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1.
J Affect Disord ; 367: 174-183, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39236878

RESUMO

OBJECTIVES: This study aimed to investigate the interplay between genetic susceptibility and socioeconomic disparities on psychiatric disorders. METHODS: In this study, we utilized data from the UK Biobank to analyze the Generalized Anxiety Disorder (GAD)-7 scale (N = 74,425) and the Patient Health Questionnaire (PHQ)-9 (N = 74,101), along with the Index of Multiple Deprivation (IMD). The polygenic risk score (PRS) was calculated to assess the genetic risk associated with GAD-7/PHQ-9 scores, and the individuals were classified into low, medium, and high genetic risk groups according to tertiles of PRSs related to the GAD-7/PHQ-9. Linear regression models were used to explore the relationships between GAD-7/PHQ-9 scores and IMD scores in patients with different genetic susceptibilities. RESULTS: Disadvantaged socioeconomic status was associated with the risk of anxiety and depression across all strata of genetic risk, and stronger associations were shown for individuals with greater genetic susceptibility. From low to high genetic risk, the risk of psychiatric disorders increased for the GAD-7 (ß = 0.002 to 0.032) and PHQ-9 (ß = 0.003 to 0.045) scores. In addition, strong associations of high genetic risk with anxiety (ß = 0.875) and depression (ß = 1.152) were detected in the IMD quartile 4 group compared with the least deprivation quartile group. Furthermore, income and employment were estimated to contribute strongly to anxiety (ßemployment = 7.331, ßincome = 4.492) and depression (ßemployment = 9.951, ßincome = 6.453) in the high genetic risk group. CONCLUSION: The results suggest that we should pay more attention to psychiatric disorders with high genetic susceptibility and try to improve their socioeconomic status to prevent the development of psychiatric disorders.

2.
Sleep Health ; 10(4): 402-409, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38772848

RESUMO

BACKGROUND: Sleep is a natural and essential physiological need for individuals. Our study aimed to research the associations between accumulated social risks and sleep disorders. METHODS: In this study, we came up with a polysocial risk score (PsRS), which is a cumulative social risk index composed of 13 social determinants of health. This research includes 239,165 individuals with sleep disorders and social determinants of health data from the UK Biobank cohort. First, logistic regression models were performed to examine the associations of social determinants of health and sleep disorders, including chronotype, narcolepsy, insomnia, snoring, short and long sleep duration. Then, PsRS was calculated based on statistically significant social determinants of health for each sleep disorder. Third, a genome-wide gene-environment interaction study was conducted to explore the interactions between single-nucleotide polymorphisms and PsRS in relation to sleep disorders. RESULTS: Higher PsRS scores were associated with worse sleep status, with the adjusted odds ratio (OR) ranging from 1.10 (95% Confidence interval [CI]: 1.09-1.11) to 1.29 (95% CI: 1.27-1.30) for sleep disorders. Emotional stress (OR = 1.36, 95% CI: 1.28-1.43) and not in paid employment (OR = 2.62, 95% CI: 2.51-2.74) were found to have significant contributions for sleep disorders. Moreover, multiple single-nucleotide polymorphisms were discovered to have interactions with PsRS, such as FRAS1 (P = 2.57 × 10-14) and CACNA1A (P = 8.62 × 10-14) for narcolepsy, and ACKR3 (P = 1.24 × 10-8) for long sleep. CONCLUSIONS: Our findings suggested that cumulative social risks was associated with sleep disorders, while the interactions between genetic susceptibility and disadvantaged social status are risk factors for the development of sleep disorders.


Assuntos
Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Transtornos do Sono-Vigília , Classe Social , Humanos , Masculino , Feminino , Transtornos do Sono-Vigília/epidemiologia , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Determinantes Sociais da Saúde , Fatores de Risco , Populações Vulneráveis , Estudos de Coortes , Idoso , Adulto
4.
Neurosci Biobehav Rev ; 140: 104806, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35926729

RESUMO

BACKGROUND: Limited studies have been conducted to explore the interaction effects of social environmental and genetic factors on the risks of common psychiatric disorders. METHODS: 56,613-106,695 individuals were collected from the UK Biobank cohort. Logistic or liner regression models were first used to evaluate the associations of index of multiple deprivation (IMD) with bipolar disorder (BD), depression and anxiety in UK Biobank cohort. Then, for the significant IMD associated with BD, depression and anxiety, genome-wide gene-environment interaction study (GWEIS) was performed by PLINK 2.0. RESULT: Totally, the higher levels of IMD were significantly associated with higher risks of BD, depression and anxiety. For BD, GWEIS identified multiple significant SNPs interacting with IMD, such as rs75182167 for income and rs111841503 for education. For depression and anxiety, GWEIS found significant SNPs interacting with income and education, such as rs147013419 for income and rs142366753 for education. CONCLUSION: Social environmental deprivations contributed to the risks of psychiatric disorders. Besides, we reported multiple candidate genetic loci interacting with IMD, providing novel insights into the biological mechanism.


Assuntos
Transtorno Bipolar , Polimorfismo de Nucleotídeo Único , Transtornos de Ansiedade , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos
5.
Blood Cells Mol Dis ; 97: 102678, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35716403

RESUMO

The T cell-mediated immune responses associated with asymptomatic infection (AS) of SARS-CoV-2 remain largely unknown. The diversity of T-cell receptor (TCR) repertoire is essential for generating effective immunity against viral infections in T cell response. Here, we performed the single-cell TCR sequencing of the PBMC samples from five AS subjects, 33 symptomatic COVID-19 patients and eleven healthy controls to investigate the size and the diversity of TCR repertoire. We subsequently analyzed the TCR repertoire diversity, the V and J gene segment deference, and the dominant combination of αß VJ gene pairing among these three study groups. Notably, we revealed significant TCR preference in the AS group, including the skewed usage of TRAV1-2-J33-TRBV6-4-J2-2 and TRAV1-2-J33-TRBV6-1-J2-3. Our findings may shed new light on understanding the immunopathogenesis of COVID-19 and help identify optimal TCRs for development of novel therapeutic strategies against SARS-CoV-2 infection.


Assuntos
COVID-19 , Humanos , Leucócitos Mononucleares , Receptores de Antígenos de Linfócitos T/genética , SARS-CoV-2 , Linfócitos T
6.
Front Immunol ; 13: 812514, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281000

RESUMO

The cell-mediated protective and pathogenic immune responses to SARS-CoV-2 infection remain largely elusive. Here we identified 76 distinct cell subsets in the PBMC samples that were associated with various clinical presentations of COVID-19 using scRNA-seq technology coupled with a deep and comprehensive analysis of unique cell surface markers and differentially expressed genes. We revealed that (TRAV1-2+CD8+)MAIT cells and (NCAM1hiCD160+)NK cells significantly enriched in the asymptomatic subjects whereas (LAG3+CD160+CD8+)NKT cells increased in the symptomatic patients. We also observed that (CD68-CSF1R-IL1BhiCD14+)classical monocytes were positively correlated with the disease severity. Moreover, (CD33-HLA-DMA-CD14+)classical monocytes and (CLEC10A-S100A9lo)pDC were associated with the viral persistence. The GO and KEGG analyses identified enriched pathways related to immune responses, inflammation, and apoptosis. These findings may enhance our understanding of the immunopathogenesis of COVID-19 and help develop novel strategies against SARS-CoV-2 infection.


Assuntos
COVID-19/diagnóstico , COVID-19/imunologia , Células Matadoras Naturais/imunologia , Monócitos/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , SARS-CoV-2/fisiologia , Infecções Assintomáticas , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Carga Viral
7.
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.


Assuntos
Metilação de DNA , Epigenoma , Doença de Kashin-Bek/genética , RNA Mensageiro/genética , Selênio/metabolismo , Transcriptoma , Adulto , Idoso , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Estudos de Casos e Controles , Células Cultivadas , Epigenômica , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Doença de Kashin-Bek/diagnóstico , Doença de Kashin-Bek/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo
8.
Cell Death Dis ; 10(2): 136, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755598

RESUMO

Resistance to radiotherapy results in relapse and treatment failure in locally advanced esophageal squamous cell carcinoma (ESCC). High mobility group box 1 (HMGB1) is reported to be associated with the radioresistance in bladder and breast cancer. However, the role of HMGB1 in the radiotherapy response in ESCC has not been fully elucidated. Here, we investigated the role of HMGB1 to radioresistance in ESCC clinical samples and cell lines. We found that HMGB1 expression was associated with tumor recurrence after postoperative radiotherapy in locally advanced ESCC patients. HMGB1 knockdown in ESCC cells resulted in increased radiosensitivity both in vitro and in vivo. Autophagy level was found depressed in HMGB1 inhibition cells and activation of autophagy brought back cell's radioresistance. Our results demonstrate that HMGB1 activate autophagy and consequently promote radioresistance. HMGB1 may be used as a predictor of poor response to radiotherapy in ESCC patients. Our finding also highlights the importance of the utility of HMGB1 in ESCC radiosensitization.


