Questionnaire (MLHFQ) to SF-6Dv2 in Chinese patients with heart failure.

PURPOSE: Mapping the Minnesota Living with Heart Failure Questionnaire (MLHFQ) to SF-6Dv2 in Chinese patients with chronic heart failure, and to obtain the health utility value for health economic assessment. METHODS: Four statistical algorithms, including ordinary least square method (OLS), Tobit model, robust MM estimator (MM) and censored least absolute deviations (CLAD), were used to establish the alternative model. Models were validated by using a tenfold cross-validation technique. The mean absolute error (MAE) and root mean square error (RMSE) were used to evaluate the prediction performance of the model. The Spearman correlation coefficient and Intraclass Correlation Coefficients (ICC) were used to examine the relationship between the predicted and observed SF-6Dv2 values. RESULTS: A total of 195 patients with chronic heart failure were recruited from 3 general hospitals in Beijing. The MLHFQ summary score and domain scores of the study sample were negatively correlated with SF-6Dv2 health utility value. The OLS regression model established based on the MLHFQ domain scores was the optimal fitting model and the predicted value was highly positively correlated with the observed value. CONCLUSION: The MLHFQ can be mapped to SF-6Dv2 by OLS, which can be used for health economic assessment of cardiovascular diseases such as chronic heart failure.

Additive interaction between potentially modifiable risk factors and ethnicity among individuals in the Han, Tujia and Miao populations with first-ever ischaemic stroke.

BACKGROUND: As a country with one-fifth of the global population, China has experienced explosive growth in ischaemic stroke (IS) burden with significant ethnic and geographic disparities. The aim of this study was to examine the differences in potentially modifiable risk factors for ischaemic stroke among the Han population and two ethnic minorities (Tujia and Miao). METHODS: A case-control study was conducted with 324 cases of first-ever ischaemic stroke from the hospitals of the Xiangxi Tujia and Miao Autonomous Prefecture and 394 controls from communities covering the same area between May 1, 2018, and April 30, 2019. Structured questionnaires were administered, and physical examinations were performed in the same manner for cases and controls. Univariate and multivariate logistic regression analyses with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were used to examine the association between risk factors and ischaemic stroke. An additive model was used to study the interaction between the modifiable risk factors and ethnicity with R software. RESULTS: Higher high-sensitivity C-reactive protein levels (OR 50.54, 95%CI 29.76-85.85), higher monthly family income (4.18, 2.40-7.28), increased frequency of hot pot consumption (2.90, 1.21-6.93), diabetes mellitus (2.62, 1.48-4.62), a higher apolipoprotein (Apo)B/ApoA1 ratio (2.60, 1.39-4.85), hypertension (2.52, 1.45-4.40) and moderate-intensity physical activity (0.50, 0.28-0.89) were associated with ischaemic stroke. There was an additive interaction between the ApoB/ApoA1 ratio and ethnicity in the Tujia and Miao populations with first-ever ischaemic stroke (the relative excess risk due to the interaction was 5.75, 95% CI 0.58 ~ 10.92; the attributable proportion due to the interaction was 0.65, 95% CI 0.38 ~ 0.91; the synergy index was 3.66, 95% CI 1.35 ~ 9.93). CONCLUSIONS: This is the first case-control study examining modifiable risk factors for ischaemic stroke among the Han population and two ethnic minorities (Tujia and Miao) in China. Some differences were observed in the impact of risk factors among these ethnic groups. Our results may help interpret health-related data, including surveillance and research, when developing strategies for stroke prevention.

Source apportionment of PM2.5 and visibility in Jinan, China.

Atmospheric extinction is impacted by the chemical composition of particles. To better understand the chemical composition of PM2.5 (particles with diameters of less than 2.5 µm) and its relationship with extinction, one-month sampling campaigns were carried out in four different seasons from 2013 to 2014 in Jinan, China. The seasonal average concentrations of PM2.5 were 120.9 (autumn), 156.6 (winter), 102.5 (spring), and 111.8 µg/m3 (summer). The reconstructed PM2.5 chemical composition showed that sulfate, nitrate, chlorine salt, organic matter (OM), mineral dust, elemental carbon (EC) and others accounted for 25%, 14%, 2%, 24%, 22%, 3% and 10%, respectively. The relationship between the chemical composition of PM2.5 and visibility was reconstructed by the IMPROVE method, and ammonium sulfate, ammonium nitrate, OM and EC dominated the visibility. Seven main sources were resolved for PM2.5, including secondary particles, coal combustion, biomass burning, industry, motor vehicle exhaust, soil dust and cooking, which accounted for 37%, 21%, 13%, 13%, 12%, 3% and 1%, respectively. The contributions of different sources to visibility were similar to those to PM2.5. With increasing severity of air pollution, the contributions of secondary particles and coal combustion increased, while the contribution of motor vehicle exhaust decreased. The results showed that coal combustion and biomass burning were still the main sources of air pollution in Jinan.

