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Abstract The metabolomic profile of aging is complex. Here, we analyse 325 nuclear magnetic resonance (NMR) biomarkers from 250,341 UK Biobank participants, identifying 54 representative aging-related biomarkers associated with all-cause mortality. We conduct genome-wide association studies (GWAS) for these 325 biomarkers using whole-genome sequencing (WGS) data from 95,372 individuals and perform multivariable Mendelian randomization (MVMR) analyses, discovering 439 candidate “biomarker - disease” causal pairs at the nominal significance level. We develop a metabolomic aging score that outperforms other aging metrics in predicting short-term mortality risk and exhibits strong potential for discriminating aging-accelerated populations and improving disease risk prediction. A longitudinal analysis of 13,263 individuals enables us to calculate a metabolomic aging rate which provides more refined aging assessments and to identify candidate anti-aging and pro-aging NMR biomarkers. Taken together, our study has presented a comprehensive aging-related metabolomic profile and highlighted its potential for personalized aging monitoring and early disease intervention.

Due to differences in raw materials and production processes, different spirits exhibit various flavor even if undergo distillation operation. In this study, sensory analysis could clearly distinguish 5 types spirits, and had been validated through quantitative targeted flavoromics analysis. Consequently, 44 potential differential markers between 5 types spirits were screened. Among, 34 definite differential markers were further confirmed to be highly correlated with target sensory attributes and could effectively distinguish types of spirits. Ultimately, 14 key differential markers (including 2-methylbutane, linalool, acetaldehyde, d-limonene, β-myrcene, phenylethyl alcohol, phenethyl acetate, heptyl formate, ethyl octanoate, ethyl decanoate, ethyl pentanoate, ethyl hexanoate, hexanoic acid, and ethyl hexadecanoate) could reveal the chemical sources of spirit sensory and serve as targets for identifying different types of spirits. Overall, the results of flavoromic characterization of 5 types spirits provided a significant step forwards in understanding of differentiation of spirits by sensory coupled with quantitative, and statistical analysis

Tartaric acid is one of the characteristic acids in wine, playing a crucial role in wine characteristics. However, superabundant tartaric acid will form insoluble salts and precipitate in the form of crystals, affecting consumers' purchasing appetite. Therefore, tartaric stability is also one of the important indices for controlling the wine quality. At present, the main processing methods for tartaric stability include cold stabilization, ion exchange treatment, electrodialysis and the addition of exogenous components (gum arabic, metatartaric acid, carboxymethyl cellulose, mannoprotein and potassium polyaspartate). This review summarizes and analyzes the origin of tartaric acid in wine, factors influencing the tartaric stability, detection methods, treatments for tartaric stabilization, and the effects of these methods on the sensory quality of wine. Comparing the effects of these methods on wine quality can provide a basis for the further study of tartaric stabilization methods in order to select an appropriate tartaric stabilization method.

Background: Smoking is a widespread behavior, while the relationship between smoking and various diseases remains a topic of debate. Objective: We conducted analysis to further examine the identified associations and assess potential causal relationships. Methods: We utilized seven single nucleotide polymorphisms (SNPs) known to be linked to smoking extracting genotype data from the UK Biobank, a large-scale biomedical repository encompassing comprehensive health-related and genetic information of European descent. Phenome-wide association study (PheWAS) analysis was conducted to map the association of genetically predicted smoking status with 1,549 phenotypes. The associations identified in the PheWAS were then meticulously examined through two-sample Mendelian randomization (MR) analysis, utilizing data from the UK Biobank (n = 487,365) and the Sequencing Consortium of Alcohol and Nicotine Use (GSCAN) (n = 337,334). This approach allowed us to comprehensively characterize the links between smoking and disease patterns. Results: The PheWAS analysis produced 34 phenotypes that demonstrated significant associations with smoking (P = 0.05/1460). Importantly, sickle cell anemia and type 2 diabetes exhibited the most significant SNPs (both 85.71% significant SNPs). Furthermore, the MR analyses provided compelling evidence supporting causal associations between smoking and the risk of following diseases: obstructive chronic bronchitis (IVW: Beta = 0.48, 95% confidence interval (CI) 0.36-0.61, P = 1.62×10−13), cancer of the bronchus (IVW: Beta = 0.92, 95% CI 0.68-1.17, P = 2.02×10−13), peripheral vascular disease (IVW: Beta = 1.09, 95% CI 0.71-1.46, P = 1.63×10−8), emphysema (IVW: Beta = 1.63, 95% CI 0.90-2.36, P = 1.29×10−5), pneumococcal pneumonia (IVW: Beta = 0.30, 95% CI 0.11-0.49, P = 1.60×10−3), chronic airway obstruction (IVW: Beta = 0.83, 95% CI 0.30-1.36, P = 2.00×10−3) and type 2 diabetes (IVW: Beta = 0.53, 95% CI 0.16-0.90, P = 5.08×10−3). Conclusion: This study affirms causal relationships between smoking and obstructive chronic bronchitis, cancer of the bronchus, peripheral vascular disease, emphysema, pneumococcal pneumonia, chronic airway obstruction, type 2 diabetes, in the European population. These findings highlight the broad health impacts of smoking and support smoking cessation efforts.

Abstract. Background:. Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson's disease (PD) risk factors; however, no comprehensive analyses of these genes in patients with PD have been undertaken. Therefore, we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD. Methods:. Whole-exome sequencing (WES) was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls. Additionally, whole-genome sequencing (WGS) was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls. Results:. We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts, respectively. Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD. However, the significance did not pass the Bonferroni correction. Meanwhile, 72 and 1730 common variants were found in the WES and WGS cohorts, respectively. Unfortunately, single-variant logistic association analyses did not identify significant associations between common variants and PD. Conclusions:. Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients. However, we highlight the complexity of PD and the need for extensive research elucidating its etiology.

Abstract Substantial evidence shown that the age at onset (AAO) of Parkinson’s disease (PD) is a major determinant of clinical heterogeneity. However, the mechanisms underlying heterogeneity in the AAO remain unclear. To investigate the risk factors with the AAO of PD, a total of 3156 patients with PD from the UK Biobank were included in this study. We evaluated the effects of polygenic risk scores (PRS), nongenetic risk factors, and their interaction on the AAO using Mann–Whitney U tests and regression analyses. We further identified the genes interacting with nongenetic risk factors for the AAO using genome-wide environment interaction studies. We newly found physical activity (P

Abstract Introduction Recently, chloride channel CLIC‐like 1 (CLCC1) was reported to be a novel ALS‐related gene. We aimed to screen CLCC1 variants in our ALS cohort and further explore the genotype–phenotype correlation of CLCC1‐related ALS. Methods We screened rare damaging variants in CLCC1 from our cohorts of 1005 ALS patients and 1224 healthy controls with whole‐exome sequencing in Central South China. Fisher's exact test was conducted for association analysis at the entire gene level and single variant level. Results In total, four heterozygous missense variants in CLCC1 were identified from four unrelated sporadic ALS patients and predicted to be putative pathogenic by in silico tools and protein model prediction, accounting for 0.40% of all patients (4/1005). The four variants were c.A275C (p.Q92P), c.G1139A (p.R380K), c.C1244T (p.T415M), and c.G1328A (p.R443Q), respectively, which had not been reported in ALS patients previously. Three of four variants were located in exon 10. Patients harboring CLCC1 variants seemed to share a group of similar clinical features, including earlier age at onset, rapid progression, spinal onset, and vulnerable cognitive status. Statistically, we did not find CLCC1 to be associated with the risk of ALS at the entire gene level or single variant level. Conclusion Our findings further expanded the genetic and clinical spectrum of CLCC1‐related ALS and provided more genetic evidence for anion channel involvement in the pathogenesis of ALS, but further investigations are needed to verify our findings.

Abstract Obesity increases the risk of cognitive impairment and dementia, and the gut microbiota can affect brain cognitive function and obesity through a variety of pathways such as the gut-brain axis. This study aimed to discover how fatty acid affect cognitive function by regulating intestinal flora in obesity. Obese subjects were recruited for cognitive function assessment, and participants were divided into obese group with cognitive impairment (MCI, n = 49) and obese cognitively normal group (Non_MCI, n = 55). In the erythrocyte membrane, the proportion of polyunsaturated fatty acids (PUFA), linoleic acid (C18:2 n-6) and arachidonic acid (C20:4 n-6) and n-6/n-3 ratio was higher in the MCI group than in the Non_MCI group. However, the α-linolenic acid (C18:3 n-3) percentage of the erythrocyte membrane was lower in the MCI group. We found that Coriobacteriales_Incertae_Sedis was positively correlated with erythrocyte membrane C20:4 n-6 and n-6 PUFA and negatively correlated with cognitive scores in obese patients. In addition, several of the functional pathways we predicted were significantly different in the MCI and Non_MCI groups. Higher levels of n-6/n-3 polyunsaturated fatty acids ratio in the erythrocyte membranes may influence the inflammatory response in the organism causing obesity induced cognitive damage. Moreover, high levels of n-6/n-3 polyunsaturated fatty acids ratio may also affect the intestinal flora of obese patients, which in turn may affect the cognitive function of obese patients.

Baijiu is popular with a long history and balanced flavor. Flavor type is the most widely used classification mode for Baijiu. However, the evolutionary relationships of Baijiu flavor types and the differential markers between flavor types are still unclear, significantly impacting the development of the Baijiu industry. In this study, a total of 319 trace components were identified using gas chromatography–olfactometry–mass spectrometry and gas chromatography–mass spectrometry. Among them, 91 trace components with high odor active values or taste active values were recognized as flavor components. Then random forests were conducted to screen differential markers between the derived and basic flavor types, while a principal component analysis assessed their effectiveness in distinguishing the flavor types of Baijiu. Finally, 19 differential markers (including 3-methylbutyric acid, pentanoic acid, 2-butanol, 2,3-butanediol, ethyl pro-panoate, isobutyl acetate, ethyl butanoate, ethyl hexanoate, ethyl heptanoate, ethyl lactate, ethyl 2-hydroxy butanoate, isopentyl hexanoate, ethyl nonanoate, isopropyl myristate, ethyl tetradecanoate, ethyl benzoate, 2,4-di-t-butylphenol, 2-methylbutanal and 3-octanone) were screened and proven to effectively reveal the evolution of Baijiu flavor types; these were further verified as key differential markers using addition tests and a correlation analysis.

Abstract Objectives Hereditary spastic paraplegia (HSP) is a genetically heterogeneous disease caused by over 70 genes, with a significant number of patients still genetically unsolved. In this study, we recruited a suspected HSP family characterized by spasticity, developmental delay, ataxia and hypomyelination, and intended to reveal its molecular etiology by whole exome sequencing (WES) and long‐read sequencing (LRS) analyses. Methods WES was performed on 13 individuals of the family to identify the causative mutations, including analyses of SNVs (single‐nucleotide variants) and CNVs (copy number variants). Accurate circular consensus (CCS) long‐read sequencing (LRS) was used to verify the findings of CNV analysis from WES. Results SNVs analysis identified a missense variant c.195G>T (p.E65D) of MORF4L2 at Xq22.2 co‐segregating in this family from WES data. Further CNVs analysis revealed a microdeletion, which was adjacent to the MORF4L2 gene, also co‐segregating in this family. LRS verified this microdeletion and confirmed the deletion range (chrX: 103,690,507–103,715,018, hg38) with high resolution at nucleotide level accuracy. Interpretations In this study, we identified an Xq22.2 microdeletion (about 24.5 kb), which contains distal enhancers of the PLP1 gene, as a likely cause of SPG2 in this family. The lack of distal enhancers may result in transcriptional repression of PLP1 in oligodendrocytes, potentially affecting its role in the maintenance of myelin, and causing SPG2 phenotype. This study has highlighted the importance of noncoding genomic alterations in the genetic etiology of SPG2.

Abstract GBA1 variants are important risk factors for Parkinson’s disease (PD). Most studies assessing GBA1-related PD risk have been performed in European-derived populations. Although the coding region of the GBA1 gene in the Chinese population has been analyzed, the sample sizes were not adequate. In this study, we aimed to investigate GBA1 variants in a large Chinese cohort of patients with PD and healthy control and explore the associated clinical characteristics. GBA1 variants in 4034 patients and 2931 control participants were investigated using whole-exome and whole-genome sequencing. The clinical features of patients were evaluated using several scales. Regression analysis, chi-square, and Fisher exact tests were used to analyze GBA1 variants and the clinical symptoms of different groups. We identified 104 variants, including 8 novel variants, expanding the spectrum of GBA1 variants. The frequency of GBA1 variants in patients with PD was 7.46%, higher than that in the control (1.81%) (P

Abstract Long single-molecular sequencing technologies, such as PacBio circular consensus sequencing (CCS) and nanopore sequencing, are advantageous in detecting DNA 5-methylcytosine in CpGs (5mCpGs), especially in repetitive genomic regions. However, existing methods for detecting 5mCpGs using PacBio CCS are less accurate and robust. Here, we present ccsmeth, a deep-learning method to detect DNA 5mCpGs using CCS reads. We sequence polymerase-chain-reaction treated and M.SssI-methyltransferase treated DNA of one human sample using PacBio CCS for training ccsmeth. Using long (≥10 Kb) CCS reads, ccsmeth achieves 0.90 accuracy and 0.97 Area Under the Curve on 5mCpG detection at single-molecule resolution. At the genome-wide site level, ccsmeth achieves >0.90 correlations with bisulfite sequencing and nanopore sequencing using only 10× reads. Furthermore, we develop a Nextflow pipeline, ccsmethphase, to detect haplotype-aware methylation using CCS reads, and then sequence a Chinese family trio to validate it. ccsmeth and ccsmethphase can be robust and accurate tools for detecting DNA 5-methylcytosines.

Non-coding variants in the human genome significantly influence human traits and complex diseases via their regulation and modification effects. Hence, an increasing number of computational methods are developed to predict the effects of variants in human non-coding sequences. However, it is difficult for inexperienced users to select appropriate computational methods from dozens of available methods. To solve this issue, we assessed 12 performance metrics of 24 methods on four independent non-coding variant benchmark datasets: (1) rare germline variants from clinical relevant sequence variants (ClinVar), (2) rare somatic variants from Catalogue Of Somatic Mutations In Cancer (COSMIC), (3) common regulatory variants from curated expression quantitative trait locus (eQTL) data, and (4) disease-associated common variants from curated genome-wide association studies (GWAS). All 24 tested methods performed differently under various conditions, indicating varying strengths and weaknesses under different scenarios. Importantly, the performance of existing methods was acceptable for rare germline variants from ClinVar with the area under the receiver operating characteristic curve (AUROC) of 0.4481–0.8033 and poor for rare somatic variants from COSMIC (AUROC = 0.4984–0.7131), common regulatory variants from curated eQTL data (AUROC = 0.4837–0.6472), and disease-associated common variants from curated GWAS (AUROC = 0.4766–0.5188). We also compared the prediction performance of 24 methods for non-coding de novo mutations in autism spectrum disorder, and found that the combined annotation-dependent depletion (CADD) and context-dependent tolerance score (CDTS) methods showed better performance. Summarily, we assessed the performance of 24 computational methods under diverse scenarios, providing preliminary advice for proper tool selection and guiding the development of new techniques in interpreting non-coding variants.

Summary: Background: Genomic variants outside of the canonical splicing site (±2) may generate abnormal mRNA splicing, which are defined as non-canonical splicing variants (NCSVs). However, the clinical interpretation of NCSVs in neurodevelopmental disorders (NDDs) is largely unknown. Methods: We investigated the contribution of NCSVs to NDDs from 345,787 de novo variants (DNVs) in 47,574 patients with NDDs. We performed functional enrichment and protein–protein interaction analysis to assess the association between genes carrying prioritised NCSVs and NDDs. Minigene was used to validate the impact of NCSVs on mRNA splicing. Findings: We observed significantly more NCSVs (p = 0.02, odds ratio [OR] = 2.05) among patients with NDD than in controls. Both canonical splicing variants (CSVs) and NCSVs contributed to an equal proportion of patients with NDD (0.76% vs. 0.82%). The candidate genes carrying NCSVs were associated with glutamatergic synapse and chromatin remodelling. Minigene successfully validated 59 of 79 (74.68%) NCSVs that led to abnormal splicing in 40 candidate genes, and 9 of the genes (ARID1B, KAT6B, TCF4, SMARCA2, SHANK3, PDHA1, WDR45, SCN2A, SYNGAP1) harboured recurrent NCSVs with the same variant present in more than two unrelated patients with NDD. Moreover, 36 of 59 (61.02%) NCSVs are novel clinically relevant variants, including 34 unreported and 2 clinically conflicting interpretations or of uncertain significance NCSVs in the ClinVar database. Interpretation: This study highlights the common pathology and clinical importance of NCSVs in unsolved patients with NDD. Funding: The present study was funded by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, the Hunan Youth Science and Technology Innovation Talent Project, the Provincial Natural Science Foundation of Hunan, The Scientific Research Program of FuRong laboratory, and the Natural Science Project of the University of Anhui Province

Abstract Background Dietary fat intake affects brain composition and function. Different types of dietary fatty acids alter species and abundance of brain lipids in mice. The aim of this study is to explore whether the changes are effective through gut microbiota. Methods In our study, 8-week-old male C57BL/6 mice were randomly divided into 7 groups and fed with high-fat diet (HFD) with different fatty acid compositions, control (CON) group, long-chain saturated fatty acid (LCSFA) group, medium-chain saturated fatty acid (MCSFA) group, n-3 polyunsaturated fatty acid (n-3 PUFA) group, n-6 polyunsaturated fatty acid (n-6 PUFA) group, monounsaturated fatty acid (MUFA) group and trans fatty acid (TFA) group. Then, the fecal microbiota transplant (FMT) was performed in other pseudo germ-free mice after antibiotic treatment. The experimental groups were orally perfused with gut microbiota that induced by HFD with different types of dietary fatty acids. The mice were fed with regular fodder before and after FMT. High-performance liquid chromatography-mass spectrometry (LC-MS) was used to analysis the composition of fatty acids in the brain of HFD-fed mice and hippocampus of mice treated with FMT which was collected from HFD-fed mice. Results The content of acyl-carnitines (AcCa) increased and lysophosphatidylgylcerol (LPG) decreased in all kinds of HFD groups. phosphatidic acids (PA), phosphatidylethanolamine (PE) and sphingomyelin (SM) contents were significantly increased in the n-6 PUFA-fed HFD group. The HFD elevated the saturation of brain fatty acyl (FA). Lysophosphatidylcholine (LPC), lysodi-methylphosphatidylethanolamine (LdMePE), monolysocardiolipin (MLCL), dihexosylceramides (Hex2Cer), and wax ester (WE) significantly increased after LCSFA-fed FMT. MLCL reduced and cardiolipin (CL) raised significantly after n-3 PUFA-fed FMT. Conclusions The study revealed, HFD and FMT in mice had certain effects on the content and composition of fatty acids in the brain, especially on glycerol phospholipid (GP). The change of AcCa content in FA was a good indicator of dietary fatty acid intake. By altering the fecal microbiota, dietary fatty acids might affect brain lipids.

Abstract Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson’s disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P combined = 1.47 × 10−9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P

Abstract Objectives CYLD was a novel causative gene for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Given the clinical and pathological overlap of FTD and Alzheimer's disease (AD), it is necessary to screen CYLD in AD patients and FTD patients in the Chinese population. Methods In our study, using a targeted sequencing panel, we sequenced the CYLD gene in a large cohort of 2485 participants in the Chinese population, including 1008 AD patients, 105 FTD patients, and 1372 controls. Results In the present study, the average onset age of AD and FTD patients was 66.84 ± 30.42 years old and 60 ± 10.00 years old, respectively. Our study reported three novel CYLD variants: p.Phe288Leu (patient No. 1, AD), p.Tyr485Phe (patients No. 6–9, all AD) and p.Thr951Ala (patient No. 10, AD), plus a previously reported variant: p.Arg397Ser (patient No. 2–5, AD and No. 11, FTD). These variants were absent in our in‐house controls and predicted to be deleterious according to the MutationTaster. The variant carriers were composed of 10 AD patients and one FTD patient, and the average onset age was 61.2 ± 10.9 years. The frequency of CYLD variants in AD was similar to that in FTD, which was 0.99% (10/1008) and 0.95% (1/105), respectively. Interpretation Our finding extended the genotype and phenotype of the CYLD gene and demonstrated that CYLD rare damaging variants may be implicated in AD and FTD pathogenesis.

Abstract Background Cardiometabolic multimorbidity (CMM) is becoming increasingly common in patients with hypertension, and it is well established that healthy lifestyle plays a key role in the prevention of hypertension. However, the association between combined lifestyle factors and CMM in patients with hypertension is uncertain. Methods This prospective analysis included the data (obtained from the UK biobank) of participants with hypertension who did not have coronary heart disease (CHD), stroke, or diabetes. The outcome was the occurrence of CMM, defined as ≥ 1 disease of CHD, stroke, and diabetes that occurred in participants with hypertension. Four lifestyle factors (smoking, alcohol consumption, diet, and physical activity) were assessed using a weighted healthy lifestyle score, and participants were divided into four groups: the very unhealthy, unhealthy, healthy, and very healthy groups. The flexible parameter Royston-Parmar proportional hazard model was used to estimate hazard ratios (HRs) between lifestyles and CMM, as well as the difference in CMM-free life expectancy. Results During a median follow-up of 12.2 years, 9812 (18.4%) of the 53,397 hypertensive patients occurred CMM. Compared with the very unhealthy group, the very healthy group had a 41% reduction in the risk for CMM in hypertensive patients and a 32–50% reduction in the risk for specific cardiometabolic diseases such as CHD, stroke, and diabetes. For each lifestyle factor, non-smoking had the greatest protective effect against CMM (HR: 0.64, 95% confidence interval (CI) 0.60–0.68). A lifestyle combining multiple healthy factors extended CMM-free life expectancy (e.g., six years longer at age 45 years for participants in the very healthy group). Conclusions Combined healthy lifestyle factors were associated with a lower risk for CMM in hypertensive patients. This suggests that combined healthy lifestyle should be supported to decrease disease burden.

ObjectiveThere is controversial evidence that FMR1 premutation or “gray zone” (GZ) allele (small CGG expansion, 45–54 repeats) was associated with Parkinson’s disease (PD). We aimed to explore further the association between FMR1 CGG repeat expansions and PD in a large sample of Chinese origin.MethodsWe included a cohort of 2,362 PD patients and 1,072 controls from the Parkinson’s Disease and Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) in this study and conducted repeat-primed polymerase chain reaction (RP-PCR) for the size of FMR1 CGG repeat expansions.ResultsTwo PD patients were detected with FMR1 premutation (61 and 56 repeats), and the other eleven PD patients were detected with the GZ allele of FMR1 CGG repeat expansions. Those thirteen PD patients responded well to levodopa and were diagnosed with clinically established PD. Specifically, one female PD patient with GZ allele was also found with premature ovarian failure. However, compared to healthy controls, we found no significant enrichment of GZ allele carriers in PD patients or other subgroups of PD cases, including the subgroups of female, male, early-onset, and late-onset PD patients. Furthermore, we did not find any correlation between the FMR1 gene CGG repeat sizes and age at onset of PD.ConclusionIt suggested that FMR1 premutation was related to PD, but the GZ allele of FMR1 CGG repeat expansions was not significantly enriched in PD cases of Chinese origin. Further larger multiple ethnic studies are needed to determine further the role of the FMR1 GZ allele in PD.

Abstract Background Although the association between beverages and a single cardiometabolic disease has been well studied, their role in disease progression from the single cardiometabolic disease state to cardiometabolic multimorbidity (CMM) state remains unclear. This study examined the associations between three types of beverages: sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and pure fruit/vegetable juices, and the incidence of CMM in patients with a single cardiometabolic disease. Methods Our analysis included 37,994 participants from the UK Biobank who completed at least one dietary questionnaire and were diagnosed with only one cardiometabolic disease at the time of recruitment. Competing risk models were used to examine the association between the three types of beverages and incidence of CMM. We conducted analysis both in patients with any single cardiometabolic disease and in patients with specific cardiometabolic disease. Results During a median follow-up of 9.1 years (interquartile range [IQR] 9.0–9.8), a total of 6399 participants developed CMM. The consumption of SSBs and ASBs (>1 serving per day) was associated with a higher risk of CMM (SSBs: hazard ratio [HR] 1.19, 95% confidence interval [95% CI] 1.08–1.31; ASBs: HR 1.15, 95% CI 1.04–1.27). Intake of pure fruit/vegetable juices was inversely associated with the incidence of CMM (0–1 serving per day: HR 0.90, 95% CI 0.85–0.94; >1 serving per day: HR 0.90, 95% CI 0.81–0.99). However, the association of the high-level consumption of pure fruit/vegetable juices (>1 serving per day) was not statistically significant after correcting for multiple testing. In the analysis of patients with specific cardiometabolic diseases, positive associations were observed in patients with hypertension for SSBs consumption, while inverse associations persisted in patients with cardiovascular disease (coronary heart disease or stroke) and in hypertensive patients for pure fruit/vegetable juice consumption. Conclusions Consuming >1 serving of SSBs and ASBs per day was associated with a higher risk of CMM in patients with a single cardiometabolic disease. In contrast, intake of pure fruit/vegetable juices was inversely associated with the risk of CMM. Our findings highlight the need to limit the use of SSBs and ASBs in patients with a single cardiometabolic disease.

ObjectiveParkinson's disease (PD) and dystonia are two closely related movement disorders with overlaps in clinical phenotype. Variants in several dystonia-related genes were demonstrated to be associated with PD; however, genetic evidence for the involvement of dystonia-related genes in PD has not been fully studied. Here, we comprehensively investigated the association between rare variants in dystonia-related genes and PD in a large Chinese cohort.MethodsWe comprehensively analyzed the rare variants of 47 known dystonia-related genes by mining the whole-exome sequencing (WES) and whole-genome sequencing (WGS) data from 3,959 PD patients and 2,931 healthy controls. We initially identified potentially pathogenic variants of dystonia-related genes in patients with PD based on different inheritance models. Sequence kernel association tests were conducted in the next step to detect the association between the burden of rare variants and the risk for PD.ResultsWe found that five patients with PD carried potentially pathogenic biallelic variants in recessive dystonia-related genes including COL6A3 and TH. Additionally, we identified 180 deleterious variants in dominant dystonia-related genes based on computational pathogenicity predictions and four of which were considered as potentially pathogenic variants (p.W591X and p.G820S in ANO3, p.R678H in ADCY5, and p.R458Q in SLC2A1). A gene-based burden analysis revealed the increased burden of variant subgroups of TH, SQSTM1, THAP1, and ADCY5 in sporadic early-onset PD, whereas COL6A3 was associated with sporadic late-onset PD. However, none of them reached statistical significance after the Bonferroni correction.ConclusionOur findings indicated that rare variants in several dystonia-related genes are suggestively associated with PD, and taken together, the role of COL6A3 and TH genes in PD is highlighted.

BackgroundPrevious epidemiological studies have reported controversial results on the relationship between smoking and Alzheimer’s disease (AD). Therefore, we sought to assess the association using Mendelian randomization (MR) analysis.MethodsWe used single nucleotide polymorphisms (SNPs) associated with smoking quantity (cigarettes per day, CPD) from genome-wide association studies (GWAS) of Japanese population as instrumental variables, then we performed two-sample MR analysis to investigate the association between smoking and AD in a Chinese cohort (1,000 AD cases and 500 controls) and a Japanese cohort (3,962 AD cases and 4,074 controls), respectively.ResultsGenetically higher smoking quantity showed no statistical causal association with AD risk (the inverse variance weighted (IVW) estimate in the Chinese cohort: odds ratio (OR) = 0.510, 95% confidence interval (CI) = 0.149–1.744, p = 0.284; IVW estimate in the Japanese cohort: OR = 1.170, 95% confidence interval CI = 0.790–1.734, p = 0.434).ConclusionThis MR study, for the first time in Chinese and Japanese populations, found no significant association between smoking and AD.

BackgroundCommon polygenic risk and de novo variants (DNVs) capture a small proportion of autism spectrum disorder (ASD) liability, and ASD phenotypic heterogeneity remains difficult to explain. Integrating multiple genetic factors contribute to clarifying the risk and clinical presentation of ASD.MethodsIn our study, we investigated the individual and combined effects of polygenic risk, damaging DNVs (including those in ASD risk genes), and sex among 2,591 ASD simplex families in the Simons Simplex Collection. We also explored the interactions among these factors, along with the broad autism phenotypes of ASD probands and their unaffected siblings. Finally, we combined the effects of polygenic risk, damaging DNVs in ASD risk genes, and sex to explain the total liability of ASD phenotypic spectrum.ResultsOur findings revealed that both polygenic risk and damaging DNVs contribute to an increased risk for ASD, with females exhibiting higher genetic burdens than males. ASD probands that carry damaging DNVs in ASD risk genes showed reduced polygenic risk. The effects of polygenic risk and damaging DNVs on autism broad phenotypes were inconsistent; probands with higher polygenic risk exhibited improvement in some behaviors, such as adaptive/cognitive behaviors, while those with damaging DNVs exhibited more severe phenotypes. Siblings with higher polygenic risk and damaging DNVs tended to have higher scores on broader autism phenotypes. Females exhibited more severe cognitive and behavioral problems compared to males among both ASD probands and siblings. The combination of polygenic risk, damaging DNVs in ASD risk genes, and sex explained 1–4% of the total liability of adaptive/cognitive behavior measurements.ConclusionOur study revealed that the risk for ASD and the autism broad phenotypes likely arises from a combination of common polygenic risk, damaging DNVs (including those in ASD risk genes), and sex.

Transcriptomics studies have yielded great insights into disease processes by detecting differentially expressed genes (DEGs). In this study, due to the high heritability of Parkinson’s disease (PD), we performed bioinformatics analyses on nine transcriptomic datasets regarding substantia nigra from Gene Expression Omnibus database, including seven microarray datasets and two next-generation sequencing datasets. As a result, between age-matched PD patients and normal control, we identified 630 DEGs, of which 22 hub DEGs involved in PD or ferroptosis were found to be associated with each other at the transcriptional level and protein-protein interaction network, suggesting their high correlations among these hub genes. Moreover, 16 DEGs were singled out due to their comparable AUC (>0.6) in random forest classifiers, including seven PD-related genes (MAP4K4, LRP10, UCHL1, PAM, RIT2, SNCA, GCH1) and nine ferroptosis-related genes (GCH1, DDIT4, RGS4, MAPK9, CAV1, RELA, DUSP1, ATP6V1G2, ATF4 and ISCU). Furthermore, to probe the potential of those hub genes in predicting the PD progression and survival, we constructed a Cox model featured by an eight-gene signature, including four PD-related genes (SNCA, UCHL1, LRP10, and GCH1) and four ferroptosis-related genes (DDIT4, RGS4, RELA, and CAV1), and validated it successful in an independent dataset, indicating that it would be an effective tool for clinical research to predict PD progression. In conclusion, ferroptosis-related DEGs identified in this study were closely correlated with the known PD-related genes, revealing the involvement of ferroptosis in the development of PD. This study presented the potential of several ferroptosis-related genes as novel clinical biomarkers for PD.

IntroductionParkinson's disease (PD) is a progressive movement disorder caused by a loss of dopaminergic neurons. Previous studies have highlighted the importance of mitochondria dynamics in the pathogenesis of PD. Dynamin-1-like (DNM1L) is a gene that encodes dynamin-related protein 1 (DRP1), a GTPase essential for proper mitochondria fission. In the present study, we evaluated the relationship between DNM1L variants and PD in the Chinese population.MethodsA total of 3,879 patients with PD and 2,931 healthy controls were recruited and burden genetic analysis combined with high-throughput sequencing was applied.ResultsWe identified 23 rare variants in the coding region of DNM1L, while no difference in variant burden was shown between the cases and controls. We also identified 201 common variants in the coding and flanking regions and found two significant SNPs, namely, rs10844308 and rs143794289 [odds ratio (OR) = 1.220 and 0.718, p = 0.025 and 0.036, respectively]. We also performed a meta-analysis to correlate the two SNPs with PD risk. However, none of the common variants was significant using logistic regression.ConclusionDespite the critical role of DRP1, our study did not support the relationship between DNM1L variants and PD risk in the Chinese population.

Abstract Closure of the neural tube represents a highly complex and coordinated process, the failure of which constitutes common birth defects. The serine/threonine kinase p21‐activated kinase 2 (PAK2) is a critical regulator of cytoskeleton dynamics; however, its role in the neurulation and pathogenesis of neural tube defects (NTDs) remains unclear. Here, the results show that Pak2−/− mouse embryos fail to develop dorsolateral hinge points (DLHPs) and exhibit craniorachischisis, a severe phenotype of NTDs. Pak2 knockout activates BMP signaling that involves in vertebrate bone formation. Single‐cell transcriptomes reveal abnormal differentiation trajectories and transcriptional events in Pak2−/− mouse embryos during neural tube development. Two nonsynonymous and one recurrent splice‐site mutations in the PAK2 gene are identified in five human NTD fetuses, which exhibit attenuated PAK2 expression and upregulated BMP signaling in the brain. Mechanistically, PAK2 regulates Smad9 phosphorylation to inhibit BMP signaling and ultimately induce DLHP formation. Depletion of pak2a in zebrafish induces defects in the neural tube, which are partially rescued by the overexpression of wild‐type, but not mutant PAK2. The findings demonstrate the conserved role of PAK2 in neurulation in multiple vertebrate species, highlighting the molecular pathogenesis of PAK2 mutations in NTDs.

ObjectiveCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene. Previous studies have established a link between NOTCH3 variants and Parkinson’s disease (PD) in terms of neuropathology and clinical characteristics. In this study, we aimed to explore the role of NOTCH3 gene in PD in a large Chinese cohort.MethodsA total of 1,917 patients with early-onset or familial PD and 1,652 matched controls were included. All variants were divided into common or rare types by minor allele frequency (MAF) at a threshold of 0.01 (MAF > 0.01 into common variants and others into rare variants). Common variants were subjected to single-variant tests by PLINK, then gene-based analyses were used for rare variants with the optimized sequence kernel association test (SKAT-O). For genotype–phenotype correlation assessment, regression models were conducted to compare clinical features between the studied groups.ResultsThree common variants (rs1044006, rs1043997, and rs1043994) showed a nominal protective effect against PD. However, none of these SNPs survived Bonferroni correction. The results in the validation cohort revealed a significant but opposite association between these variants and PD. The gene-based analyses of rare variants showed no significant associations of NOTCH3 with PD. Although we did not find significant associations in the following genotype–phenotype analysis, the higher clinical scores of motor symptoms in NOTCH3-variant carriers were of interest.ConclusionOur results indicated that NOTCH3 gene may not play an important role in the early-onset or familial PD of Chinese population.

Background: Genetics plays an important role in progressive supranuclear palsy (PSP) and remains poorly understood. A detailed literature search identified 19 PSP-associated genes: MAPT, LRRK2, LRP10, DCTN1, GRN, NPC1, PARK, TARDBP, TBK1, BSN, GBA, STX6, EIF2AK3, MOBP, DUSP10, SLCO1A2, RUNX2, CXCR4, and APOE. To date, genetic studies on PSP have focused on Caucasian population. The gaps in PSP genetic study on East Asian populations need to be filled. Methods: Exon and flanking regions of the PSP-associated genes were sequenced in 104 patients with PSP and 488 healthy controls. Common variant-based association analysis and gene-based association tests of rare variants were performed using PLINK 1.9 and the sequence kernel association test-optimal, respectively. Additionally, the association of APOE and MAPT genotypes with PSP was evaluated. The above association analyses were repeated among probable PSP patients. Finally, PLINK 1.9 was used to test variants associated with the onset age of PSP. Results: A rare non-pathogenic variant of MAPT (c.425C > T,p.A142V) was detected in a PSP patient. No common variants were significantly associated with PSP. In both the rare-variant and the rare-damaging-variant groups, the combined effect for GBA reached statistical significance (p = 1.43 × 10−3, p = 4.98 × 10−4). The result between APOE, MAPT genotypes and PSP risk were inconsistent across all PSP group and probably PSP group. Conclusions: The pathogenic variant in MAPT were uncommon in PSP patients. Moreover, GBA gene was likely to increase the risk of PSP, and GBA-associated diseases were beyond α-synucleinopathies. The association between APOE, MAPT and PSP is still unclear among the non-Caucasian population.

Baijiu is a traditional spirit with high reputation in the Chinese community, and whisky, on the other hand, is a renowned spirit in Western culture, with both contributing a major proportion to the consumption and revenue in the global spirit market. Interestingly, starting with similar raw materials, such as grains, diverse production methods lead to different organoleptic profiles. In addition, such enormous attention they attract renders them as a crucial part in food and the related industry. Therefore, great efforts are made in improving product quality and optimizing production processes, such as flavor enhancement, facility development, and deep utilization of byproducts. Given the huge impacts and great involvements of these spirits in the general food industry, research focusing on either spirit is of referential significance for other relevant fields. With the aim of facilitating such collaboration, this review discusses the current research status, in a comparative manner, of both spirits in respect to key production processes-oriented sensory and flavor analysis, deep utilization of byproducts, and spirit-derived functional food investigations. Finally, the internal correlations based on the abovementioned criteria are identified, with research prospects proposed.

In recent years, intensified Qu (IQ) has been gradually applied to brewing in order to improve the aroma of Huangjiu (Chinese rice wine). In this study, Saccharomyces cerevisiae and Wickerhamomyces anomalus solutions were added to Fengmi Qu (FMQ) from Fangxian, China to produce IQ, and brewing trial was conducted. High-throughput sequencing (HTS) was used to analyze the microbial community in fermentation broth of IQ (IQFB). Headspace solid-phase microextraction (HS-SPME) combined with gas chromatography–mass spectrometry (GC-MS) and sensory evaluation were performed to analyze volatile aroma compounds (VACs) in sample without Qu and both fermentation broths. The results showed that Pediococcus, Cronobacter, Enterococcus, Weissella, and Acinetobacter and Saccharomycopsis, Wickerhamomyces, and Saccharomyces were dominant bacterial and fungal groups, respectively. A total of 115 VACs were detected, and the content of esters including ethyl acetate, isoamyl acetate, and so on was noticeably higher in IQFB. The finding of sensory evaluation reflected that adding pure yeast to Qu could enhance fruit and floral aromas. Correlation analysis yielded 858 correlations between significant microorganisms and different VACs. In addition, prediction of microbial community functions in IQFB revealed global and overview maps and carbohydrate metabolism to be the main one. This study is advantageous for further regulation of the fermentation process of Huangjiu by microbial means.

Abstract Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and complicated etiology. There exist potential genetic component overlaps between different neurodegenerative dementias. Here, 1795 patients with neurodegenerative dementias from South China were enrolled, including 1592 with Alzheimer’s disease (AD), 110 with frontotemporal dementia (FTD), and 93 with dementia with Lewy bodies (DLB). Genes targeted sequencing analysis were performed. According to the American College of Medical Genetics (ACMG) guidelines, 39 pathogenic/likely pathogenic (P/LP) variants were identified in 47 unrelated patients in 14 different genes, including PSEN1, PSEN2, APP, MAPT, GRN, CHCHD10, TBK1, VCP, HTRA1, OPTN, SQSTM1, SIGMAR1, and abnormal repeat expansions in C9orf72 and HTT. Overall, 33.3% (13/39) of the variants were novel, the identified P/LP variants were seen in 2.2% (35/1592) and 10.9% (12/110) of AD and FTD cases, respectively. The overall molecular diagnostic rate was 2.6%. Among them, PSEN1 was the most frequently mutated gene (46.8%, 22/47), followed by PSEN2 and APP. Additionally, the age at onset of patients with P/LP variants (51.4 years), ranging from 30 to 83 years, was ~10 years earlier than those without P/LP variants (p

Existing treatments can only delay the progression of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) after onset, so the prediction of the age at onset (AAO) can facilitate early intervention and follow-up to improve treatment efficacy. The objective of this study was to develop an explainable artificial intelligence (XAI) based on feature optimization to provide an interpretable and more accurate AAO prediction. A total of 1,008 affected SCA3/MJD subjects from mainland China were analyzed. The expanded cytosine-adenine-guanine (CAG) trinucleotide repeats of 10 polyQ-related genes were genotyped and included in related models as potential AAO modifiers. The performance of 4 feature optimization methods and 10 machine learning (ML) algorithms were compared, followed by building the XAI based on the SHapley Additive exPlanations (SHAP). The model constructed with an artificial neural network (ANN) and feature optimization of Crossing-Correlation-StepSVM performed best and achieved a coefficient of determination (R2) of 0.653 and mean absolute error (MAE), root mean square error (RMSE), and median absolute error (MedianAE) of 4.544, 6.090, and 3.236 years, respectively. The XAI explained the predicted results, which suggests that the factors affecting the AAO were complex and associated with gene interactions. An XAI based on feature optimization can improve the accuracy of AAO prediction and provide interpretable and personalized prediction.

ObjectivesParkinson’s disease (PD) is a neurodegenerative disorder with the manifestation of motor symptoms and non-motor symptoms. Previous studies have indicated the role of several transmembrane (TMEM) protein family genes in PD pathogenesis.Materials and MethodsIn order to better investigate the genetic role of PD-related TMEM protein family genes in PD, including TMEM230, TMEM59, TMEM108, TMEM163, TMEM175, and TMEM229B, 1,917 sporadic early onset PD (sEOPD) or familial PD (FPD) patients and 1,652 healthy controls were analyzed by whole-exome sequencing (WES) while 1,962 sporadic late-onset PD (sLOPD) and 1,279 healthy controls were analyzed by whole-genome sequencing (WGS). Rare and common variants for each gene were included in the analysis.ResultsOne hundred rare damaging or loss of function variants of six genes were found at the threshold of MAF < 0.1%. Three rare Dmis variants of TMEM230 were specifically identified in PD. Rare missense variants of TMEM59 were statistically significantly associated with PD in the WES cohort, indicating the role of TMEM59 in FPD and sEOPD. Rare missense variants of TMEM108 were suggestively associated with PD in the WGS cohort, indicating the potential role of TMEM108 in sLOPD. The rare variant of the other three genes and common variants of six genes were not significantly associated with PD.ConclusionWe performed a large case-control study to systematically investigate the role of several PD-related TMEM protein family genes in PD. We identified three PD-specific variants in TMEM230, the significant association of TMEM59 with FPD, and sEOPD and the suggestive association of TMEM108 with sLOPD.

Summary: Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. The common variants of specific oxytocin-related genes (OTRGs), particularly OXTR, are associated with the aetiology of ASD. The contribution of rare genetic variations in OTRGs to ASD aetiology remains unclear. Methods: We catalogued publicly available de novo mutations (DNMs) [from 6,511 patients with ASD and 3,391 controls], rare inherited variants (RIVs) [from 1,786 patients with ASD and 1,786 controls], and both de novo copy number variations (dnCNVs) and inherited CNVs (ihCNVs) [from 15,581 patients with ASD and 6,017 controls] in 963 curated OTRGs to explore their contribution to ASD pathology, respectively. Finally, a combined model was designed to prioritise the contribution of each gene to ASD aetiology by integrating DNMs and CNVs. Findings: The rare genetic variations of OTRGs were significantly associated with ASD aetiology, in the order of dnCNVs > ihCNVs > DNMs. Furthermore, 172 OTRGs and their connected 286 ASD core genes were prioritised to positively contribute to ASD aetiology, including top-ranked MAPK3. Probands carrying rare disruptive variations in these genes were estimated to account for 10∼11% of all ASD probands. Interpretation: Our findings suggest that rare disruptive variations in 172 OTRGs and their connected 286 ASD core genes are associated with ASD aetiology and may be potential biomarkers predicting the effects of oxytocin treatment. Funding: Guangdong Key Project, National Natural Science Foundation of China, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province.

BackgroundThe prevalence of cardiometabolic multimorbidity (CMM), which significantly increases the risk of mortality, is increasing globally. However, the role of healthy lifestyle in the secondary prevention of CMM is unclear.MethodsIn total, 290,795 participants with CMM, which was defined as coexistence of at least two of hypertension (HTN), diabetes mellitus (DM), coronary heart disease (CHD), and stroke (ST), and those without these four diseases at baseline were derived from UK Biobank. The associations between specific CMM patterns and mortality, and that between healthy lifestyle (including physical activity, smoking, alcohol consumption, and vegetable and fruit consumption) and mortality in patients with specific CMM patterns were calculated using the flexible parametric Royston-Parmar proportion-hazard model. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated.ResultsDuring a median 12.3-year follow up period, 15,537 (5.3%) deaths occurred. Compared with participants without cardiometabolic diseases, the HRs for all-cause mortality were 1.54 [95% confidence interval (CI): 1.30, 1.82] in participants with HTN + DM, 1.84 (95% CI: 1.59, 2.12) in those with HTN + CHD, 1.89 (95% CI: 1.46, 2.45) in those with HTN + ST, and 2.89 (95% CI: 2.28, 3.67) in those with HTN + DM + CHD. At the age of 45 years, non-current smoking was associated with an increase in life expectancy by 3.72, 6.95, 6.75, and 4.86 years for participants with HTN + DM, HTN + CHD, HTN + ST, and HTN + DM + CHD, respectively. A corresponding increase by 2.03, 1.95, 2.99, and 1.88 years, respectively, was observed in participants with regular physical activity. Non-/moderate alcohol consumption and adequate fruit/vegetable consumption were not significantly associated with life expectancy in patients with specific CMM patterns.ConclusionCardiometabolic multimorbidity was associated with an increased risk of mortality. Regular physical activity and non-current smoking can increase life expectancy in patients with specific CMM patterns.

Folate deficiency is an environmental risk factor for several developmental disorders. De novo mutations (DNMs) also play important etiological roles in various developmental disorders. However, it remains unclear whether DNMs in folate-related genes (FRGs) contribute to developmental disorders. We obtained a list of 1,821 FRGs from folate metabolism pathways and the Comparative Toxicogenomics Database, along with data concerning DNMs in 15,404 cases and 3,391 controls from the Gene4Denovo database. We used a TADA-Denovo model to prioritize candidate disease-associated FRGs, and characterized these genes in terms of genic intolerance, functional networks, and expression patterns. Compared with the controls, FRGs were significantly enriched in likely damaging DNMs (ldDNMs) in patients with developmental disorders (1.54 ≤ odds ratio ≤ 3.39, Padj ≤ 0.0075). Furthermore, FRGs with ldDNMs rather than with likely non-damaging DNMs (lndDNMs) overlapped significantly among the five developmental disorders included in the datasets. The TADA-Denovo model prioritized 96 candidate disease-associated FRGs, which were intolerant to genetic variants. Their functional networks mainly involved pathways associated with chromatin modification, organ development, and signal transduction pathways. DNMT3A, KMT2B, KMT2C, and YY1 emerged as hub FRGs from the protein–protein interaction network. These candidate disease-associated FRGs are preferentially expressed in the excitatory neurones during embryonic development, and in the cortex, cerebellum, striatum, and amygdala during foetal development. Overall, these findings show that DNMs in FRGs are associated with the risk of developmental disorders. Further research on these DNMs may facilitate the discovery of developmental disorder biomarkers and therapeutic targets, enabling detailed, personalized, and precise folate treatment plan.

Genotype–phenotype correlations are the basis of precision medicine of human genetic diseases. However, it remains a challenge for clinicians and researchers to conveniently access detailed individual-level clinical phenotypic features of patients with various genetic variants. To address this urgent need, we manually searched for genetic studies in PubMed and catalogued 8,309 genetic variants in 1,288 genes from 17,738 patients with detailed clinical phenotypic features from 1,855 publications. Based on genotype–phenotype correlations in this dataset, we developed an user-friendly online database called GPCards (http://genemed.tech/gpcards/), which not only provided the association between genetic diseases and disease genes, but also the prevalence of various clinical phenotypes related to disease genes and the patient-level mapping between these clinical phenotypes and genetic variants. To accelerate the interpretation of genetic variants, we integrated 62 well-known variant-level and gene-level genomic data sources, including functional predictions, allele frequencies in different populations, and disease-related information. Furthermore, GPCards enables automatic analyses of users’ own genetic data, comprehensive annotation, prioritization of candidate functional variants, and identification of genotype–phenotype correlations using custom parameters. In conclusion, GPCards is expected to accelerate the interpretation of genotype–phenotype correlations, subtype classification, and candidate gene prioritisation in human genetic diseases.

During the field studies, a Translucidithyrium-like taxon was collected in Xishuangbanna of Yunnan Province, during an investigation into the diversity of microfungi in the southwest of China. Morphological observations and phylogenetic analysis of combined LSU and ITS sequences revealed that the new taxon is a member of the genus Translucidithyrium and it is distinct from other species. Therefore, Translucidithyrium chinense sp. nov. is introduced here. The Maximum Clade Credibility (MCC) tree from LSU rDNA of Translucidithyrium and related species indicated the divergence time of existing and new species of Translucidithyrium was crown age at 16 (4–33) Mya. Combining the estimated divergence time, paleoecology and plate tectonic movements with the corresponding geological time scale, we proposed a hypothesis that the speciation (estimated divergence time) of T. chinense was earlier than T. thailandicum. Our findings provided new insights into the species of Translucidithyrium about ecological adaptation and speciation in two separate areas.

Background: Short tandem repeats (STRs) are highly variable elements that play a pivotal role in multiple genetic diseases and the regulation of gene expression. Long-read sequencing (LRS) offers a potential solution to genome-wide STR analysis. However, characterizing STRs in human genomes using LRS on a large population scale has not been reported.Methods: We conducted the large LRS-based STR analysis in 193 unrelated samples of the Chinese population and performed genome-wide profiling of STR variation in the human genome. The repeat dynamic index (RDI) was introduced to evaluate the variability of STR. We sourced the expression data from the Genotype-Tissue Expression to explore the tissue specificity of highly variable STRs related genes across tissues. Enrichment analyses were also conducted to identify potential functional roles of the high variable STRs.Results: This study reports the large-scale analysis of human STR variation by LRS and offers a reference STR database based on the LRS dataset. We found that the disease-associated STRs (dSTRs) and STRs associated with the expression of nearby genes (eSTRs) were highly variable in the general population. Moreover, tissue-specific expression analysis showed that those highly variable STRs related genes presented the highest expression level in brain tissues, and enrichment pathways analysis found those STRs are involved in synaptic function-related pathways.Conclusion: Our study profiled the genome-wide landscape of STR using LRS and highlighted the highly variable STRs in the human genome, which provide a valuable resource for studying the role of STRs in human disease and complex traits.

Increasing evidence reveals sex as an important factor in the development of Parkinson’s disease (PD), but associations between genes on the sex chromosomes and PD remain unknown. TAF1 is a gene located on the X chromosome which is known to cause X-linked syndromic mental retardation-33 (MRXS33) and X-linked Dystonia-Parkinsonism (XDP). In this study, we conducted whole-exome sequencing (WES) among 1,917 patients with early-onset or familial PD and 1,652 controls in a Chinese population. We detected a hemizygous frameshift variant c.29_53dupGGA(CAG)2CTACCATCA(CTG)2C (p.A19Dfs*50) in two unrelated male patients. Further segregation analysis showed an unaffected family member carried this variant, which suggested the penetrance of the variant may be age-related and incomplete. To verify the effects of TAF1 on PD, genetic analyses were carried separately by gender. Analysis of rare variants by optimal sequence kernel association (SKAT-O) test showed a nominally significant difference in variant burden between the male PD patients and controls (2.01 vs. 1.38%, p = 0.027). In the female group, none of the variant types showed significant association with PD in this study. In conclusion, we found rare variants in TAF1 may be implicated in PD, but further genetic and functional analyses were needed.

Abstract Background Both de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD). This study aimed to use exome data to prioritize recessive inherited genes (RIGs) with biallelically inherited variants in autosomes or X-linked inherited variants in males and investigate the functional relationships between RIGs and genes with de novo variants (DNGs). Methods We used a bioinformatics pipeline to analyze whole-exome sequencing data from 1799 ASD quads (containing one proband, one unaffected sibling, and their parents) from the Simons Simplex Collection and prioritize candidate RIGs with rare biallelically inherited variants in autosomes or X-linked inherited variants in males. The relationships between RIGs and DNGs were characterized based on different genetic perspectives, including genetic variants, functional networks, and brain expression patterns. Results Among the biallelically or hemizygous constrained genes that were expressed in the brain, ASD probands carried significantly more biallelically inherited protein-truncating variants (PTVs) in autosomes (p = 0.038) and X-linked inherited PTVs in males (p = 0.026) than those in unaffected siblings. We prioritized eight autosomal, and 13 X-linked candidate RIGs, including 11 genes already associated with neurodevelopmental disorders. In total, we detected biallelically inherited variants or X-linked inherited variants of these 21 candidate RIGs in 26 (1.4%) of 1799 probands. We then integrated previously reported known or candidate genes in ASD, ultimately obtaining 70 RIGs and 87 DNGs for analysis. We found that RIGs were less likely to carry multiple recessive inherited variants than DNGs were to carry multiple de novo variants. Additionally, RIGs and DNGs were significantly co-expressed and interacted with each other, forming a network enriched in known functional ASD clusters, although RIGs were less likely to be enriched in these functional clusters compared with DNGs. Furthermore, although RIGs and DNGs presented comparable expression patterns in the human brain, RIGs were less likely to be associated with prenatal brain regions, the middle cortical layers, and excitatory neurons than DNGs. Limitations The RIGs analyzed in this study require functional validation, and the results should be replicated in more patients with ASD. Conclusions ASD RIGs were functionally associated with DNGs; however, they exhibited higher heterogeneity than DNGs.

Hearing loss (HL) is one of the most common disabilities in the world. In industrialized countries, HL occurs in 1–2/1,000 newborns, and approximately 60% of HL is caused by genetic factors. Next generation sequencing (NGS) has been widely used to identify many candidate genes and variants in patients with HL, but the data are scattered in multitudinous studies. It is a challenge for scientists, clinicians, and biologists to easily obtain and analyze HL genes and variant data from these studies. Thus, we developed a one-stop database of HL-related genes and variants, Gene4HL (http://www.genemed.tech/gene4hl/), making it easy to catalog, search, browse and analyze the genetic data. Gene4HL integrates the detailed genetic and clinical data of 326 HL-related genes from 1,608 published studies, along with 62 popular genetic data sources to provide comprehensive knowledge of candidate genes and variants associated with HL. Additionally, Gene4HL supports the users to analyze their own genetic engineering network data, performs comprehensive annotation, and prioritizes candidate genes and variations using custom parameters. Thus, Gene4HL can help users explain the function of HL genes and the clinical significance of variants by correlating the genotypes and phenotypes in humans.

As a deep-processed product of peach, the aroma characteristics of peach spirit have not been systematically studied, and there has been no research on improving the aroma quality through process improvement. Pervaporation technology was used for the first time in the production of peach spirit instead of distillation, and its critical aroma compounds were analyzed compared with distilled peach spirit. Compared to the distilled peach spirit, pervaporation produced peach spirit presented stronger fruity, honey, and acidic aromas, and lighter cooked-apple aroma. Sixty-two and 65 aroma-active regions were identified in the distilled and pervaporation produced peach spirits, and 40 and 43 of them were quantified. The concentrations of esters, lactones, and acids were significantly higher in the pervaporation produced peach spirit than those in the distilled peach spirit, while terpenoids showed opposite tendency. Both of the overall aromas of distilled and pervaporation produced peach spirits were reconstituted successfully by the compounds with OAV ≥ 1. The omission tests identified 10 and 18 compounds as important aroma compounds for distilled and pervaporation-produced peach spirits, respectively. The differences in the key aroma compounds between the two types of peach spirits explained the differences in the aroma profiles.

BackgroundThe expression pattern represents a quantitative phenotype that provides an in-depth view of the molecular mechanism in Parkinson’s disease (PD); however, the expression patterns of PD-associated genes (PAGs) and their relation to age at onset (AAO) remain unclear.MethodsThe known PD-causing genes and PD-risk genes, which were collected from latest published authoritative meta-analysis, were integrated as PAGs. The expression data from Genotype-Tissue Expression database, Allen Brian Map database, and BrainSpan database, were extracted to characterize the tissue specificity, inhibitory-excitatory neuron expression profile, and spatio-temporal expression pattern of PAGs, respectively. The AAO information of PD-causing gene was download from Gene4PD and MDSgene database.ResultsWe prioritized 107 PAGs and found that the PAGs were more likely to be expressed in brain-related tissues than non-brain tissues and that more PAGs had higher expression levels in excitatory neurons than inhibitory neurons. In addition, we identified two spatio-temporal expression modules of PAGs in human brain: the first module showed a higher expression level in the adult period than in the prenatal period, and the second module showed the opposite features. It showed that more PAGs belong to the first module that the second module. Furthermore, we found that the median AAO of patients with mutations in PD-causing genes of the first module was lower than that of the second module.ConclusionIn conclusion, this study provided comprehensive landscape of expression patterns, AAO features and their relationship for the first time, improving the understanding of pathogenesis, and precision medicine in PD.

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.

BackgroundNon-alcoholic fatty liver disease (NAFLD) poses a significant health concern worldwide. With the progression of urbanization, light pollution may be a previously unrecognized risk factor for NAFLD/NASH development. However, the role of light pollution on NAFLD is insufficiently understood, and the underlying mechanism remains unclear. Interestingly, recent studies indicate the gut microbiota affects NAFLD/NASH development. Therefore, the present study explored effects of constant light exposure on NAFLD and its related microbiotic mechanisms.Materials and MethodsTwenty-eight SD male rats were divided into four groups (n = 7 each): rats fed a normal chow diet, and exposed to standard light-dark cycle (ND-LD); rats fed a normal chow diet, and exposed to constant light (ND-LL); rats fed a high fat diet, and exposed to standard light-dark cycle (HFD-LD); and rats on a high fat diet, and exposed to constant light (HFD-LL). Body weight, hepatic pathophysiology, gut microbiota, and short/medium chain fatty acids in colon contents, serum lipopolysaccharide (LPS), and liver LPS-binding protein (LBP) mRNA expression were documented post intervention and compared among groups.ResultIn normal chow fed groups, rats exposed to constant light displayed glucose abnormalities and dyslipidemia. In HFD-fed rats, constant light exposure exacerbated glucose abnormalities, insulin resistance, inflammation, and liver steatohepatitis. Constant light exposure altered composition of gut microbiota in both normal chow and HFD fed rats. Compared with HFD-LD group, HFD-LL rats displayed less Butyricicoccus, Clostridium, and Turicibacter, butyrate levels in colon contents, decreased colon expression of occludin-1 and zonula occluden−1 (ZO-1), and increased serum LPS and liver LBP mRNA expression.ConclusionConstant light exposure impacts gut microbiota and its metabolic products, impairs gut barrier function and gut-liver axis, promotes NAFLD/NASH progression in HFD rats.

Dietary fatty acid intake is closely related to the cognitive function of the overweight and obese population. However, few studies have specified the correlation between exact fatty acids and cognitive functions in different body mass index (BMI) groups. We aimed to explain these relationships and reference guiding principles for the fatty acid intake of the overweight and obese population. Normal weight, overweight, and obese participants were recruited to receive a cognitive function assessment and dietary survey, dietary fatty acids intake was calculated, and the erythrocyte membrane fatty acid profile was tested by performing a gas chromatography analysis. The percentages of saturated fatty acids (SFAs) in the obese group were higher, while monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) were lower than in the normal weight and overweight groups. In the erythrocyte membrane, the increase of n-3 PUFAs was accompanied by cognitive decline in the overweight group, which could be a protective factor for cognitive function in the obese group. High n-6 PUFAs intake could exacerbate the cognitive decline in the obese population. Dietary fatty acid intake had different effects on the cognitive function of overweight and obese people, especially the protective effect of n-3 PUFAs; more precise dietary advice is needed to prevent cognitive impairment.

De novo variants (DNVs) are critical to the treatment of neurodevelopmental disorders (NDDs). However, effectively identifying candidate genes in small cohorts is challenging in most NDDs because of high genetic heterogeneity. We hypothesised that integrating DNVs from multiple NDDs with genetic similarity can significantly increase the possibility of prioritising the candidate gene. We catalogued 66,186 coding DNVs in 50,028 individuals with nine types of NDDs in cohorts with sizes spanning from 118 to 31,260 from Gene4Denovo database to validate this hypothesis. Interestingly, we found that integrated DNVs can effectively increase the number of prioritised candidate genes for each disorder. We identified 654 candidate genes including 481 shared candidate genes carrying putative functional variants in at least two disorders. Notably, 13.51% (65/481) of shared candidate genes were prioritised only via integrated analysis including 44.62% (29/65) genes validated in recent large cohort studies. Moreover, we estimated that more novel candidate genes will be prioritised with the increase in cohort size, in particular for some disorders with high putative functional DNVs per individual. In conclusion, integrated DNVs may increase the power of prioritising candidate genes, which is important for NDDs with small cohort size.