Assuntos
Autofagia , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Proteína HMGB1/metabolismo , Tolerância a Radiação/genética , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Feminino , Técnicas de Silenciamento de Genes , Proteína HMGB1/genética , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , RNA Interferente Pequeno/genética , Transfecção , Carga Tumoral/genética
9.
Schizophr Bull ; 45(3): 709-715, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29912442

RESUMO

BACKGROUND: Psychiatric disorders are usually caused by the dysfunction of various brain regions. Incorporating the genetic information of brain regions into correlation analysis can provide novel clues for pathogenetic and therapeutic studies of psychiatric disorders. METHODS: The latest genome-wide association study (GWAS) summary data of schizophrenia (SCZ), bipolar disorder (BIP), autism spectrum disorder (AUT), major depression disorder (MDD), and attention-deficit/hyperactivity disorder (ADHD) were obtained from the Psychiatric GWAS Consortium (PGC). The expression quantitative trait loci (eQTLs) datasets of 10 brain regions were driven from the genotype-tissue expression (GTEx) database. The PGC GWAS summaries were first weighted by the GTEx eQTLs summaries for each brain region. Linkage disequilibrium score regression was applied to the weighted GWAS summary data to detect genetic correlation for each pair of 5 disorders. RESULTS: Without considering brain region difference, significant genetic correlations were observed for BIP vs SCZ (P = 1.68 × 10-63), MDD vs SCZ (P = 5.08 × 10-45), ADHD vs MDD (P = 1.93 × 10-44), BIP vs MDD (P = 6.39 × 10-9), AUT vs SCZ (P = .0002), and ADHD vs SCZ (P = .0002). Utilizing brain region related eQTLs weighted LD score regression, different strengths of genetic correlations were observed within various brain regions for BIP vs SCZ, MDD vs SCZ, ADHD vs MDD, and SCZ vs ADHD. For example, the most significant genetic correlations were observed at anterior cingulate cortex (P = 1.13 × 10-34) for BIP vs SCZ. CONCLUSIONS: This study provides new clues for elucidating the mechanism of genetic correlations among various psychiatric disorders.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Transtorno Bipolar/genética , Encéfalo , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação/genética , Locos de Características Quantitativas/genética , Esquizofrenia/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Humanos , Esquizofrenia/fisiopatologia
10.
Biomed Res Int ; 2018: 3848560, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854750

RESUMO

To identify novel susceptibility genes and gene sets for obesity, we conducted a genomewide expression association analysis of obesity via integrating genomewide association study (GWAS) and expression quantitative trait loci (eQTLs) data. GWAS summary data of body mass index (BMI) and waist-to-hip ratio (WHR) was driven from a published study, totally involving 339,224 individuals. The eQTLs dataset (containing 927,753 eQTLs) was obtained from eQTLs meta-analysis of 5,311 subjects. Integrative analysis of GWAS and eQTLs data was conducted by SMR software. The SMR single gene analysis results were further subjected to gene set enrichment analysis (GSEA) for identifying obesity associated gene sets. A total of 13,311 annotated gene sets were analyzed in this study. SMR single gene analysis identified 20 BMI associated genes (TUFM, SPI1, APOB48R, etc.). Also 3 WHR associated genes were detected (CPEB4, WARS2, and L3MBTL3). The significant association between Chr16p11 and BMI was observed by GSEA (FDR adjusted p value = 0.040). The TGCTGCT, MIR-15A, MIR-16, MIR-15B, MIR-195, MIR-424, and MIR-497 (FDR adjusted p value = 0.049) gene set appeared to be linked with WHR. Our results provide novel clues for the genetic mechanism studies of obesity. This study also illustrated the good performance of SMR for susceptibility gene mapping.


Assuntos
Predisposição Genética para Doença/genética , Obesidade/genética , Locos de Características Quantitativas/genética , Índice de Massa Corporal , Mapeamento Cromossômico/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , MicroRNAs/genética , Anotação de Sequência Molecular/métodos , Relação Cintura-Quadril/métodos
11.
Arthritis Res Ther ; 20(1): 41, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29514696

RESUMO

BACKGROUND: Kashin-Beck disease (KBD) is an endemic osteochondropathy of unknown etiology. Osteoarthritis (OA) is a form of degenerative joint disease sharing similar clinical manifestations and pathological changes to articular cartilage with KBD. METHODS: A genome-wide DNA methylation profile of articular cartilage from five KBD patients and five OA patients was first performed using the Illumina Infinium HumanMethylation450 BeadChip. Together with a previous gene expression profiling dataset comparing KBD cartilage with OA cartilage, an integrative pathway enrichment analysis of the genome-wide DNA methylation and the mRNA expression profiles conducted in articular cartilage was performed by InCroMAP software. RESULTS: We identified 241 common genes altered in both the DNA methylation profile and the mRNA expression profile of articular cartilage of KBD versus OA, including CHST13 (NM_152889, fold-change = 0.5979, P methy = 0.0430), TGFBR1 (NM_004612, fold-change = 2.077, P methy = 0.0430), TGFBR2 (NM_001024847, fold-change = 1.543, P methy = 0.037), TGFBR3 (NM_001276, fold-change = 0.4515, P methy = 6.04 × 10-4), and ADAM12 (NM_021641, fold-change = 1.9768, P methy = 0.0178). Integrative pathway enrichment analysis identified 19 significant KEGG pathways, including mTOR signaling (P = 0.0301), glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate (P = 0.0391), glycosaminoglycan biosynthesis-keratan sulfate (P = 0.0278), and PI3K-Akt signaling (P = 0.0243). CONCLUSION: This study identified different molecular features between Kashin-Beck disease and primary osteoarthritis and provided novel clues for clarifying the pathogenetic differences between KBD and OA.


Assuntos
Metilação de DNA , Perfilação da Expressão Gênica/métodos , Genoma Humano/genética , Doença de Kashin-Bek/genética , Osteoartrite/genética , Idoso , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Diagnóstico Diferencial , Feminino , Humanos , Doença de Kashin-Bek/diagnóstico , Doença de Kashin-Bek/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Osteoartrite/diagnóstico , Osteoartrite/metabolismo , Transdução de Sinais/genética
12.
J Clin Endocrinol Metab ; 103(5): 1850-1855, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29506141

RESUMO

Context: Osteoporosis is a metabolic bone disease. The effect of blood metabolites on the development of osteoporosis remains elusive. Objective: To explore the relationship between blood metabolites and osteoporosis. Design and Methods: We used 2286 unrelated white subjects for the discovery samples and 3143 unrelated white subjects from the Framingham Heart Study (FHS) for the replication samples. The bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using Affymetrix Human SNP Array 6.0 (for discovery samples) and Affymetrix SNP 500K and 50K array (for FHS replication samples). The SNP sets significantly associated with blood metabolites were obtained from a reported whole-genome sequencing study. For each subject, the genetic risk score of the metabolite was calculated from the genotype data of the metabolite-associated SNP sets. Pearson correlation analysis was conducted to evaluate the potential effect of blood metabolites on the variations in bone phenotypes; 10,000 permutations were conducted to calculate the empirical P value and false discovery rate. Results: We analyzed 481 blood metabolites. We identified multiple blood metabolites associated with hip BMD, such as 1,5-anhydroglucitol (Pdiscovery < 0.0001; Preplication = 0.0361), inosine (Pdiscovery = 0.0018; Preplication = 0.0256), theophylline (Pdiscovery = 0.0048; Preplication = 0.0433, gamma-glutamyl methionine (Pdiscovery = 0.0047; Preplication = 0.0471), 1-linoleoyl-2-arachidonoyl-GPC (18:2/20:4n6; Pdiscovery = 0.0018; Preplication = 0.0390), and X-12127 (Pdiscovery = 0.0002; Preplication = 0.0249). Conclusions: Our results suggest a modest effect of blood metabolites on the variations of BMD and identified several candidate blood metabolites for osteoporosis.


