Associations of liver dysfunction with incident dementia, cognition, and brain structure: A prospective cohort study of 431 699 adults.

The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross-sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow-up were included from the UK Biobank; 5542 all-cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR = 0.010), AST to ALT ratio (HR, 1.195; PFDR <0.001), gamma-glutamyl transpeptidase (GGT; HR, 1.066; PFDR <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U-shaped association between Alb and AST and incident ACD (Pnonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR <0.05). In sensitivity analysis, metabolic dysfunction-associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence.

Lung function and risk of incident dementia: A prospective cohort study of 431,834 individuals.

BACKGROUND: Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms. METHODS: This population-based cohort included 43,1834 non-demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen-carrying indices, metabolites, and brain structures. FINDINGS: During a follow-up of 3,736,181 person-years (mean follow-up 8.65 years), 5,622 participants (1.30 %) developed all-cause dementia, which consisted of 2,511 Alzheimer's dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all-cause dementia (forced expiratory volume in 1 s [liter]: hazard ratio [HR, 95 %CI], 1.24 [1.14-1.34], P = 1.10 × 10-07; forced vital capacity [liter]: 1.16 [1.08-1.24], P = 2.04 × 10-05; peak expiratory flow [liter/min]: 1.0013 [1.0010-1.0017], P = 2.73 × 10-13). Low lung function generated similar hazard estimates for AD and VD risks. As underlying biological mechanisms, systematic inflammatory markers, oxygen-carrying indices, and specific metabolites mediated the effects of lung function on dementia risks. Besides, brain grey and white matter patterns mostly affected in dementia were substantially changed with lung function. INTERPRETATION: Life-course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention.

Sleep, physical activity, sedentary behavior, and risk of incident dementia: a prospective cohort study of 431,924 UK Biobank participants.

Although sleep, physical activity and sedentary behavior have been found to be associated with dementia risk, findings are inconsistent and their joint relationship remains unclear. This study aimed to investigate independent and joint associations of these three modifiable behaviors with dementia risks. A total of 431,924 participants (median follow-up 9.0 years) without dementia from UK Biobank were included. Multiple Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Models fitted with restricted cubic spline were conducted to test for linear and nonlinear shapes of each association. Sleep duration, leisure-time physical activity (LTPA), and screen-based sedentary behavior individually associated with dementia risks in different non-linear patterns. Sleep duration associated with dementia in a U-shape with a nadir at 7 h/day. LTPA revealed a curvilinear relationship with dementia in diminishing tendency, while sedentary behavior revealed a J-shaped relationship. The dementia risk was 17% lower in the high LTPA group (HR[95%CI]: 0.83[0.76-0.91]) and 22% higher in the high sedentary behavior group (1.22[1.10-1.35]) compared to the corresponding low-level group, respectively. A combination of seven-hour/day sleep, moderate-to-high LTPA, and low-to-moderate sedentary behavior showed the lowest dementia risk (0.59[0.50-0.69]) compared to the referent group (longer or shorter sleep/low LTPA/high sedentary behavior). Notably, each behavior was non-linearly associated with brain structures in a pattern similar to its association with dementia, suggesting they may affect dementia risk by affecting brain structures. Our findings highlight the potential to change these three daily behaviors individually and simultaneously to reduce the risk of dementia.

Visible-Light-Induced Tandem Radical Brominative Addition/Cyclization of Activated Alkynes with CBr4 for the Synthesis of 3-Bromocoumarins.

A visible-light-induced tandem radical brominative addition/spiro-cyclization/1,2-ester migration of activated alkynes with CBr4 is developed. This protocol features good functional group tolerance, operational simplicity, and mild reaction conditions without the use of catalysts and external additives, providing easy access to valuable 3-bromocoumarins in generally high yields.

Liver X receptor agonists exert antitumor effects against hepatocellular carcinoma via inducing REPS2 expression.