Identification of novel functional CpG-SNPs associated with type 2 diabetes and coronary artery disease.

Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) and coronary artery disease (CAD), respectively. Nevertheless, these studies were generally performed for single-trait/disease and failed to assess the pleiotropic role of the identified variants. To identify novel functional loci and the pleiotropic relationship between CAD and T2D, the targeted cFDR analysis on CpG-SNPs was performed by integrating two independent large and multi-centered GWASs with summary statistics of T2D (26,676 cases and 132,532 controls) and CAD (60,801 cases and 123,504 controls). Applying the cFDR significance threshold of 0.05, we observed a pleiotropic enrichment between T2D and CAD by incorporating pleiotropic effects into a conditional analysis framework. We identified 79 novel CpG-SNPs for T2D, 61 novel CpG-SNPs for CAD, and 18 novel pleiotropic loci for both traits. Among these novel CpG-SNPs, 33 of them were annotated as methylation quantitative trait locus (meQTL) in whole blood, and ten of them showed expression QTL (eQTL), meQTL, and metabolic QTL (metaQTL) effects simultaneously. To the best of our knowledge, we performed the first targeted cFDR analysis on CpG-SNPs, and our findings provided novel insights into the shared biological mechanisms and overlapped genetic heritability between T2D and CAD.

Exposure to firework chemicals from production factories in pregnant women and risk of preterm birth occurrence in Liuyang, China.

In the production of fireworks, various pollutants including particles of metals and organic compounds are released into the environment. Although the adverse effects of these air pollutants are known, the impact on pregnant women residing in this area remains to be determined. The aim of this study was to examine the association between maternal exposure to fireworks production chemicals and frequency of preterm birth in Liuyang, China. Maternal exposure to fireworks production was estimated at the residential district level and assessed using factory density, which was defined as the number of fireworks factories per 1000 residents in each district. The association of maternal exposure to particulates released from fireworks production plants with frequency of preterm birth was determined using data obtained from a cohort study conducted in Liuyang, China. Data were analyzed utilizing linear regression and logistic regression. There was no significant association between factory density and spontaneous preterm or medically induced preterm birth. Unexpectedly, pregnant women residing in areas with higher density of fireworks factories were at a reduced risk of preterm premature rupture of membranes (PPROM). Data demonstrated that residential density of fireworks factories appeared to be negatively correlated with preterm birth rate as evidenced by PPROM. At present, it is difficult to reconcile the inverse relationship between firework chemical exposure and frequency of preterm births as ambient particulate inhalation is known to adversely affect preterm birth occurrence.

Spatio-temporal clustering analysis and its determinants of hand, foot and mouth disease in Hunan, China, 2009-2015.

BACKGROUND: Hand, foot and mouth disease (HFMD) is one of the highest reported infectious diseases with several outbreaks across the world. This study aimed at describing epidemiological characteristics, investigating spatio-temporal clustering changes, and identifying determinant factors in different clustering areas of HFMD. METHODS: Descriptive statistics was used to evaluate the epidemic characteristics of HFMD from 2009 to 2015. Spatial autocorrelation and spatio-temporal cluster analysis were used to explore the spatial temporal patterns. An autologistic regression model was employed to explore determinants of HFMD clustering. RESULTS: The incidence rates of HFMD ranged from 54.31/10 million to 318.06/10 million between 2009 and 2015 in Hunan. Cases were mainly prevalent in children aged 5 years and even younger, with an average male-to-female sex ratio of 1.66, and two epidemic periods in each year. Clustering areas gathered in the northern regions in 2009 and in the central regions from 2010 to 2012. They moved to central-southern regions in 2013 and 2014 and central-western regions in 2015. The significant risk factors of HFMD clusters were rainfall (OR = 2.187), temperature (OR = 4.329) and humidity (OR = 2.070). The protect factor was wind speed (OR = 0.258). CONCLUSIONS: The HFMD incidence from 2009 to 2015 in Hunan showed a new spatiotemporal clustering tendency, with the shifting trend of clustering areas toward south and west. Meteorological factors showed a strong association with HFMD clustering, which may assist in predicting future spatial-temporal clusters.

