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1.
Sci Rep ; 9(1): 12717, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481703

RESUMO

Recent studies imply that rare variants contribute to the risk of schizophrenia, however, the exact variants or genes responsible for this condition are largely unknown. In this study, we conducted whole genome sequencing (WGS) of 20 Chinese families. Each family consisted of at least two affected siblings diagnosed with schizophrenia and at least one unaffected sibling. We examined functional variants that were found in affected sibling(s) but not in unaffected sibling(s) within a family. Matching this criterion, a frameshift heterozygous deletion of CA (-/CA) at chromosome 18:24722722, also referred to as rs752084147, in the Carbohydrate Sulfotransferase 9 (CHST9) gene, was detected in two families. This deletion was confirmed by PCR-based Sanger sequencing. With the observed frequency of 0.00076 in Han Chinese population, we performed both case-control and family-based analyses to evaluate its association with schizophrenia. In the case-control analyses, Chi-square test P-value was 6.80e-12 and the P-value was 0.0008 after one million simulations. In family-based segregation analyses, segregation P-value was 7.72e-7 and simulated P-value was 5.70e-6. For both the case-control and family-based analyses, the CA deletion was significantly associated with schizophrenia in the Chinese population. Further investigation of this gene  is warranted in the development of schizophrenia by utilizing larger and more ethnically diverse samples.

2.
Nicotine Tob Res ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294817

RESUMO

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

3.
J Neuroimmune Pharmacol ; 13(4): 532-540, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30276764

RESUMO

Schizophrenia is genetically heterogeneous and comorbid with many conditions. In this study, we explored polygenic scores (PGSs) from genetically related conditions and traits to predict schizophrenia diagnosis using both logistic regression and deep neural network (DNN) models. We used the combined Molecular Genetics of Schizophrenia and Swedish Schizophrenia Case Control Study (MGS + SSCCS) data for training and testing the models, and used the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) data as independent validation. We screened 28 conditions and traits comorbid with schizophrenia to identify traits as potential predictors and used LASSO regression to select predictors for model construction. We investigated how PGS calculation influenced model performance. We found that the inclusion of comorbid traits improved model performance and PGSs calculated from two traits were more generalizable in independent validation. With a DNN model using 19 PGS predictors, we accomplished a prediction accuracy of 0.813 and an AUC of 0.905 in the MGS + SSCCS data. When this model was validated with the CATIE data, it achieved an accuracy of 0.721 and AUC of 0.747. Our results indicate that PGSs alone may not be sufficient to predict schizophrenia accurately and the inclusion of behavioral and clinical data may be necessary for more accurate prediction model.

4.
Alzheimers Dement (N Y) ; 4: 414-432, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30225339

RESUMO

Minimotifs are modular contiguous peptide sequences in proteins that are important for posttranslational modifications, binding to other molecules, and trafficking to specific subcellular compartments. Some molecular functions of proteins in cellular pathways can be predicted from minimotif consensus sequences identified through experimentation. While a role for minimotifs in regulating signal transduction and gene regulation during disease pathogenesis (such as infectious diseases and cancer) is established, the therapeutic use of minimotif mimetic drugs is limited. In this review, we discuss a general theme identifying a pervasive role of minimotifs in the pathomechanism of neurodegenerative diseases. Beyond their longstanding history in the genetics of familial neurodegeneration, minimotifs are also major players in neurotoxic protein aggregation, aberrant protein trafficking, and epigenetic regulation. Generalizing the importance of minimotifs in neurodegenerative diseases offers a new perspective for the future study of neurodegenerative mechanisms and the investigation of new therapeutics.

