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1.
Sleep Med ; 85: 184-190, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34343768

RESUMO

STUDY OBJECTIVES: We aim to explore the mechanism of relationship between insomnia and liver metabolism by examining the gene × insomnia interactions. METHODS: Individual level genotypic and phenotypic data were obtained from the UK Biobank cohort. Regression analysis was first conducted to test the association of insomnia with plasma total bilirubin (TBil; n = 186,793), direct bilirubin (DBil; n = 159,854) and total protein (TP; n = 171,574) in UK Biobank cohort. Second, genome-wide gene-environment interaction study (GWGEIS) was conducted by PLINK 2.0, and FUMA platform was used to identify enriched pathway terms. RESULTS: In UK Biobank cohort, we found that TP (P < 2.00 × 10-16), DBil (P = 1.72 × 10-3) and TBil (P = 3.38 × 10-5) were significantly associated with insomnia. GWGEIS of both DBil and TBil observed significant G × INSOMNIA effects between insomnia and UDP Glucuronosyltransferase Family 1 (rs6431558, P = 6.26 × 10-11) gene. GWGEIS of TP also detected several significant genes interacting with insomnia, such as KLF15, (rs70940816, P = 6.77 × 10-10) and DOK7, (rs2344205, P = 1.37 × 10-9). Multiple gene ontology (GO) terms were identified for bilirubin, such as GO_URONIC_ACID_METABOLIC_PROCESS (adjusted P = 4.15 × 10-26). CONCLUSION: Our study results suggested negative associations between insomnia and DBil and TBil; and a positive association between insomnia and TP.

2.
FEBS J ; 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34324261

RESUMO

Kashin-Beck disease (KBD) is an endemic osteochondropathy. Due to a lack of suitable animal or cellular disease models, the research progress on KBD has been limited. Our goal was to establish the first disease-specific human induced pluripotent stem cell (hiPSC) cellular disease model of KBD, and to explore its etiology and pathogenesis exploiting transcriptome sequencing. HiPSCs were reprogrammed from dermal fibroblasts of two KBD and one healthy control donor via integration-free vectors. Subsequently, hiPSCs were differentiated into chondrocytes through three-week culture. Gene expression profiles in KBD, normal primary chondrocytes, and hiPSC-derived chondrocytes were defined by RNA sequencing. A Venn diagram was constructed to show the number of shared differentially expressed genes (DEGs) between KBD and normal. Gene oncology and Kyoto Encyclopedia of Genes and Genomes annotations were performed, and six DEGs were further validated in other individuals by RT-qPCR. KBD cellular disease models were successfully established by generation of hiPSC lines. Seventeen consistent and significant DEGs present in all compared groups (KBD and normal) were identified. RT-qPCR validation gave consistent results with the sequencing data. Glycosaminoglycan biosynthesis-heparan sulfate/heparin; PPAR signaling pathway; and cell adhesion molecules (CAMs) were identified to be significantly altered in KBD. Differentiated chondrocytes derived from KBD-origin hiPSCs provide the first cellular disease model for etiological studies of KBD. This study also provides new sights into the pathogenesis and etiology of KBD and is likely to inform the development of targeted therapeutics for its treatment.

3.
Aging (Albany NY) ; 13(13): 17789-17817, 2021 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-34247149

RESUMO

Chemokines play a significant role in cancer. CXC-motif chemokine ligands (CXCLs) are associated with the tumorigenesis and progression of head and neck squamous cell carcinoma (HNSC); however, their specific functions in the tumor microenvironment remain unclear. Here, we analyzed the molecular networks and transcriptional data of HNSC patients from the Oncomine, GEPIA, String, cBioPortal, Metascape, TISCH, and TIMER databases. To verify immune functions of CXCLs, their expression was analyzed in different immune cell types. To our knowledge, this is the first report on the correlation between CXCL9-12 and 14 expression and advanced tumor stage. CXCL2, 3, 8, 10, 13, and 16 were remarkably related to tumor immunity. Kaplan-Meier and TIMER survival analyses revealed that high expression of CXCL1, 2, 4, and 6-8 is correlated with low survival in HNSC patients, whereas high expression of CXCL9, 10, 13, 14, and 17 predicts high survival. Only CXCL13 and 14 were associated with overall survival in human papilloma virus (HPV)-negative patients. Single-cell datasets confirmed that CXCLs are associated with HNSC-related immune cells. Thus, CXCL1-6, 8-10, 12-14, and 17 could be prognostic targets for HNSC, and CXCL13 and 14 could be novel biomarkers of HPV-negative HNSC.