Recent studies show that liver X receptor (LXR) agonists exert significant antitumor effects in a variety of tumor cell lines including hepatocellular carcinoma (HCC). But the molecular mechanisms underlying LXR antitumor activity are not fully understood. In this study we investigated the effect of LXR agonist T0901317 (T317) on HCC development and its relationship with RalA binding protein 1 (RALBP1)-associated EPS domain containing 2 (REPS2)/epidermal growth factor receptor (EGFR) signaling axis. We showed that T317 (0.1-0.5 µM) dose-dependently increased REPS2 expression in normal hepatocytes (BNLCL.2 and LO2) and HCC cells (HepG2 and Huh-7). Using promoter activity assay and chromatin immunoprecipitation (CHIP) assay we demonstrated that T317 enhanced REPS2 expression at the transcriptional level via promoting the binding of LXR protein to the LXR-response element (LXRE) in the REPS2 promoter region. We showed that the inhibitory effect of T317 on the proliferation and migration of HCC cells was closely related to REPS2. Moreover, we revealed that T317 (400 nM) increased expression of REPS2 in HepG2 cells, thus inhibiting epidermal growth factor (EGF)-mediated endocytosis of EGFR as well as the downstream activation of AKT/NF-κB, p38MAPK, and ERK1/2 signaling pathways. Clinical data analysis revealed that REPS2 expression levels were inversely correlated with the development of HCC and reduced REPS2 expression associated with poor prognosis, suggesting that REPS2 might be involved in the development of HCC. In conclusion, this study provides new insights into the potential mechanisms of LXR agonist-inhibited HCC.

Omics-based biomarkers discovery for Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorders presenting with the pathological hallmarks of amyloid plaques and tau tangles. Over the past few years, great efforts have been made to explore reliable biomarkers of AD. High-throughput omics are a technology driven by multiple levels of unbiased data to detect the complex etiology of AD, and it provides us with new opportunities to better understand the pathophysiology of AD and thereby identify potential biomarkers. Through revealing the interaction networks between different molecular levels, the ultimate goal of multi-omics is to improve the diagnosis and treatment of AD. In this review, based on the current AD pathology and the current status of AD diagnostic biomarkers, we summarize how genomics, transcriptomics, proteomics and metabolomics are all conducing to the discovery of reliable AD biomarkers that could be developed and used in clinical AD management.

Associations of grip strength, walking pace, and the risk of incident dementia: A prospective cohort study of 340212 participants.

INTRODUCTION: Grip strength and walking pace have been linked to cognitive dysfunction. Their relationships, however, demand further clarification as the evidence is derived primarily from less-comprehensive investigations. METHODS: A total of 340212 UK Biobank participants without dementia and cardiovascular diseases at baseline were analyzed. Cox proportional hazard models assessed the longitudinal associations. RESULTS: Over a mean follow-up of 8.51 ± 2.68 years, 2424 incident dementia cases were documented. A 5 kg increment of absolute grip strength was associated with lower risks of all-cause dementia (hazard ratio [HR] 0.857), Alzheimer's disease (HR 0.874), and vascular dementia (HR 0.788). The patterns of associations remained similar when grip strength was expressed in relative terms and quintiles. A slow walking pace demonstrated consistent associations with increased risks of all dementia types. DISCUSSION: Our findings provide amplified evidence and suggest that muscle fitness, reflected by objective grip strength measures and self-reported walking pace, may be imperative for estimating the risks of dementia.

Probiotics-Fermented Grifola frondosa Total Active Components: Better Antioxidation and Microflora Regulation for Alleviating Alcoholic Liver Damage in Mice.

Alcoholic liver damage is caused by long-term drinking, and it further develops into alcoholic liver diseases. In this study, we prepared a probiotic fermentation product of Grifola frondosa total active components (PFGF) by fermentation with Lactobacillus acidophilus, Lactobacillus rhamnosus, and Pediococcus acidilactici. After fermentation, the total sugar and protein content in the PFGF significantly decreased, while the lactic acid level and antioxidant activity of the PFGF increased. Afterward, we investigated the alleviating effect of PFGF on alcoholic liver injury in alcohol-fed mice. The results showed that the PFGF intervention reduced the necrosis of the liver cells, attenuated the inflammation of the liver and intestines, restored the liver function, increased the antioxidant factors of the liver, and maintained the cecum tissue barrier. Additionally, the results of the 16S rRNA sequencing analysis indicated that the PFGF intervention increased the relative abundance of beneficial bacteria, such as Lactobacillus, Ruminococcaceae, Parabacteroids, Parasutterella, and Alistipes, to attenuate intestinal inflammation. These results demonstrate that PFGF can potentially alleviate alcoholic liver damage by restoring the intestinal barrier and regulating the intestinal microflora.

PPh3-Triggered Tandem Synthesis of 2,3-Disubstituted Benzofuran Derivatives from o-Quinone Methides with Acyl Chlorides.

A PPh3-triggered tandem strategy for the efficient synthesis of valuable 2,3-disubstituted benzofuran derivatives in generally good to high yields from aryl or alkyl acyl chlorides and o-quinone methides has been developed. This method features mild reaction conditions, simple operation, and a broad substrate scope.

Muricauda chongwuensis sp. nov., isolated from coastal seawater of China.

In the course of screening for bacterial predators, a Gram-stain-negative, non-flagellated, gliding, long rod-shaped, and yellow-pigmented bacterium, designated strain HICWT, was isolated from coastal seawater of China. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain HICWT represented a member of the genus Muricauda and showed the highest sequence similarity to M. aquimarina JCM11811T (98.8%) and M. ruestringensis DSM13258T (98.1%). The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain HICWT and M. aquimarina JCM11811T were 79.2% and 34.1%, respectively. NaCl was required for growth. Optimum growth occurred at 25-30 °C, 2.0-3.0% (w/v) NaCl with pH 7.0. Strain HICWT showed some similar characteristics to the nonobligate bacterial predators, and the cells can attach to the prey cells. Strain HICWT contained MK-6 as the predominant respiratory quinone and had iso-C15:0, iso-C15:1 G, and iso-C17:0 3-OH as the major cellular fatty acids. The polar lipids contained phosphatidylethanolamine (PE), three unidentified phospholipids (PL1-PL3), one unidentified amino lipids (AL), and three unidentified polar lipids (L1-L3). The genome size of strain HICWT was approximately 3.8 Mbp, with a G + C content of 41.4%. Based on the polyphasic evidence, strain HICWT is proposed as representing a new species of the genus Muricauda, for which the name Muricauda chongwuensis sp. nov. is proposed. The type strain is HICWT (= JCM 33643 T = MCCC 1K03769T).

Advances in the application of mesenchymal stem cells, exosomes, biomimetic materials, and 3D printing in osteoporosis treatment.

Owing to an increase in the aging population, osteoporosis has become a severe public health concern, with a high prevalence among the elderly and postmenopausal adults. Osteoporosis-related fracture is a major cause of morbidity and mortality in elderly and postmenopausal adults, posing a considerable socioeconomic burden. However, existing treatments can only slow down the process of osteoporosis, reduce the risk of fractures, and repair fractures locally. Therefore, emerging methods for treating osteoporosis, such as mesenchymal stem cell transplantation, exosome-driving drug delivery systems, biomimetic materials, and 3D printing technology, have received increasing research attention, with significant progress. Mesenchymal stem cells (MSCs) are pluripotent stem cells that can differentiate into different types of functional cells. Exosomes play a key role in regulating cell microenvironments through paracrine mechanisms. Bionic materials and 3D printed scaffolds are beneficial for the reconstruction and repair of osteoporotic bones and osteoporosis-related fractures. Stem cells, exosomes, and biomimetic materials represent emerging technologies for osteoporosis treatment. This review summarizes the latest developments in these three aspects.