Assuntos
Biomarcadores/sangue , Osteoporose/sangue , Osteoporose/genética , Absorciometria de Fóton , Adulto , Idoso , Biomarcadores/análise , Biomarcadores/metabolismo , Densidade Óssea/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Osteoporose/epidemiologia , Osteoporose/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Distribuição Aleatória
13.
Brief Bioinform ; 19(5): 725-730, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28334273

RESUMO

Genome-wide association study (GWAS)-based pathway association analysis is a powerful approach for the genetic studies of human complex diseases. However, the genetic confounding effects of environment exposure-related genes can decrease the accuracy of GWAS-based pathway association analysis of target diseases. In this study, we developed a pathway association analysis approach, named Mendelian randomization-based pathway enrichment analysis (MRPEA), which was capable of correcting the genetic confounding effects of environmental exposures, using the GWAS summary data of environmental exposures. After analyzing the real GWAS summary data of cardiovascular disease and cigarette smoking, we observed significantly improved performance of MRPEA compared with traditional pathway association analysis (TPAA) without adjusting for environmental exposures. Further, simulation studies found that MRPEA generally outperformed TPAA under various scenarios. We hope that MRPEA could help to fill the gap of TPAA and identify novel causal pathways for complex diseases.


Assuntos
Exposição Ambiental/efeitos adversos , Exposição Ambiental/estatística & dados numéricos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Biologia Computacional/métodos , Simulação por Computador , Variação Genética , Humanos , Modelos Genéticos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fumar/efeitos adversos , Fumar/genética
14.
Genet Epidemiol ; 42(2): 168-173, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29265413

RESUMO

Chemical elements are closely related to human health. Extensive genomic profile data of complex diseases offer us a good opportunity to systemically investigate the relationships between elements and complex diseases/traits. In this study, we applied gene set enrichment analysis (GSEA) approach to detect the associations between elements and complex diseases/traits though integrating element-gene interaction datasets and genome-wide association study (GWAS) data of complex diseases/traits. To illustrate the performance of GSEA, the element-gene interaction datasets of 24 elements were extracted from the comparative toxicogenomics database (CTD). GWAS summary datasets of 24 complex diseases or traits were downloaded from the dbGaP or GEFOS websites. We observed significant associations between 7 elements and 13 complex diseases or traits (all false discovery rate (FDR) < 0.05), including reported relationships such as aluminum vs. Alzheimer's disease (FDR = 0.042), calcium vs. bone mineral density (FDR = 0.031), magnesium vs. systemic lupus erythematosus (FDR = 0.012) as well as novel associations, such as nickel vs. hypertriglyceridemia (FDR = 0.002) and bipolar disorder (FDR = 0.027). Our study results are consistent with previous biological studies, supporting the good performance of GSEA. Our analyzing results based on GSEA framework provide novel clues for discovering causal relationships between elements and complex diseases.


Assuntos
Doença/genética , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla/métodos , Metais/metabolismo , Fenótipo , Alumínio/metabolismo , Doença de Alzheimer/metabolismo , Transtorno Bipolar/metabolismo , Densidade Óssea/fisiologia , Cálcio/metabolismo , Bases de Dados Factuais , Humanos , Hipertrigliceridemia/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Magnésio/metabolismo , Níquel/metabolismo , Polimorfismo de Nucleotídeo Único
15.
Artigo em Inglês | MEDLINE | ID: mdl-29024729

RESUMO

Schizophrenia is a serious mental disease with high heritability. To better understand the genetic basis of schizophrenia, we conducted a large scale integrative analysis of genome-wide association study (GWAS) and expression quantitative trait loci (eQTLs) data. GWAS summary data was derived from a published GWAS of schizophrenia, containing 9394 schizophrenia patients and 12,462 healthy controls. The eQTLs dataset was obtained from an eQTLs meta-analysis of 5311 subjects, containing 923,021 cis-eQTLs for 14,329 genes and 4732 trans-eQTLs for 2612 genes. Genome-wide single gene expression association analysis was conducted by SMR software. The SMR analysis results were further subjected to gene set enrichment analysis (GSEA) to identify schizophrenia associated gene sets. SMR detected 49 genes significantly associated with schizophrenia. The top five significant genes were CRELD2 (p value=1.65×10-11), DIP2B (p value=3.94×10-11), ZDHHC18 (p value=1.52×10-10) and ZDHHC5 (p value=7.45×10-10), C11ORF75 (p value=3.70×10-9). GSEA identified 80 gene sets with p values <0.01. The top five significant gene sets were COWLING_MYCN_TARGETS (p value <0.001) and CHR16P11 (p value <0.001), ACTACCT_MIR196A_MIR196B (p value=0.002), CELLULAR_COMPONENT_DISASSEMBLY (p value=0.002) and GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN (p value=0.002). Our results provide useful information for revealing the genetic basis of schizophrenia.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Esquizofrenia/genética , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , População Branca/genética
16.
Cell Mol Neurobiol ; 38(3): 635-639, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28639078

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with strong genetic components. To identity novel risk variants for ALS, utilizing the latest genome-wide association studies (GWAS) and eQTL study data, we conducted a genome-wide expression association analysis by summary data-based Mendelian randomization (SMR) method. Summary data were derived from a large-scale GWAS of ALS, involving 12577 cases and 23475 controls. The eQTL annotation dataset included 923,021 cis-eQTL for 14,329 genes and 4732 trans-eQTL for 2612 genes. Genome-wide single gene expression association analysis was conducted by SMR software. To identify ALS-associated biological pathways, the SMR analysis results were further subjected to gene set enrichment analysis (GSEA). SMR single gene analysis identified one significant and four suggestive genes associated with ALS, including C9ORF72 (P value = 7.08 × 10-6), NT5C3L (P value = 1.33 × 10-5), GGNBP2 (P value = 1.81 × 10-5), ZNHIT3(P value = 2.94 × 10-5), and KIAA1600(P value = 9.97 × 10-5). GSEA identified 7 significant biological pathways, such as PEROXISOME (empirical P value = 0.006), GLYCOLYSIS_GLUCONEOGENESIS (empirical P value = 0.043), and ARACHIDONIC_ACID_ METABOLISM (empirical P value = 0.040). Our study provides novel clues for the genetic mechanism studies of ALS.


Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Proteína C9orf72/genética , Humanos , Locos de Características Quantitativas/genética , Proteínas Supressoras de Tumor/genética
17.
Biomed Res Int ; 2017: 1758636, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28744461

RESUMO

AIM: To identify novel candidate genes and gene sets for diabetes. METHODS: We performed an integrative analysis of genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) data for diabetes. Summary data was driven from a large-scale GWAS of diabetes, totally involving 58,070 individuals. eQTLs dataset included 923,021 cis-eQTL for 14,329 genes and 4,732 trans-eQTL for 2,612 genes. Integrative analysis of GWAS and eQTLs data was conducted by summary data-based Mendelian randomization (SMR). To identify the gene sets associated with diabetes, the SMR single gene analysis results were further subjected to gene set enrichment analysis (GSEA). A total of 13,311 annotated gene sets were analyzed in this study. RESULTS: SMR analysis identified 6 genes significantly associated with fasting glucose, such as C11ORF10 (p value = 6.04 × 10-8), MRPL33 (p value = 1.24 × 10-7), and FADS1 (p value = 2.39 × 10-7). Gene set analysis identified HUANG_FOXA2_TARGETS_UP (false discovery rate = 0.047) associated with fasting glucose. CONCLUSION: Our study provides novel clues for clarifying the genetic mechanism of diabetes. This study also illustrated the good performance of SMR approach and extended it to gene set association analysis for complex diseases.


Assuntos
Diabetes Mellitus/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Glicemia/metabolismo , Dessaturase de Ácido Graxo Delta-5 , Jejum/sangue , Humanos , Insulina/sangue , Análise da Randomização Mendeliana
18.
Artigo em Inglês | MEDLINE | ID: mdl-28552732

RESUMO

Neuroticism is a fundamental personality trait with significant genetic determinant. To identify novel susceptibility genes for neuroticism, we conducted an integrative analysis of genomic and transcriptomic data of genome wide association study (GWAS) and expression quantitative trait locus (eQTL) study. GWAS summary data was driven from published studies of neuroticism, totally involving 170,906 subjects. eQTL dataset containing 927,753 eQTLs were obtained from an eQTL meta-analysis of 5311 samples. Integrative analysis of GWAS and eQTL data was conducted by summary data-based Mendelian randomization (SMR) analysis software. To identify neuroticism associated gene sets, the SMR analysis results were further subjected to gene set enrichment analysis (GSEA). The gene set annotation dataset (containing 13,311 annotated gene sets) of GSEA Molecular Signatures Database was used. SMR single gene analysis identified 6 significant genes for neuroticism, including MSRA (p value=2.27×10-10), MGC57346 (p value=6.92×10-7), BLK (p value=1.01×10-6), XKR6 (p value=1.11×10-6), C17ORF69 (p value=1.12×10-6) and KIAA1267 (p value=4.00×10-6). Gene set enrichment analysis observed significant association for Chr8p23 gene set (false discovery rate=0.033). Our results provide novel clues for the genetic mechanism studies of neuroticism.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Neuroticismo , Locos de Características Quantitativas/genética , Bases de Dados Genéticas , Humanos
19.
Sci Rep ; 7(1): 540, 2017 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-28373711

RESUMO

Kashin-Beck disease (KBD) is a chronic osteochondropathy with unclear pathogeny. In this study, we compared the microRNA expression profiles of 16 KBD patients, 16 osteoarthritis (OA) patients and 16 rheumatoid arthritis (RA) patients and 16 healthy controls in their blood specimens. miRNAs expression profiling was performed using Exiqon miRCURY LNATM miRNAs Array. miRNAs target genes were predicted using miRror suite. Another independent mRNA expression profile dataset of 20 KBD patients and 15 healthy controls were integrated with the miRNA expression profiles of KBD. We identified 140 differently expressed miRNAs in KBD vs. CONTROLS: GO enrichment analysis found that hypoxia, Wnt receptor signaling pathway and vitamin B6 biosynthesis related GO terms were significantly overrepresented in the target genes of differently expressed miRNAs in KBD vs. CONTROL: 18 differently expressed common miRNAs were identified in KBD vs. Control, KBD vs. OA and KBD vs. RA. Integrating the lists of differently expressed miRNA target genes and mRNA differently expressed genes detected 6 common genes for KBD. Our results demonstrated the altered miRNAs expression profiles of KBD comparing to healthy controls, OA and RA, which provide novel clues for clarifying the mechanism of KBD.


Assuntos
Artrite Reumatoide/genética , Doença de Kashin-Bek/genética , MicroRNAs/genética , Osteoartrite/genética , Transcriptoma , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Estudos de Casos e Controles , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Doença de Kashin-Bek/diagnóstico , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnóstico , Fenótipo , Interferência de RNA , RNA Mensageiro/genética
20.
Sci Rep ; 7: 40020, 2017 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-28059113

RESUMO

Kashin-Beck disease (KBD) is a chronic osteochondropathy. The pathogenesis of growth and development failure of hand of KBD remains elusive now. In this study, we conducted a two-stage genome-wide association study (GWAS) of palmar length-width ratio (LWR) of KBD, totally including 493 study subjects. Affymetrix Genome Wide Human SNP Array 6.0 was applied for genome-wide SNP genotyping of 90 KBD patients. Association analysis was conducted by PLINK. Imputation analysis was performed by IMPUTE against the reference panel of the 1000 genome project. Two SNPs were selected for replication in an independent validation sample of 403 KBD patients. In the discovery GWAS, significant association was observed between palmar LWR and rs2071358 of COL2A1 gene (P value = 4.68 × 10-8). In addition, GWAS detected suggestive association signal at rs4760608 of COL2A1 gene (P value = 1.76 × 10-4). Imputation analysis of COL2A1 further identified 2 SNPs with association evidence for palmar LWR. Replication study observed significant association signals at both rs2071358 (P value = 0.017) and rs4760608 (P value = 0.002) of COL2A1 gene. Based on previous and our study results, we suggest that COL2A1 was a likely susceptibility gene involved in the hand development failure of KBD.


Assuntos
Colágeno Tipo II/genética , Estudo de Associação Genômica Ampla/métodos , Doença de Kashin-Bek/genética , Polimorfismo de Nucleotídeo Único , Idoso , Povo Asiático , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade
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