Assuntos
Quimiocinas CXC/genética , Biologia Computacional/métodos , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Microambiente Tumoral/genética , Biomarcadores Tumorais/análise , Quimiocinas CXC/análise , Sondas de DNA de HPV/análise , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Redes e Vias Metabólicas/genética , Prognóstico , Sensibilidade e Especificidade , Análise de Sobrevida
4.
J Psychiatr Res ; 140: 149-158, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34118634

RESUMO

BACKGROUND: Maternal smoking during pregnancy (MSDP) has been reported to be associated with increased anxiety and depression behaviors in offspring. However, there is still scant evidence to support the link between MSDP and anxiety/depression. METHODS: Using the subjects from the UK Biobank cohort (n = 371,903-432,881). Logistic regression analyses were first conducted to test the correlation between MSDP and anxiety/depression in offspring. Second, genome-wide gene-environment interaction study (GWGEIS) analyses were conducted by PLINK, using MSDP as environmental factor. Genetic correlation analysis of anxiety/depression and smoking was conducted by the LDSC software using the published genome-wide association study (GWAS) summary data of four smoking traits (n = 337,334-1,232,091), anxiety (n = 31,880) and depression (n = 490,359). Finally, pathway enrichment analysis was carried out to detect the pathway involved in the development of offspring anxiety caused by the interaction of MSDP × SNPs. RESULTS: Observational analyses showed that anxiety and depression status in offspring were significantly associated with MSDP (all p < 0.0001). Further GWEGI analyses observed significant MSDP-gene interaction effects at UNC80 gene for anxiety (p = 9.09 × 10-9). LDSC did not detect significant genetic correlation between anxiety and smoking traits. Pathway analysis identified 19 significant pathways for anxiety, such as MANALO_HYPOXIA_UP (FDR = 5.50 × 10-4), REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS (FDR = 0.0304) and ONDER_CDH1_TARGETS_2_UP (FDR = 0.0371). CONCLUSION: Our study results suggested the important impact of MDSP on the risk of anxiety in offspring, partly attributing to environment-gene interactions effects.


Assuntos
Interação Gene-Ambiente , Efeitos Tardios da Exposição Pré-Natal , Ansiedade/epidemiologia , Ansiedade/genética , Bancos de Espécimes Biológicos , Proteínas de Transporte , Depressão/epidemiologia , Depressão/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Fumar , Reino Unido/epidemiologia
5.
Endocrine ; 73(3): 702-711, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34046847

RESUMO

INTRODUCTION: Serum urate is associated with BMD and may be a protective factor. However, the exact association and mechanism are still unclear. We performed a genome-wide gene-environmental interaction study (GWGEIS) to explore the interaction effects between gene and urate on BMD, using data from the UK Biobank cohort. METHODS: A total of 4575 participants for femur total BMD, 4561 participants for L1-L4 BMD, and 237799 participants for heel BMD were included in the present study. Linear regression models were used to test for associations between urate and BMD (femur total BMD, L1-L4 BMD, heel BMD) by R software. GWGEIS was conducted by PLINK 2.0 using a generalize linear model, adjusted for age, sex, weight, smoking behavior, drinking behavior, physical activity and 10 principle components for population structure. RESULTS: Results showed that urate was positively associated with femur total BMD, L1-L4 BMD and heel BMD and similar findings were observed in both the male and female subgroups. GWGEIS identified 261 genome-wide significant (P < 5.00 × 10-8) SNP × urate interaction effects for femur total BMD (rs8192585 in NOTCH4, rs116080577 in PBX1, rs9409991 in COL5A1), 17 genome-wide significant SNP × urate interaction effects for heel BMD (rs145344540 in PDE11A and rs78485379 in DKK2), 17 suggestive genome-wide SNP × urate interaction effects (P < 1.00 × 10-5) for L1-L4 BMD (rs10977015 in PTPRD). We also detected genome-wide significant and suggestive SNP × urate interaction effects for BMD in both the male and female subgroups. CONCLUSIONS: This study reported several novel candidate genes, and strengthen the evidence of the interactive effects between gene and urate on the variations of BMD.