Halobacteriovorax vibrionivorans sp. nov., a novel prokaryotic predator isolated from coastal seawater of China.

Three prokaryotic predator strains, BL9T, BL10 and BL28, were isolated with Vibrio alginolyticus from coastal seawater of PR China. Cells of the strains were Gram-negative, vibrioid-shaped and motile with a single sheathed flagellum (25-28 nm wide). Cells were around 0.3×0.5-1.0 µm in size. The three strains were obligate predators that exhibited a biphasic life cycle: a free-swimming attack phase and an intraperiplasmic growth phase within the prey. Bdelloplasts were formed. NaCl was required for growth. Optimum growth occurred at ~37 °C, with 2-4 % (w/v) NaCl and at pH 7.0-8.0. The results of phylogenetic analyses based on 16S rRNA gene sequences indicated that the three strains shared 99.9 % similarity to each other, were affiliated with the genus Halobacteriovorax in the class Oligoflexia, and represented the same new species. Strain BL9T (=MCCC 1K03527T=JCM 32962T) was designated as the type strain. Genome sequencing of strain BL9T revealed a genome size of 3.14 Mb and a G+C content of 35.8 mol%. The estimated digital DNA-DNA hybridization (dDDH) values and the whole genome average nucleotide identity (gANI) values between the genome of strain BL9T and those of Bdellovibrionales and Bacteriovoracales were 12.5-19 and 63.49-76.15 %, respectively. On the basis of life cycle features, results of physiological analyses, gANI data and dDDH data, strain BL9T represents a new species within the genus Halobacteriovorax, for which the name Halobacteriovoraxvibrionivorans sp. nov. is proposed.

The Application of Deep Learning in the Risk Grading of Skin Tumors for Patients Using Clinical Images.

According to diagnostic criteria, skin tumors can be divided into three categories: benign, low degree and high degree malignancy. For high degree malignant skin tumors, if not detected in time, they can do serious harm to patients' health. However, in clinical practice, identifying malignant degree requires biopsy and pathological examination which is time costly. Furthermore, in many areas, due to the severe shortage of dermatologists, it's inconvenient for patients to go to hospital for examination. Therefore, an easy to access screening method of malignant skin tumors is needed urgently. Firstly, we spend 5 years to build a dataset which includes 4,500 images of 10 kinds of skin tumors. All instances are verified pathologically thus trustworthy; Secondly, we label each instance to be either low-risk, high-risk or dangerous in which Junctional nevus, Intradermal nevus, Dermatofibroma, Lipoma and Seborrheic keratosis are low-risk, Basal cell carcinoma, Bowen's disease and Actinic keratosis are high-risk, Squamous cell carcinoma and Malignant melanoma are dangerous; Thirdly, we apply the Xception architecture to build the risk degree classifier. The area under the curve (AUC) for three risk degrees reach 0.959, 0.919 and 0.947 respectively. To further evaluate the validity of the proposed risk degree classifier, we conduct a competition with 20 professional dermatologists. The results showed the proposed classifier outperforms dermatologists. Our system is helpful to patients in preliminary screening. It can identify the patients who are at risk and alert them to go to hospital for further examination.

Hepatitis C virus core protein increases Snail expression and induces epithelial-mesenchymal transition through the signal transducer and activator of transcription 3 pathway in hepatoma cells.