5.
Sci Rep ; 6: 25671, 2016 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-27164557

RESUMO

It is well known that most schizophrenia patients smoke cigarettes. There are different hypotheses postulating the underlying mechanisms of this comorbidity. We used summary statistics from large meta-analyses of plasma cotinine concentration (COT), Fagerström test for nicotine dependence (FTND) and schizophrenia to examine the genetic relationship between these traits. We found that schizophrenia risk scores calculated at P-value thresholds of 5 × 10(-3) and larger predicted FTND and cigarettes smoked per day (CPD), suggesting that genes most significantly associated with schizophrenia were not associated with FTND/CPD, consistent with the self-medication hypothesis. The COT risk scores predicted schizophrenia diagnosis at P-values of 5 × 10(-3) and smaller, implying that genes most significantly associated with COT were associated with schizophrenia. These results implicated that schizophrenia and FTND/CPD/COT shared some genetic liability. Based on this shared liability, we identified multiple long non-coding RNAs and RNA binding protein genes (DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, DA902558, RBFOX1 and TINCR), protein modification genes (MANBA, UBE2D3, and RANGAP1) and energy production genes (XYLB, MTRF1 and ENOX1) that were associated with both conditions. Further analyses revealed that these shared genes were enriched in calcium signaling, long-term potentiation and neuroactive ligand-receptor interaction pathways that played a critical role in cognitive functions and neuronal plasticity.


Assuntos
Cotinina/sangue , Medição de Risco/métodos , Esquizofrenia/genética , Tabagismo/genética , Feminino , Redes Reguladoras de Genes/genética , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/sangue , Transdução de Sinais/genética , Tabagismo/sangue
6.
Sci Rep ; 6: 20092, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26833182

RESUMO

Genome-wide association studies (GWAS) of complex behavioural phenotypes such as cigarette smoking typically employ self-report phenotypes. However, precise biomarker phenotypes may afford greater statistical power and identify novel variants. Here we report the results of a GWAS meta-analysis of levels of cotinine, the primary metabolite of nicotine, in 4,548 daily smokers of European ancestry. We identified a locus close to UGT2B10 at 4q13.2 (minimum p = 5.89 × 10(-10) for rs114612145), which was consequently replicated. This variant is in high linkage disequilibrium with a known functional variant in the UGT2B10 gene which is associated with reduced nicotine and cotinine glucuronidation activity, but intriguingly is not associated with nicotine intake. Additionally, we observed association between multiple variants within the 15q25.1 region and cotinine levels, all located within the CHRNA5-A3-B4 gene cluster or adjacent genes, consistent with previous much larger GWAS using self-report measures of smoking quantity. These results clearly illustrate the increase in power afforded by using precise biomarker measures in GWAS. Perhaps more importantly however, they also highlight that biomarkers do not always mark the phenotype of interest. The use of metabolite data as a proxy for environmental exposures should be carefully considered in the context of individual differences in metabolic pathways.


Assuntos
Cromossomos Humanos Par 4/genética , Cotinina , Loci Gênicos , Desequilíbrio de Ligação , Fumar/genética , Feminino , Estudo de Associação Genômica Ampla , Glucuronosiltransferase/genética , Humanos , Masculino
7.
Sci Rep ; 5: 9521, 2015 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-25826680

RESUMO

Nicotine is the psychoactive agent involved in nicotine dependence. However, nicotine as a drug, and its effects on human psychology are largely under-investigated in genetic studies. In this study, we recruited 208 current non-smokers to evaluate the effect of nicotine and its relationship to genetic risks to nicotine dependence. Exploratory and confirmatory factor analyses, as well as measurement invariance testing, were conducted to evaluate the latent factor structures of the POMS, PANAS and DEN questionnaires across 3 nicotine doses. Structural models were used to examine the effects of nicotine and their relationship to genetic risks of nicotine dependence. We found that nicotine administration led to the change of both measurement construct and factor means, indicating the causal effect of nicotine on the psychological responses. The genotypes of rs588765 predicted the scores of the DEN Confused and Dizzy factors (p = 0.0003 and 0.001 respectively), and rs16969968 and rs588765 were associated with the PANAS Nervous factor (p = 0.006 and 0.007 respectively). Our study suggested that genetic risk of nicotine dependence is associated with acute psychological responses. The integration of psychometric analyses and dose effects could be a powerful approach for genetic study of nicotine dependence.


Assuntos
Afeto , Predisposição Genética para Doença , Nicotina/efeitos adversos , Tabagismo/epidemiologia , Tabagismo/genética , Adulto , Alelos , Análise Fatorial , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Nicotina/administração & dosagem , Polimorfismo de Nucleotídeo Único , Psicometria , Adulto Jovem
8.
Neurosci Bull ; 31(1): 87-98, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25652814

RESUMO

Schizophrenia (SCZ) is a complex and heterogeneous mental disorder that affects about 1% of global population. In recent years, considerable progress has been made in genetic studies of SCZ. A number of common variants with small effects and rare variants with relatively larger effects have been identified. These variants include risk loci identified by genome-wide association studies, rare copy-number variants identified by comparative genomic analyses, and de novo mutations identified by high-throughput DNA sequencing. Collectively, they contribute to the heterogeneity of the disease. In this review, we update recent discoveries in the field of SCZ genetics, and outline the perspectives of future directions.