[Epidemiological situation and temporal-spatial clustering changes of hand-foot-mouth disease from 2009 to 2015 in Hunan].

OBJECTIVE: To investigate the epidemiological situation and temporal-spatial clustering changes of hand-foot-mouth disease (HFMD) in Hunan.
 METHODS: Spatial autocorrelation and temporal-spatial clustering analysis were used to analyze the HFMD in Hunan.
 RESULTS: The incidence rates of HFMD ranged from 54.31/10 million to 318.06/10 million between 2009 and 2015 in Hunan. Cases mainly displayed in 5-year-old or even younger children and there were two epidemic periods each year. HFMD cases did not show a random distribution but with significant spatial aggregation. When local autocorrelation analysis was applied at the county/district level, 4 hot spots in Changsha, Yiyang, Loudi and Zhuzhou were discovered. The tendency for temporal and spatial clustering existed among HFMD cases in Hunan. The temporal dimension of HFMD was from April to July annually. Clustering areas gathered in the northern regions in 2009 and in the middle regions from 2010 to 2012. They moved to middle-southern regions in 2013 or 2014 and middle-western regions in 2015. 
 CONCLUSION: The HFMD incidence from 2009 to 2015 in Hunan showed temporal and spatial clustering tendency, with the shifting trend of clustered areas toward south and west.

[Characteristics of HIV's sexual behavior and their effect on the secondary transmission rate].

OBJECTIVE: To analyze the sexual behavior characteristics of the sexually transmitted HIV-positive people and to estimate the secondary transmission rate.
 METHODS: Field investigation and literature review were conducted among sexually transmitted HIV-positive people to collect general information during the last 6 months before notification of HIV infection. A mathematical model was used to estimate the secondary transmission rate.
 RESULTS: A total of 769 HIV-positive people were recruited for the study, 186 of them were women, 286 were men who have sex with women (MSW), 242 were men who have sex with men (MSM) and 55 were men who have sex with men and women (MSMW). During 6 months, the average sex partner among these 4 groups were 2.29, 1.61, 3.32 and 4.10, respectively; the sexual behavior frequency were 26.03, 20.97, 14.77 and 25.51, respectively; the rates of non-use of condom were 74.14%, 73.53%, 59.60% and 72.06%, respectively; the secondary transmission rate were 0.0095, 0.0151, 0.1759 and 0.1985, respectively. Under constant conditions of other factors, the secondary transmission rates decreased by 30.13%-82.00%, 23.00%-49.51%, and 16.10%-19.09%, respectively, if there was a reduction in 1 sex partner, 1 time/month for the sexual frequency and 20% of rate for non-use of condom.
 CONCLUSION: The HIV secondary transmission from MSMW HIV-positive people to general population was the highest. Change in sexual behavior of the HIV-positive people can decrease the HIV secondary transmission rate significantly.

Two new spirooxindole alkaloids from rhizosphere strain Streptomyces sp. xzqh-9.

Two new spirooxindole alkaloids spindomycins A (1) and B (2) were isolated from rhizosphere strain Streptomyces sp. xzqh-9. Their structures were elucidated by comprehensive spectroscopic analyses of NMR and MS data. The absolute configurations of 1 and 2 were determined by experimental and theoretical calculation of electronic circular dichroism (ECD). Antitumor, lactate dehydrogenase, and tyrosine kinase inhibitory activities of two compounds were evaluated, while only spindomycin B (2) exhibited weak inhibitory activity against tyrosine kinase Bcr-Abl.

Extracellular vesicles related gene HSPH1 exerts anti-tumor effects in prostate cancer via promoting the stress response of CD8 + T cells.