AIM: Aberrant expression of Snail, a mediator of epithelial-mesenchymal transition (EMT), is crucial for cancer invasiveness and metastasis. Although hepatitis C virus (HCV) core protein has been implicated in hepatocarcinogenesis, the relationship between HCV core and Snail expression has not been clarified. METHODS: HepG2 and Huh7 stable cell lines were established by transfection with pcDNA-HCVc. HepG2-HCVc and Huh7-HCVc cells were co-administered with AG490. Cell migration and invasiveness were tested. STAT3 and Snail expression was analyzed by Real-time PCR and Western blot. RESULTS: We found that HCV core is capable of increasing Snail expression and inducing EMT in hepatoma cells. HCV core-induced Snail expression was accompanied by activation of signal transducer and activator of transcription 3 (STAT3), inhibition of STAT3 abrogated HCV core-induced Snail expression and EMT. Furthermore, chromatin immunoprecipitation showed that phosphorylated STAT3 directly binds to the Snail promoter. CONCLUSION: Collectively, these results suggest that HCV core would play a role in hepatocellular carcinoma invasiveness and metastasis by activating the STAT3 pathway, increasing Snail expression and subsequently triggering EMT. These findings would advance the understanding of HCV-mediated invasiveness and metastasis, and might provide a new potential therapeutic target for HCV-related hepatocellular carcinoma.

Multiresidue analysis of 59 nonallowed substances and other contaminants in cosmetics.

A method was developed for the determination of 59 glucocorticoids, sex hormones, nonsteroidal anti-inflammatory drugs, antibiotics, and other contaminants in cosmetics simultaneously by ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Acetonitrile was used to extract the sample, and the mixed sorbents were dispersed for purification. With the optimal conditions, the optimized pretreatment processes led to no significant interference on analysis from an extremely complicated sample matrix, and the linear ranges of 59 analytes were 0-480.0 µg/kg with the correlation coefficients above 0.99 and the limits of quantification (S/N≥10) were 5-40 µg/kg. Statistical evaluation revealed that the average recoveries were in the range of 61.2-131.2%, and relative standard deviations were in the range of 2.0-22.8%, meanwhile the interday precision ranged from 3.8 to 21.8%. This method is simple, fast, and credible, and it can be applied to simultaneous screening and determination of various classes of substances under investigations illegally presented in cosmetic products, covering a wide diversity of polarities, and pKa values.

Single-cell transcriptional profiling in osteosarcoma and the effect of neoadjuvant chemotherapy on the tumor microenvironment.

Osteosarcoma (OS), a malignant tumor, originates from the bone marrow. Currently, treatment for OS remains limited, making it urgent to understand the immune response in the tumor microenvironment of patients with OS. A comprehensive bioinformatics analysis was performed, including cell clustering subgroups, differential expression genes screening, proposed temporal order, and genomic variant analysis on single-cell RNA-sequencing data, from ten pre-chemotherapy patients and eleven post-chemotherapy patients. Subsequently, we analyzed the differentiation trajectories of osteoblasts, osteoclasts, fibroblasts, myeloid cells, and tumor-infiltrating lymphocytes (TILs) in detail to compare the changes in cell proportions and differential genes pre- and post-chemotherapy. The nine cell types were identified, including fibroblasts, myeloid cells, osteoblasts, TILs, osteoclasts, proliferative osteoblasts, pericytes, endothelial cells, and B cells. Post-chemotherapy treatment, the proportions of myeloid cells and TILs in OS were declined, while the number of osteoblasts was elevated. Besides, a decrease was observed in CD74, FTL, FTH1, MT1X and MT2A, and an increase in PTN, COL3A1, COL1A1, IGFBP7 and FN1. Meanwhile, EMT, DNA repair, G2M checkpoint, and E2F targets were highly enriched post-chemotherapy. Furthermore, there was a down-regulation in the proportions of CD14 monocytes, Tregs, NK cells and CD1C-/CD141-DCs, while an up-regulation was observed in the proportions of SELENOP macrophages, IL7R macrophages, COL1A1 macrophages, CD1C DCs, CD4+ T cells and CD8+ T cells. Overall, these findings revealed changes in the tumor microenvironment of OS post-chemotherapy treatment, providing a new direction for investigating OS treatment.

Genetic associations of protein-coding variants in venous thromboembolism.

Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.

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.

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.

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.