Assuntos
Mutação , Esquizofrenia/genética , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Humanos
9.
Int J Clin Exp Med ; 8(11): 20157-67, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26884928

RESUMO

Abnormal expression of microRNAs plays important functions in osteosarcoma. The aim of this study was to investigate expression, functions and molecular mechanisms of microRNA-363 in osteosarcoma. Quantitative Real-time PCR was used to detect the expression level of microRNA-363 in osteosarcoma tissue samples and cell lines. After transfection, CCK8 assay, cell migration and invasion assay, western blot and Dual-Luciferase report assay were performed in human osteosarcoma cells. According to the results, we found that microRNA-363 was down-regulated in osteosarcoma tissues and cell lines. In addition, low expression level of microRNA-363 was associated with tumor size, clinical stage and distant metastasis. Moreover, microRNA-363 targeted MAP2K4 to inhibit osteosarcoma cell growth, migration and invasion. In conclusion, microRNA-363 played a tumor suppressive role in osteosarcoma by directly targeting MAP2K4. These findings indicated that microRNA-363 may have therapeutic value in treating osteosarcoma.

10.
Mol Psychiatry ; 20(5): 563-572, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25113377

RESUMO

Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental disorders with high heritability. Clinicians have long noticed the similarities of clinic symptoms between these disorders. In recent years, accumulating evidence indicates some shared genetic liabilities. However, what is shared remains elusive. In this study, we conducted whole transcriptome analysis of post-mortem brain tissues (cingulate cortex) from SCZ, BPD and control subjects, and identified differentially expressed genes in these disorders. We found 105 and 153 genes differentially expressed in SCZ and BPD, respectively. By comparing the t-test scores, we found that many of the genes differentially expressed in SCZ and BPD are concordant in their expression level (q⩽0.01, 53 genes; q⩽0.05, 213 genes; q⩽0.1, 885 genes). Using genome-wide association data from the Psychiatric Genomics Consortium, we found that these differentially and concordantly expressed genes were enriched in association signals for both SCZ (P<10(-7)) and BPD (P=0.029). To our knowledge, this is the first time that a substantially large number of genes show concordant expression and association for both SCZ and BPD. Pathway analyses of these genes indicated that they are involved in the lysosome, Fc gamma receptor-mediated phagocytosis, regulation of actin cytoskeleton pathways, along with several cancer pathways. Functional analyses of these genes revealed an interconnected pathway network centered on lysosomal function and the regulation of actin cytoskeleton. These pathways and their interacting network were principally confirmed by an independent transcriptome sequencing data set of the hippocampus. Dysregulation of lysosomal function and cytoskeleton remodeling has direct impacts on endocytosis, phagocytosis, exocytosis, vesicle trafficking, neuronal maturation and migration, neurite outgrowth and synaptic density and plasticity, and different aspects of these processes have been implicated in SCZ and BPD.


Assuntos
Citoesqueleto de Actina/genética , Transtorno Bipolar/genética , Predisposição Genética para Doença/genética , Lisossomos/fisiologia , Dobramento de Proteína , Esquizofrenia/genética , Citoesqueleto de Actina/metabolismo , Transtorno Bipolar/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Modelos Biológicos , Análise Multivariada , Esquizofrenia/patologia , Transdução de Sinais/genética , Estatística como Assunto
11.
Am J Hum Genet ; 95(6): 744-53, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25434007

RESUMO

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.


Assuntos
Transtorno Bipolar/genética , Regulação da Expressão Gênica/genética , Variação Genética , MicroRNAs/genética , Esquizofrenia/genética , Alelos , Sequência de Bases , Linhagem Celular Tumoral , Frequência do Gene , Genes Reporter , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Risco , Análise de Sequência de DNA
12.
Genet Epidemiol ; 37(8): 846-59, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24186853

RESUMO

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.


Assuntos
Predisposição Genética para Doença , Família Multigênica/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Nicotínicos/genética , Fumar/genética , Adolescente , Idade de Início , Cotinina/metabolismo , Feminino , Loci Gênicos/genética , Humanos , Internacionalidade , Desequilíbrio de Ligação/genética , Masculino , Proteínas do Tecido Nervoso/genética , Fenótipo , Tabagismo/genética
13.
Psychiatr Genet ; 23(1): 20-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23196875

RESUMO

BACKGROUND: Rates of tobacco smoking are significantly higher in patients with schizophrenia compared with the general population. The underlying mechanism for this comorbidity is unclear. One hypothesis is that there are common genetic factors that predispose to both nicotine dependence (ND) and schizophrenia. To investigate this hypothesis, we examined the association of the 15q25 gene cluster, the most significant candidate region to date implicated in ND and smoking behavior, with schizophrenia and bipolar disorder. METHODS: Five variants in the 15q25 gene cluster (rs951266, rs16969968, rs1051730, rs8040868, and rs17477223) were selected to test for association with schizophrenia diagnosis, bipolar disorder diagnosis, and the presence of negative symptoms of schizophrenia. Effects of the variants on 15q25 gene expression were analyzed using publically available postmortem brain expression data. RESULTS: A meta-analysis revealed four markers associated with risk for schizophrenia and bipolar disorder (rs951266, rs16969968, rs8040868, and rs17477223), and with the presence of negative symptoms of schizophrenia (rs951266, rs1051730, rs8040868, and rs17477223). The associations were in the same direction as that found for ND. Gene expression analysis indicated an association between genotypes of the rs1051730 variant and CHRNA5 expression in brain and peripheral blood mononuclear cells, and with the rs16969968 and rs17477223 variants in brain. CONCLUSION: Variants in the 15q25 gene cluster are associated with risk for schizophrenia/bipolar illness, negative symptoms of schizophrenia, and influence CHRNA5 expression in the brain and peripheral blood mononuclear cells. These results are consistent with the notion that there are genetic mechanisms common to schizophrenia, ND, and bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 15/genética , Predisposição Genética para Doença , Variação Genética , Família Multigênica/genética , Esquizofrenia/genética , Adulto , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Fatores de Risco
14.
PLoS One ; 7(11): e50375, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23226269

RESUMO

One of the most significant evolutionary changes underlying the highly developed cognitive abilities of humans is the greatly enlarged brain volume. In addition to being far greater than in most other species, the volume of the human brain exhibits extensive variation and distinct sexual dimorphism in the general population. However, little is known about the genetic mechanisms underlying normal variation as well as the observed sex difference in human brain volume. Here we show that interleukin-3 (IL3) is strongly associated with brain volume variation in four genetically divergent populations. We identified a sequence polymorphism (rs31480) in the IL3 promoter which alters the expression of IL3 by affecting the binding affinity of transcription factor SP1. Further analysis indicated that IL3 and its receptors are continuously expressed in the developing mouse brain, reaching highest levels at postnatal day 1-4. Furthermore, we found IL3 receptor alpha (IL3RA) was mainly expressed in neural progenitors and neurons, and IL3 could promote proliferation and survival of the neural progenitors. The expression level of IL3 thus played pivotal roles in the expansion and maintenance of the neural progenitor pool and the number of surviving neurons. Moreover, we found that IL3 activated both estrogen receptors, but estrogen didn't directly regulate the expression of IL3. Our results demonstrate that genetic variation in the IL3 promoter regulates human brain volume and reveals novel roles of IL3 in regulating brain development.


Assuntos
Biomarcadores Tumorais/genética , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Interleucina-3/genética , Células-Tronco Neurais/metabolismo , Polimorfismo Genético , Regiões Promotoras Genéticas , Receptores Imunológicos/genética , Animais , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Sobrevivência Celular/genética , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-3/metabolismo , Subunidade alfa de Receptor de Interleucina-3/genética , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Masculino , Camundongos , Células-Tronco Neurais/citologia , Tamanho do Órgão , Ligação Proteica , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores Imunológicos/metabolismo , Caracteres Sexuais
15.
Arch Gen Psychiatry ; 69(8): 854-60, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22868939

RESUMO

CONTEXT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES: Primary data. STUDY SELECTION: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01). CONCLUSION: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.