Assuntos
Densidade Óssea , Ácido Úrico , Bancos de Espécimes Biológicos , Densidade Óssea/genética , Feminino , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Reino Unido
6.
Cell Death Dis ; 12(6): 551, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045450

RESUMO

Chondrocytes are the key target cells of the cartilage degeneration that occurs in Kashin-Beck disease (KBD) and osteoarthritis (OA). However, the heterogeneity of articular cartilage cell types present in KBD and OA patients and healthy controls is still unknown, which has prevented the study of the pathophysiology of the mechanisms underlying the roles of different populations of chondrocytes in the processes leading to KBD and OA. Here, we aimed to identify the transcriptional programmes and all major cell populations in patients with KBD, patients with OA and healthy controls to identify the markers that discriminate among chondrocytes in these three groups. Single-cell RNA sequencing was performed to identify chondrocyte populations and their gene signatures in KBD, OA and healthy cells to investigate their differences as related to the pathogenetic mechanisms of these two osteochondral diseases. We performed immunohistochemistry and quantitative reverse-transcription PCR (qRT-PCR) assays to validate the markers for chondrocyte population. Ten clusters were labelled by cell type according to the expression of previously described markers, and one novel population was identified according to the expression of a new set of markers. The homeostatic and mitochondrial chondrocyte populations, which were identified by the expression of the unknown markers MT1X and MT2A and MT-ND1 and MT-ATP6, were markedly expanded in KBD. The regulatory chondrocyte population, identified by the expression of CHI3L1, was markedly expanded in OA. Our study allows us to better understand the heterogeneity of chondrocytes in KBD and OA and provides new evidence of differences in the pathogenetic mechanisms between these two diseases.


Assuntos
Condrócitos/metabolismo , Doença de Kashin-Bek/diagnóstico , Osteoartrite/diagnóstico , RNA-Seq/métodos , Feminino , Humanos , Masculino
7.
Biol Psychiatry ; 89(9): 888-895, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33500177

RESUMO

BACKGROUND: Psychiatric disorders are among the largest and fastest-growing categories of the global disease burden. However, limited effort has been made to further elucidate associations between socioeconomic factors and psychiatric disorders from a genetic perspective. METHODS: We randomly divided 501,882 participants in the UK Biobank cohort with socioeconomic Townsend deprivation index (TDI) data into a discovery cohort and a replication cohort. For both cohorts, we first conducted regression analyses to evaluate the associations between the TDI and common psychiatric disorders or traits, including anxiety, bipolar disorder, self-harm, and depression (based on self-reported depression and Patient Health Questionnaire scores). We then performed a genome-wide gene-by-environment interaction study using PLINK 2.0 with the TDI as an environmental factor to explore interaction effects. RESULTS: In the discovery cohort, significant associations were observed between the TDI and psychiatric disorders (p < 4.00 × 10-16), including anxiety (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.07-1.10), bipolar disorder (OR = 1.42, 95% CI = 1.36-1.48), self-harm (OR = 1.21, 95% CI = 1.19-1.23), self-reported depression (OR = 1.22, 95% CI = 1.20-1.24), and Patient Health Questionnaire scores (ß = .07, SE = 0.004). We observed similar significant associations in the replication cohort. In addition, multiple candidate loci were identified by the genome-wide gene-by-environment interaction study, including rs10886438 at 10q26.11 (GRK5) (p = 5.72 × 10-11) for Patient Health Questionnaire scores and rs162553 at 2p22.2 (CYP1B1) (p = 2.25 × 10-9) for self-harm. CONCLUSIONS: Our findings suggest the relevance of the TDI to psychiatric disorders. The genome-wide gene-by-environment interaction study identified several candidate genes interacting with the TDI, providing novel clues for understanding the biological mechanism of associations between the TDI and psychiatric disorders.


Assuntos
Bancos de Espécimes Biológicos , Esquizofrenia , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Fatores Socioeconômicos , Reino Unido/epidemiologia
8.
Arthritis Res Ther ; 23(1): 38, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482886

RESUMO

OBJECTIVE: To identify rheumatoid arthritis (RA)-associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression profile data. METHODS: A transcriptome-wide association study (TWAS) was conducted by the FUSION software for RA considering EBV-transformed lymphocytes (EL), transformed fibroblasts (TF), peripheral blood (NBL), and whole blood (YBL). GWAS summary data was driven from a large-scale GWAS, involving 5539 autoantibody-positive RA patients and 20,169 controls. The TWAS-identified genes were further validated using the mRNA expression profiles and made a functional exploration. RESULTS: TWAS identified 692 genes with PTWAS values < 0.05 for RA. CRIPAK (PEL = 0.01293, PTF = 0.00038, PNBL = 0.02839, PYBL = 0.0978), MUT (PEL = 0.00377, PTF = 0.00076, PNBL = 0.00778, PYBL = 0.00096), FOXRED1 (PEL = 0.03834, PTF = 0.01120, PNBL = 0.01280, PYBL = 0.00583), and EBPL (PEL = 0.00806, PTF = 0.03761, PNBL = 0.03540, PYBL = 0.04254) were collectively expressed in all the four tissues/cells. Eighteen genes, including ANXA5, AP4B1, ATIC (PTWAS = 0.0113, downregulated expression), C12orf65, CMAH, PDHB, RUNX3 (PTWAS = 0.0346, downregulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, and TLR5 (PTWAS = 0.04665, upregulated expression), were validated with integrative analysis of TWAS and mRNA expression profiles. TWAS-identified genes functionally involved in endoplasmic reticulum organization, regulation of cytokine production, TNF signaling pathway, immune response-regulating signaling pathway, regulation of autophagy, etc. CONCLUSION: We identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA.


Assuntos
Artrite Reumatoide , Transcriptoma , Artrite Reumatoide/genética , Perfilação da Expressão Gênica , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Chaperonas Moleculares , Proteínas Nucleares , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases , RNA Mensageiro , Proteínas de Ligação a RNA , Transcriptoma/genética
9.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(11): 1628-1633, 2020 Nov 30.
Artigo em Chinês | MEDLINE | ID: mdl-33243751

RESUMO

OBJECTIVE: To evaluate the effect of rosmarinic acid (RA) on mitophagy and hypertrophy of cardiomyocytes exposed to high glucose (HG). METHODS: Rat cardiomyocytes (H9c2) exposed to HG (25 mmol/L) were treated with 50 µmol/L RA or with both RA treatment and Parkin siRNA transfection, with the cells cultured in normal glucose (5.5 mmol/L) and HG as the controls. The expressions of PINK1, Parkin and LC3II/LC3I in the cells were detected by Western blotting. The formation of mitochondrial autophagosomes was observed by transmission electron microscope. Flow cytometry was employed to detect the level of reactive oxygen species (ROS) and apoptotic rate of the cells. The activities of respiratory chain complex enzymes were measured by spectrophotometry. Fluorescence enzyme labeling and 3H-leucine labeling were used for determining the level of membrane potential and protein synthesis rate, respectively. The cell surface area was observed by light microscopy. RESULTS: RA treatment significantly increased the expression levels of PINK1, Parkin and LC3-II/I (P < 0.05), promoted the formation of mitochondrail autophagosome, inhibited the production of reactive oxygen species (P < 0.05), restored the activities of mitochondrial respiratory chain complex enzymes and mitochondrial membrane potential (P < 0.05), inhibited apoptosis (P < 0.05), and reduced the cell surface area and protein synthesis rate of H9c2 cells induced by HG exposure (P < 0.05). The protective effects of RA against HG-induced oxidative stress and cardiomyocyte hypertrophy was obviously blocked by inhibition of mitophagy mediated by transfection with Parkin siRNA (P < 0.05). CONCLUSIONS: RA can protect rat cardiomyocytes against oxidative stress injury and cardiomyocyte hypertrophy induced by HG by activating Parkin-mediated mitophagy.


Assuntos
Mitofagia , Miócitos Cardíacos , Animais , Cinamatos , Depsídeos , Glucose , Hipertrofia , Proteínas Quinases , Ratos , Espécies Reativas de Oxigênio , Ubiquitina-Proteína Ligases/genética
10.
Cell Cycle ; 19(18): 2351-2366, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32816579

RESUMO

Kashin-Beck disease (KBD) is an endemic chronic osteochondropathy. The etiology of KBD remains unknown. In this study, we conducted an integrative analysis of genome-wide DNA methylation and mRNA expression profiles between KBD and normal controls to identify novel candidate genes and pathways for KBD. Articular cartilage samples from 17 grade III KBD patients and 17 healthy controls were used in this study. DNA methylation profiling of knee cartilage and mRNA expression profile data were obtained from our previous studies. InCroMAP was performed to integrative analysis of genome-wide DNA methylation profiles and mRNA expression profiles. Gene ontology (GO) enrichment analysis was conducted by online DAVID 6.7. The quantitative real-time polymerase chain reaction (qPCR), Western blot, immunohistochemistry (IHC), and lentiviral vector transfection were used to validate one of the identified pathways. We identified 298 common genes (such as COL4A1, HOXA13, TNFAIP6 and TGFBI), 36 GO terms (including collagen function, skeletal system development, growth factor), and 32 KEGG pathways associated with KBD (including Selenocompound metabolism pathway, PI3K-Akt signaling pathway, and TGF-beta signaling pathway). Our results suggest the dysfunction of many genes and pathways implicated in the pathogenesis of KBD, most importantly, both the integrative analysis and in vitro study in KBD cartilage highlighted the importance of selenocompound metabolism pathway in the pathogenesis of KBD for the first time.

11.
Eur Psychiatry ; 63(1): e73, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32706328

RESUMO

BACKGROUND: Birth weight influences not only brain development, but also mental health outcomes, including depression, but the underlying mechanism is unclear. METHODS: The phenotypic data of 12,872-91,009 participants (59.18-63.38% women) from UK Biobank were included to test the associations between the birth weight, depression, and brain volumes through the linear and logistic regression models. As birth weight is highly heritable, the polygenic risk scores (PRSs) of birth weight were calculated from the UK Biobank cohort (154,539 participants, 56.90% women) to estimate the effect of birth weight-related genetic variation on the development of depression and brain volumes. Finally, the mediation analyses of step approach and mediation analysis were used to estimate the role of brain volumes in the association between birth weight and depression. All analyses were conducted sex stratified to assess sex-specific role in the associations. RESULT: We observed associations between birth weight and depression (odds ratio [OR] = 0.968, 95% confidence interval [CI] = 0.957-0.979, p = 2.29 × 10-6). Positive associations were observed between birth weight and brain volumes, such as gray matter (B = 0.131, p = 3.51 × 10-74) and white matter (B = 0.129, p = 1.67 × 10-74). Depression was also associated with brain volume, such as left thalamus (OR = 0.891, 95% CI = 0.850-0.933, p = 4.46 × 10-5) and right thalamus (OR = 0.884, 95% CI = 0.841-0.928, p = 2.67 × 10-5). Additionally, significant mediation effects of brain volume were found for the associations between birth weight and depression through steps approach and mediation analysis, such as gray matter (B = -0.220, p = 0.020) and right thalamus (B = -0.207, p = 0.014). CONCLUSIONS: Our results showed the associations among birth weight, depression, and brain volumes, and the mediation effect of brain volumes also provide evidence for the sex-specific of associations.


Assuntos
Bancos de Espécimes Biológicos , Peso ao Nascer/fisiologia , Encéfalo/anatomia & histologia , Encéfalo/fisiopatologia , Depressão/genética , Depressão/fisiopatologia , Tamanho do Órgão/fisiologia , Adulto , Idoso , Estudos de Coortes , Depressão/etiologia , Feminino , Substância Cinzenta/anatomia & histologia , Substância Cinzenta/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Regressão , Fatores de Risco , Tálamo/anatomia & histologia , Tálamo/fisiopatologia , Reino Unido/epidemiologia , Substância Branca/anatomia & histologia , Substância Branca/fisiopatologia
12.
G3 (Bethesda) ; 10(9): 3279-3284, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32690583

RESUMO

Shoulder impingement syndrome (SIS) is a common shoulder disorder with unclear genetic mechanism. In this study, Genome-wide Association Study (GWAS) was conducted to identify the candidate loci associated with SIS by using the UK Biobank samples (including 3,626 SIS patients and 3,626 control subjects). Based on the GWAS results, gene set enrichment analysis was further performed to detect the candidate gene ontology and pathways associated with SIS. We identified multiple risk loci associated with SIS, such as rs750968 (P = 4.82 × 10-8), rs754832 (P = 4.83 × 10-8) and rs1873119 (P = 6.39 × 10-8) of ANXA1 gene. Some candidate pathways have been identified related to SIS, including those linked to infection response and hypoxia, "ZHOU_INFLAMMATORY_RESPONSE_FIMA_DN" (P = 0.012) and "MANALO_HYPOXIA_UP" (P = 5.00 × 10-5). Our results provide novel clues for understanding the genetic mechanism of SIS.


Assuntos
Estudo de Associação Genômica Ampla , Síndrome de Colisão do Ombro , Bancos de Espécimes Biológicos , Humanos , Amplitude de Movimento Articular , Reino Unido
13.
Clin Transl Med ; 10(2): e108, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32564518

RESUMO

BACKGROUND: Herpes simplex virus-1 (HSV-1) infection is reported to be associated with depression. But limited efforts were made to investigate the relationship between HSV-1 infection and the risk of depression, especially from the genetic perspective. METHODS: In UK Biobank cohort, linear and logistic regression analyses were first performed to test the association of HSV-1 seropositivity/antibody with depression, including depression status (N = 2951) and Patient Health Questionnaire (PHQ) score (N = 2839). Using individual genotypic and phenotypic data from the UK Biobank, genome-wide environmental interaction study (GWEIS) was then conducted by PLINK2.0 to evaluate gene × HSV-1 interacting effect on the risk of depression. Finally, gene set enrichment analysis was conducted to identify the biological pathways involved in the observed gene × HSV-1 interaction for depression. RESULT: In UK Biobank cohort, significant associations were observed between depression status and HSV-1 (odds ratio [OR] = 1.09; 95% confidence interval [CI], 1.02-1.16; P = 2.40 × 10-2 for HSV-1 antibody and OR = 1.28; 95% CI, 1.12-1.47, P = 2.59 × 10-3 for HSV-1 seropositivity). GWEIS revealed four significant gene × HSV-1 interaction signals for PHQ score (all P < 5.0 × 10-8 ) and the leading loci was SULF2 (rs6094791, P = 8.60 × 10-9 ). Pathway analyses identified 21 pathways for PHQ score and 19 for depression status, including multiple neural development- and immune-related ones, such as KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION (false discovery rate [FDR] = 3.18 × 10-2 ) for depression and LU_AGING_BRAIN_UP (FDR = 4.21 × 10-2 ) for PHQ score. CONCLUSION: Our results suggested that HSV-1 was associated with the risk of depression, which was modulated by the several genes that were related to the nerve development or immune function.