BACKGROUND: T cell stress response state (TSTR), as a novel immune concept previous studies have proposed, has not yet been explored in prostate cancer (PC). As a type of cellular efflux, exosomes play important roles in the occurrence and development of PC. METHOD: Here, we conducted a combined analysis on extracellular vesicle related genes (EVRGs) in PC using data from single-cell RNA (scRNA), spatial transcriptome (ST), and bulk RNA sequencing. RESULT: Preliminary findings have revealed that heat shock protein family H (Hsp110) member 1 (HSPH1) possesses two identities, one being EVRGs and the other being a member of the heat shock protein family involved in TSTR, which may promote the differentiation of conventional T cells towards Th1 or Th2 cells through the pathway of IL2-MYC-IL2RA, thereby promoting the increase of CD8 + T cells in the tumor area, especially in the invasive zone, and inhibiting the invasion of PCs. We also notice the negative response of HSPH1 + CD8 + T cell related genes in immune checkpoint blockade (ICB). Western blot (WB) and droplet digital Polymerase Chain Reaction (ddPCR) demonstrated that the mRNA and protein levels of HSPH1 in EVs of PCs were significantly higher than those in adjacent tissues. CONCLUSION: Results above indicate the potential of HSPH1 as a critical therapeutic target in PC.

Whole exome sequencing analyses reveal novel genes in telomere length and their biomedical implications.

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.

Identifying High Gleason Score Prostate Cancer by Prostate Fluid Metabolic Fingerprint-Based Multi-Modal Recognition.

Prostate cancer (PCa) is the second most common cancer in males worldwide. The Gleason scoring system, which classifies the pathological growth pattern of cancer, is considered one of the most important prognostic factors for PCa. Compared to indolent PCa, PCa with high Gleason score (h-GS PCa, GS ≥ 8) has greater clinical significance due to its high aggressiveness and poor prognosis. It is crucial to establish a rapid, non-invasive diagnostic modality to decipher patients with h-GS PCa as early as possible. In this study, ferric nanoparticle-assisted laser desorption/ionization mass spectrometry (FeNPALDI-MS) to extract prostate fluid metabolic fingerprint (PSF-MF) is employed and combined with the clinical features of patients, such as prostate-specific antigen (PSA), to establish a multi-modal diagnosis assisted by machine learning. This approach yields an impressive area under the curve (AUC) of 0.87 to diagnose patients with h-GS, surpassing the results of single-modal diagnosis using only PSF-MF or PSA, respectively. Additionally, using various screening methods, six key metabolites that exhibit greater diagnostic efficacy (AUC = 0.96) are identified. These findings also provide insights into related metabolic pathways, which may provide valuable information for further elucidation of the pathological mechanisms underlying h-GS PCa.

Plasma metabolic profiles predict future dementia and dementia subtypes: a prospective analysis of 274,160 participants.

BACKGROUND: Blood-based biomarkers for dementia are gaining attention due to their non-invasive nature and feasibility in regular healthcare settings. Here, we explored the associations between 249 metabolites with all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD) and assessed their predictive potential. METHODS: This study included 274,160 participants from the UK Biobank. Cox proportional hazard models were employed to investigate longitudinal associations between metabolites and dementia. The importance of these metabolites was quantified using machine learning algorithms, and a metabolic risk score (MetRS) was subsequently developed for each dementia type. We further investigated how MetRS stratified the risk of dementia onset and assessed its predictive performance, both alone and in combination with demographic and cognitive predictors. RESULTS: During a median follow-up of 14.01 years, 5274 participants developed dementia. Of the 249 metabolites examined, 143 were significantly associated with incident ACD, 130 with AD, and 140 with VaD. Among metabolites significantly associated with dementia, lipoprotein lipid concentrations, linoleic acid, sphingomyelin, glucose, and branched-chain amino acids ranked top in importance. Individuals within the top tertile of MetRS faced a significantly greater risk of developing dementia than those in the lowest tertile. When MetRS was combined with demographic and cognitive predictors, the model yielded the area under the receiver operating characteristic curve (AUC) values of 0.857 for ACD, 0.861 for AD, and 0.873 for VaD. CONCLUSIONS: We conducted the largest metabolome investigation of dementia to date, for the first time revealed the metabolite importance ranking, and highlighted the contribution of plasma metabolites for dementia prediction.

Large-scale whole-exome sequencing of neuropsychiatric diseases and traits in 350,770 adults.

While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes.