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To determine the methylation levels of CpGs in the GPX3 promoter region and explore their potential effects on the apoptosis of chondrocytes. Blood specimens were collected from 32 participants; 16 KBD patients and 16 healthy subjects. Twenty-five CpGs in the promoter region of GPX3 were identified and detected by MALDI-TOF-MS. Methylation levels of CpGs were compared between KBD patients and healthy subjects as well as among the KBD patients with different degrees. C28/I2 human chondrocytes were treated with tBHP and Na 2 SeO 3. Apoptosis in chondrocytes was examined under a fluorescence microscope. The methylation levels of GPX3 -1_CpG_11 and GPX3 -1_CpG_16 in KBD patients were significantly higher than those of healthy subjects (P < 0.05). The methylation levels of the other CpGs were not significantly different between the two groups (P > 0.05). The methylation level of GPX3 -1_CpG_24 in KBD patients was significantly higher than those of healthy subjects (P < 0.05). MSP-PCR analysis indicated that the methylation rate of KBD group (9.41%) was significantly higher than that of healthy subjects (1.18%), and that GPX3 DNA methylation increased the risk of acquiring KBD 8 fold (OR = 8.000, 95% CI: 1.023–62.580); The mRNA expression of GPX3 in whole blood of KBD patients was lower than that of healthy subjects (P ＜0.05); Compared with the control group, GPX3, GPX1 and GPX4 mRNA level of the tertbutyl hydroperoxide injury group decreased significantly (P < 0.05), after supplementation with Na 2 SeO 3. The rate of chondrocytes apoptosis was decreased with the increasing of GPX3 and GPX4 mRNA levels (P ＜0.05) and GPX3 mRNA showed a similar trend without statistically significant (P ＞0.05). The methylation patterns of CpGs in GPX3 varied in KBD patients. The experiments indicated that the increased methylation of CpGs within the GPX3 promoter may down-regulate the expression of GPX3, thereby reducing the antioxidant function of GPX3 and promoting chondrocyte apoptosis, both of which accelerates the occurrence of KBD. We therefore propose a new understanding of GPX3 's potential epigenetic and genetic mechanisms that contribute to KBD. [ABSTRACT FROM AUTHOR]

This study was aimed to evaluate the associations of adult heel bone mineral density (BMD) with birth weight and growth parameters at the age of ten years. The analysis data (97178–178,494 subjects) was derived from the UK Biobank cohort. Birth weight, comparative body size and height size at the age of ten years were determined by self-report. The heel BMD was estimated by the Quantitative Ultrasound Index through the calcaneus. Linear regression analysis was applied to test the associations of adult heel BMD with birth weight and growth parameters at the age of ten years, respectively. Age, sex, body mass index and 10 principle components (PC) of population structure were used as covariates in the regression analysis of total samples. In sex-specific analysis, age, body mass index and 10 PC were used as covariates. We observed significant associations of heel BMD with birth weight (b = −0.020, P = 1.974 × 10−13), comparative body size (b = 0.020, P = 2.539 × 10−6) and comparative height size (b = −0.020, P = 5.892 × 10−11) at the age of ten years in total samples. In females, birth weight (b = −0.040, P = 2.870 × 10−24) and comparative height size (b = −0.040, P = 2.034 × 10−20) were statistically associated with adult heel BMD. In males, comparative body size appeared to be associated with adult heel BMD (b = 0.030, P = 1.590 × 10−7). Our study results support the predictive effects of birth weight and growth parameters at the age of ten years on adult heel BMD. We also observed sex-specific association between adult heel BMD and growth parameters at the age of ten years. • Birth weight was negatively associated with adult heel BMD in total sample. • Growth parameters at age 10 were correlated with adult heel BMD in total sample. • Birth weight, comparative height size at age 10 was related to heel BMD of women. • Comparative body size at age 10 was significantly associated with heel BMD of men. [ABSTRACT FROM AUTHOR]

Zirconate fibrous membranes show promising applications in high thermal insulating areas for the high melting point, low thermal conductivity and good phase stability. To satisfy the high-temperature mechanical demands, the microstructure of zirconate fibers needs further modification to accommodate high-temperature stability. In consideration of the slow ion diffusion rate and enhanced stability of solid solution, Ca x Sr 1- x ZrO 3 fibrous membranes were electrospun with molar ratio of Ca/Sr varied from 0.9 to 0.5 for the present work. The effects of strontium precursor on the pyrolysis process, phase formation and microstructure evolution were fully characterized. Modified microstructures with smaller grain size and narrow particle size distribution were achieved. Furthermore, the NIR reflectivity, thermal conductivity, and high-temperature stability were also presented. The special expansion character of fibrous membrane at high temperature would make it promising candidate to compensate the shrinkage of other oxide fibrous membrane. [ABSTRACT FROM AUTHOR]

Comparing with the general population, the pain in depression patients has more complex biological mechanism. We aim to explore the etiological mechanism of pain in depression patients from the perspective of genetics. Utilizing the UK Biobank samples with self-reported depression status or PHQ score ≥10, we conducted genome-wide association studies (GWAS) of seven pain traits (N = 1,133–58,349). Additionally, we used FUSION pipeline to perform proteome-wide association study (PWAS) and transcriptome-wide association study (TWAS) by integrating GWAS summary data with two different proteome reference weights (ROS/MAP and Banner) and Rnaseq gene expression reference weights, respectively. GWAS identified 3 significant genes associated with different pain traits in depression patients, including TRIOBP (P GWAS = 4.48 × 10−8) for stomach or abdominal pain, SLC9A9(P GWAS = 2.77 × 10−8) for multisite chronic pain (MCP) and ADGRF1 (P GWAS = 1.51 × 10−8) for neck or shoulder pain. In addition, PWAS and TWAS analysis also identified multiple candidate genes associated with different pain traits in depression patients, such as TPRG1L (P PWAS-Banner = 3.38 × 10−2) and SIRPA (P PWAS-Banner = 3.65 × 10−2) for MCP, etc. Notably, when comparing the results of PWAS and TWAS analysis, we found overlapping candidate genes in these pain traits, such as GSTM3 (P PWAS - Banner = 3.38 × 10−2, P TWAS = 6.92 × 10−3) in the stomach or abdominal pain phenotype, ATG7 (P PWAS - Rosmap = 3.15 × 10−2, P TWAS = 2.98 × 10−2) in the MCP, etc. We identified multiple novel candidate genes for pain traits in depression patients from different perspectives of genetics, which provided novel clues for understanding the genetic mechanisms underlying the pain in depression patients. [ABSTRACT FROM AUTHOR]

The effects of gene-by-environment (G×E) interactions on complex diseases are significant, especially the superimposed effects of multiple environmental factors. However, research on the multi-environments-gene interactions of anxiety, depression, and self-harm is still limited. This study included white individuals (N = 66,041–74,482) from the UK Biobank. We fitted all environmental factors to a single environmental score (ES), and the estimated ES was used to calculate the multiplicative interaction effects between ES and genome-wide SNPs. Heritability was stratified by minor allele frequency (MAF) and linkage disequilibrium (LD). Our research found 10 loci with significant interaction effects, such as rs114830993 (PRICKLE2, P = 2.30 × 10−8), rs151323364 (ASTN2, P = 2.71 × 10−10) and rs536631793 (SYN3, P = 4.09 × 10−8). In addition, we found that G×E heritability has a significant contribution to the depression of Patient Health Questionnaire-9 (PHQ-9) scores (h2 G×E (female) = 6.1%, h2 G×E (male) = 8.7%). Our research supported the important influence of multi-environments-gene interactions on anxiety, depression, and self-harm and provided clues for the prevention and etiological research of them. [ABSTRACT FROM AUTHOR]

Rare variants are believed to play a substantial role in the genetic architecture of mental disorders, particularly in coding regions. However, limited evidence supports the impact of rare variants on anxiety. Using whole-exome sequencing data from 200,643 participants in the UK Biobank, we investigated the contribution of rare variants to anxiety. Firstly, we computed genetic risk score (GRS) of anxiety utilizing genotype data and summary data from a genome-wide association study (GWAS) on anxiety disorder. Subsequently, we identified individuals within the lowest 50% GRS, a subgroup more likely to carry pathogenic rare variants. Within this subgroup, we classified individuals with the highest 10% 7-item Generalized Anxiety Disorder scale (GAD-7) score as cases (N = 1869), and those with the lowest 10% GAD-7 score were designated as controls (N = 1869). Finally, we conducted gene-based burden tests and single-variant association analyses to assess the relationship between rare variants and anxiety. Totally, 47,800 variants with MAF ≤0.01 were annotated as non-benign coding variants, consisting of 42,698 nonsynonymous SNVs, 489 nonframeshift substitution, 236 frameshift substitution, 617 stop-gain and 40 stop-loss variants. After variation aggregation, 5066 genes were included in gene-based association analysis. Totally, 11 candidate genes were detected in burden test, such as RNF123 (P Bonferroni adjusted = 3.40 × 10−6), MOAP1 (P Bonferroni adjusted = 4.35 × 10−4), CCDC110 (P Bonferroni adjusted = 5.83 × 10−4). Single-variant test detected 9 rare variants, such as rs35726701(RNF123)(P Bonferroni adjusted = 3.16 × 10−10) and rs16942615(CAMTA2) (P Bonferroni adjusted = 4.04 × 10−4). Notably, RNF123 , CCDC110 , DNAH2 , and CSKMT gene were identified in both tests. Our study identified novel candidate genes for anxiety in protein-coding regions, revealing the contribution of rare variants to anxiety. • We investigated the rare variants for anxiety among 3738 European individuals with lower anxiety GWAS-derived polygenic risk. • Gene-based burden test revealed 11 candidate genes for anxiety, such as RNF123 , DNAH2 and CCDC110. • Single variant association analysis detected 9 rare variants for anxiety, such as rs35726701(RNF123) and rs16942615(CAMTA2). [ABSTRACT FROM AUTHOR]

Kashin-Beck disease (KBD) is an endemic chronic osteochondropathy. The clinical manifestations and radiographic features of adult KBD were similar to those of osteoarthritis (OA). We first performed a genetic association scan of 32 OA susceptibility genes with KBD in 898 Han Chinese subjects. The MassARRAY genotyping system (Agena) was used for SNP genotyping. PLINK 1.9 was used for quality control and association testing. Using articular cartilage specimens from 7 adult KBD patients and 4 control subjects, lentivirus-mediated RNA interference (RNAi), qRT-PCR, Western blot and immunohistochemistry were employed to explore the functional relevance of TP63 to KBD chondrocyte. SNP genotyping and association analysis identified TP63 (rs12107036, P = 0.005, OR = 0.71) and OARD1 (rs11280, P = 0.004, OR = 1.51) were significantly associated with KBD. It was also found that TP63 was significantly up-regulated in KBD articular cartilage in both mRNA and protein level compared with the controls (P < 0.05). TP63 suppression by lentivirus-mediated RNAi notably decreased the abundance of Caspase3 and SOX9 in chondrocytes. Most importantly, compared with the scrambled sequence (shControl) group, the protein level of ACAN was increased in the shTP63 group. The mRNA expression of chondrocyte marker genes (COL2A1 and ACAN) was not significantly changed after TP63 knockdown relative to shControl group. Our study identifies TP63 as a novel susceptibility gene for KBD, and demonstrates that the inhibition of TP63 suppresses chondrocyte apoptosis and partly facilitates chondrogenesis. The combination of SNP genotyping and molecular biology techniques provides a useful tool for understanding the biological mechanism and differential diagnosis studies of KBD and OA. • Genetic association analysis identified TP63 was significantly associated with KBD. • TP63 was significantly up-regulated in KBD articular cartilage. • The inhibition of TP63 suppresses Caspase-3 mediated apoptosis and promotes chondrogenesis in KBD chondrocyte. • TP63 was proved to have an involvement in KBD development by an integrative study of SNP genotyping and RNAi. [ABSTRACT FROM AUTHOR]

Previous genetic studies of anxiety and depression were mostly based on independent phenotypes. This study aims to investigate the shared and specific genetic structure between anxiety and depression. To identify the underlying factors of Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and their combined scale (joint scale), we employed exploratory factor analysis (EFA) using the eigenvalue of parallel analysis. Subsequently, we conducted a genome-wide association study (GWAS) for these factors. In addition, we utilized LD Score Regression (LDSC) to determine the genetic correlations between the identified factors and four common mental disorders, three sleep phenotypes, and other traits that have been previously linked to anxiety and depression. The EFA uncovered two factors for the GAD-7 scale, namely nervousness and disturbance, two factors for the PHQ-9 scale, namely negative affect and sleep/appetite disturbance, and four factors for the joint scale, specifically nervousness, anhedonia, sleep/appetite disturbance, and fidget. We identified two genome-wide significant genomic loci, with overlap across GAD-7 factor 1 and joint scale factor 1: rs148579586 (P GAD-7 = 1.365 × 10−09, P Joint scale = 1.434 × 10–09) and rs201074060 (P GAD-7 = 3.672 × 10−09, P Joint scale = 3.824 × 10−09). Genetic correlations in factors ranged from 0.722 to 1.000 (all p < 1.786 × 10−03) with 27 of 28 correlations being significantly smaller than one. The genetic correlations with external phenotypes showed small variation across the eight factors. Unidimensional structures can provide more precise scores, which can aid in identifying the shared and specific genetic associations between anxiety and depression. This is a crucial step in characterizing the genetic structure of these conditions and their co-occurrence. • We used EFA to identify potential factors for GAD-7, PHQ-9 and the joint scale. • we found common and specific genetic structures between anxiety and depression. • Single-dimensional structures can build more precise fractions. [ABSTRACT FROM AUTHOR]