14.
J Psychiatr Res ; 124: 22-28, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109668

RESUMO

Subjective well-being (SWB), depressive symptoms, and neuroticism are common and vital traits of mental disorders. Genetic mechanisms of SWB, depressive symptoms and neuroticism remain elusive now. The large-scale GWAS summary datasets of SWB (n = 229,883), depressive symptoms (n = 180,866), and neuroticism (n = 170,911) were obtained from published studies. MASH tool was applied to the GWAS datasets for identifying candidate SNPs shared by SWB, depressive symptoms and neuroticism. SNPs detected by MASH, were then mapped to target genes considering regulatory SNP (rSNP), methylated quantitative trait locus (MeQTL) and the SNPs near to known genes. Gene set enrichment analysis (GSEA) was conducted by the FUMA platform. A total of 122 candidate SNPs were detected by MASH analysis, mapping to 29 target genes, such as CLDN23, MSRA and XKR6. GO enrichment analysis identified multiple immune related gene sets for SWB, depressive symptoms and neuroticism, such as GSE2770_UNTREATED_VS_IL4_TREATED_ACT_CD4_TCELL_48H_DN (P = 7.32 × 10-3), GSE6259_FLT3L_INDUCED_DEC205_POS_DC_VS_CD4_TCELL_DN (P = 2.52 × 10-2). We also found some mental disorders related gene sets were associated with three phenotypes, such as mood instability (P = 1.15 × 10-6) and neuroticism (P = 1.72 × 10-6). We identified multiple candidate genes and GO terms shared by SWB, depressive symptoms and neuroticism. Our results support the overlapping genetic mechanisms, and suggest a functional correlation between immunity and SWB, depressive symptoms and neuroticism.


Assuntos
Depressão , Estudo de Associação Genômica Ampla , Depressão/genética , Predisposição Genética para Doença/genética , Humanos , Neuroticismo , Polimorfismo de Nucleotídeo Único/genética
15.
Aging (Albany NY) ; 12(4): 3287-3297, 2020 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-32090979

RESUMO

BACKGROUND: Risky behaviors can lead to huge economic and health losses. However, limited efforts are paid to explore the genetic mechanisms of risky behaviors. RESULT: MASH analysis identified a group of target genes for risky behaviors, such as APBB2, MAPT and DCC. For GO enrichment analysis, FUMA detected multiple risky behaviors related GO terms and brain related diseases, such as regulation of neuron differentiation (adjusted P value = 2.84×10-5), autism spectrum disorder (adjusted P value =1.81×10-27) and intelligence (adjusted P value =5.89×10-15). CONCLUSION: We reported multiple candidate genes and GO terms shared by the four risky behaviors, providing novel clues for understanding the genetic mechanism of risky behaviors. METHODS: Multivariate Adaptive Shrinkage (MASH) analysis was first applied to the GWAS data of four specific risky behaviors (automobile speeding, drinks per week, ever-smoker, number of sexual partners) to detect the common genetic variants shared by the four risky behaviors. Utilizing genomic functional annotation data of SNPs, the SNPs detected by MASH were then mapped to target genes. Finally, gene set enrichment analysis of the identified candidate genes were conducted by the FUMA platform to obtain risky behaviors related gene ontology (GO) terms as well as diseases and traits, respectively.


Assuntos
Transtorno do Espectro Autista/genética , Ontologia Genética , Inteligência/genética , Neurogênese/genética , Polimorfismo de Nucleotídeo Único , Assunção de Riscos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Transcriptoma
16.
Clin Transl Med ; 9(1): 21, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32107650

RESUMO

BACKGROUNDS: To explore the genetic correlation between schizophrenia (SCZ) and osteoporosis (OP). DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: We conducted a trans-ethnic two-stage genetic correlation analysis of OP and SCZ, totally invoking 2286 Caucasia subjects in discovery stage and 4124 Chinese subjects in replication stage. The bone mineral density (BMD) and bone area values of ulna & radius, hip and spine were measured using Hologic 4500W dual energy X-ray absorptiometry machine. SCZ was diagnosed according to DSM-IV criteria. For the genome-wide association study (GWAS) of Caucasian OP, Chinese OP and Chinese SCZ, SNP genotyping was performed using Affymetrix SNP 6.0 array. For the GWAS of Caucasian SCZ, SNP genotyping was conducted using the Affymetrix 5.0 array, Affymetrix 6.0 array and Illumina 550 K array. Polygenetic risk scoring (PRS) analysis was conducted by PRSice software. Also, Linkage disequilibrium score regression (LD Score regression) analysis was performed to evaluate the genetic correlation between OP and SCZ. Multi-trait analysis of GWAS (MTAG) was performed to detect novel candidate genes for osteoporosis and SCZ. RESULTS: In the Caucasia discovery samples, significant genetic correlations were observed for ulna & radius BMD vs. SCZ (P value = 0.010), ulna & radius area vs. SCZ (P value = 0.031). In the Chinese replication samples, we observed significant correlation for ulna & radius area vs. SCZ (P value = 0.019). In addition, LD Score regression also identified significant genetic correlations between SCZ and bone phenotypes in Caucasian and Chinese sample respectively. MTAG analysis identified several novel candidate genes, such as CTNNA2 (MTAG P value = 2.24 × 10-6) for SCZ and FADS2 (MTAG P value = 2.66 × 10-7) for osteoporosis. CONCLUSIONS: Our study results support the overlapped genetic basis for osteoporosis and SCZ, and provide novel clues for elucidating the biological mechanism of increased osteoporosis risk in SCZ patients.

17.
ACS Omega ; 4(23): 20265-20274, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31815229

RESUMO

The amphiphilic graphene derivative was prepared by covalent grafting of graphene oxide (GO) with isophorone diisocyanate and N,N-dimethylethanolamine and then noncovalent grafting of GO with sodium dodecylbenzenesulfonate. The results obtained from infrared spectroscopy, X-ray photoelectron spectroscopy, thermal gravimetric analysis, and X-ray diffraction analysis revealed that the short chains were successfully grafted onto the surface of GO. Subsequently, scanning electron microscopy and optical microscopy results showed that the modified GO (IP-GO) has the best dispersibility and compatibility than GO and reduced GO in the waterborne polyurethane matrix. The relationship between the corrosion resistance of composite coatings and the dispersibility of the graphene derivative and the compatibility of the graphene derivative with a polymer matrix were discussed. The anticorrosive properties were characterized by electrochemical impedance spectroscopy analysis and salt spray tests. Through a series of anticorrosion tests, it is concluded that the anticorrosion performance of a composite coating with 0.3 wt % IP-GO is significantly improved. The excellent anticorrosion performance is due to the perfect dispersion and good compatibility of IP-GO in waterborne polyurethane.

18.
Arthritis Res Ther ; 21(1): 194, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455417

RESUMO

BACKGROUND: Chondropathies are a group of cartilage diseases, which share some common pathogenetic features. The etiology of chondropathies is still largely obscure now. METHODS: A transcriptome-wide association study (TWAS) was performed using the UK Biobank genome-wide association study (GWAS) data of chondropathies (including 1314 chondropathy patients and 450,950 controls) with gene expression references of muscle skeleton (MS) and peripheral blood (YBL). The candidate genes identified by TWAS were further compared with three gene expression profiles of osteoarthritis (OA), cartilage tumor (CT), and spinal disc herniation (SDH), to confirm the functional relevance between the chondropathies and the candidate genes identified by TWAS. Functional mapping and annotation (FUMA) was used for the gene ontology enrichment analyses. Immunohistochemistry (IHC) was conducted to validate the accuracy of integrative analysis results. RESULTS: Integrating TWAS and mRNA expression profiles detected 84 candidate genes for knee OA, such as DDX20 (PTWAS YBL = 1.79 × 10- 3, fold change (FC) = 2.69), 10 candidate genes for CT, such as SRGN (PTWAS YBL = 1.46 × 10- 3, FC = 3.36), and 4 candidate genes for SDH, such as SUPV3L1 (PTWAS YBL = 3.59 × 10- 3, FC = 3.22). Gene set enrichment analysis detected 73 GO terms for knee OA, 3 GO terms for CT, and 1 GO term for SDH, such as mitochondrial protein complex (P = 7.31 × 10- 5) for knee OA, cytokine for CT (P = 1.13 × 10- 4), and ion binding for SDH (P = 3.55 × 10- 4). IHC confirmed that the protein expression level of DDX20 was significantly different between knee OA cartilage and healthy control cartilage (P = 0.0358). CONCLUSIONS: Multiple candidate genes and GO terms were detected for chondropathies. Our findings may provide a novel insight in the molecular mechanisms of chondropathies.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Osteoartrite do Joelho/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Transcriptoma/genética , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/metabolismo , Estudos Prospectivos , RNA Mensageiro/biossíntese
19.
J Trace Elem Med Biol ; 54: 79-97, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31109624

RESUMO

BACKGROUND: Kashin-Beck disease (KBD) is a serious chronic osteochondral disease that is endemic in humans. Selenium (Se) has been considered in hypotheses of the aetiology of KBD, but few studies have explored the relationship between other elements and KBD. OBJECTIVE: This study explored the relationship between 39 elements and KBD. METHODS: In this retrospective study, 150 boys aged 6 to 14 years were randomly selected from a total population of 1,214 children. Subjects from endemic areas were divided into five groups: (KBD -Bin, N = 30; KBD + Se-Yongshou, N = 30; Control -Bin, N = 30; Control + Se -Yongshou, N = 30; and Control External -Chang'an, N = 30). Samples of occipital hair were collected from each subject, and thirty-nine elements, including 15 toxic elements, 19 nutrient elements, and 5 other elements were assayed by inductively coupled plasma mass spectrometry (ICP-MS). Correlation analysis of the elements in each group was performed by ggcorrplot (visualization of a correlation matrix using 'ggplot2') and PerformanceAnalytics packages in the program R Project. RESULTS: Among the 15 toxic elements, the levels of aluminum (Al) and bismuth (Bi) in the KBD -Bin were significantly higher than in the other groups, and the levels of silver (Ag), beryllium (Be), platinum (Pt), antimony (Sb), tin (Sn) and lead (Pb) in the KBD -Bin were significantly lower than in the other groups. Among the 19 nutrient elements, the levels of selenium (Se), iodine (I), sulfur (S), and boron (B) in the KBD -Bin were significantly lower than in the other groups. The levels of calcium (Ca), iron (Fe), manganese (Mn), chromium (Cr), strontium (Sr) and phosphorus (P) in the KBD -Bin were significantly higher than in the other groups. Correlations between various elements were remarkably different among the groups. There were positive correlations between As and Pb, Cd and Sb, Pb and Sb, Sb and U in the Control External -Chang'an, between Al and Ni, Cd and Pb, Tl and Ni, Ti and U in the Se-S KBD, and between B and I, B and Mo, Mn and V in the Control External -Chang'an. CONCLUSIONS: These findings indicate that the interactions between elements do not represent a simple reciprocal relationship in the occurrence of KBD. In fact, KBD was associated with an imbalance in multiple elements that play a dynamic and interactive role in the development of the disease.


Assuntos
Cabelo/química , Doença de Kashin-Bek/metabolismo , Oligoelementos/análise , Adolescente , Cálcio/análise , Criança , Cromo/análise , Humanos , Ferro/análise , Manganês/análise , Fósforo/análise , Estudos Retrospectivos , Selênio/análise , Titânio/análise
20.
Exp Cell Res ; 379(2): 140-149, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30951708

RESUMO

To investigate the pathogenesis of Kashin-Beck disease (KBD), we compared the common signaling pathways in peripheral blood mononuclear cells (PBMCs) obtained from healthy juvenile and adults and KBD patients, and also from osteoarthritis (OA) patients. The PBMCs from 12 KBD and 12 healthy juvenile, and those from 20 adult KBD patients and 12 healthy donors were separately collected among the people living in the KBD endemic area. The patients were distinguished according to the national diagnosis criteria. Total RNAs were extracted for the determination of gene expressions by microarray analysis. Ingenuity Pathways Analysis (IPA) was employed to identify the signaling pathways significantly affected by juveniles' and adults' KBD, and OA. The expressions of NFκB-p65, cIAP2 and RANKL in the articular cartilage from both juvenile and adults were detected by immunohistochemistry. NF-κB signaling, apoptosis signaling, death receptor signaling and IL-6 signaling pathways were revealed to be the common affected signaling pathways in the juvenile and adult KBD and the OA. BIRC3 and EGR1 were identified as two common differentially expressed genes. The percentages of positive staining of NFκB-p65, cIAP2 and RANKL were reduced in adult KBD patients but significantly increased in juvenile KBD patients. NF-κB, one of the common signaling pathways between adult and juvenile KBD, was less prominent in the adult KBD patients.


Assuntos
Doença de Kashin-Bek/metabolismo , Leucócitos Mononucleares/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Adolescente , Adulto , Apoptose/fisiologia , Cartilagem Articular/metabolismo , Humanos , Osteoartrite/metabolismo
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