Assuntos
Proteínas do Tecido Nervoso/genética , Receptores Nicotínicos/genética , Fumar , Tabagismo , Adolescente , Desenvolvimento do Adolescente/efeitos dos fármacos , Adulto , Idade de Início , Europa (Continente)/epidemiologia , Feminino , Interação Gene-Ambiente , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Nicotina/farmacologia , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Fumar/epidemiologia , Fumar/genética , Tabagismo/epidemiologia , Tabagismo/genética , Tabagismo/psicologia
16.
J Med Case Rep ; 6: 218, 2012 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-22828210

RESUMO

INTRODUCTION: Replantation of a limb to the contralateral stump after bilateral traumatic amputations is rare. To the best of our knowledge, there are only a few reports of crossover lower limb replantation in the literature. CASE PRESENTATION: We treated a 37-year-old Chinese woman with bilateral lower limb crush injuries sustained in a traffic accident. Her lower limb injuries were at different anatomic levels. We performed emergency bilateral amputations followed by crossover replantation. Five years later, the woman had recovered well, and had perfect movement and stability in her replanted leg. After reviewing the literature, we thought that presentation of our patient's case might provide useful information for clinicians. CONCLUSIONS: Crossover replantation should be considered when evaluating a patient with bilateral lower limb injuries, thus allowing the patient to touch the ground and stand using their own foot.

17.
BMC Genomics ; 13 Suppl 8: S2, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23282246

RESUMO

BACKGROUND: While genome-wide association studies identified some promising candidates for schizophrenia, the majority of risk genes remained unknown. We were interested in testing whether integration gene expression and other functional information could facilitate the identification of susceptibility genes and related biological pathways. RESULTS: We conducted high throughput sequencing analyses to evaluate mRNA expression in blood samples isolated from 3 schizophrenia patients and 3 healthy controls. We also conducted pooled sequencing of 10 schizophrenic patients and matched controls. Differentially expressed genes were identified by t-test. In the individually sequenced dataset, we identified 198 genes differentially expressed between cases and controls, of them 19 had been verified by the pooled sequencing dataset and 21 reached nominal significance in gene-based association analyses of a genome wide association dataset. Pathway analysis of these differentially expressed genes revealed that they were highly enriched in the immune related pathways. Two genes, S100A8 and TYROBP, had consistent changes in expression in both individual and pooled sequencing datasets and were nominally significant in gene-based association analysis. CONCLUSIONS: Integration of gene expression and pathway analyses with genome-wide association may be an efficient approach to identify risk genes for schizophrenia.


Assuntos
Sistema Imunitário/metabolismo , Esquizofrenia/genética , Análise de Sequência de RNA , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , RNA Mensageiro/metabolismo , Esquizofrenia/imunologia , Esquizofrenia/patologia
18.
PLoS One ; 6(12): e28790, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22205969

RESUMO

Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of Schizophrenia (MGS) sample showed similar pattern of association with number of cigarettes smoked per day (numCIG) for the same region. To further test if this locus is associated with tobacco smoking as measured by numCIG and FTND, we conducted replication and meta-analysis in 12 independent samples (n>16,000) for two markers in ACSL6 reported in our previous schizophrenia study. In the meta-analysis of the replication samples, we found that rs667437 and rs477084 were significantly associated with numCIG (p = 0.00038 and 0.00136 respectively) but not with FTND scores. We then used in vitro and in vivo techniques to test if nicotine exposure influences the expression of ACSL6 in brain. Primary cortical culture studies showed that chronic (5-day) exposure to nicotine stimulated ACSL6 mRNA expression. Fourteen days of nicotine administration via osmotic mini pump also increased ACSL6 protein levels in the prefrontal cortex and hippocampus of mice. These increases were suppressed by injection of the nicotinic receptor antagonist mecamylamine, suggesting that elevated expression of ACSL6 requires nicotinic receptor activation. These findings suggest that variations in the ACSL6 gene may contribute to the quantity of cigarettes smoked. The independent associations of this locus with schizophrenia and with numCIG in non-schizophrenic subjects suggest that this locus may be a common liability to both conditions.


Assuntos
Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Exposição Ambiental/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Nicotina/farmacologia , Fumar/genética , Adolescente , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Mecamilamina/farmacologia , Camundongos , Pessoa de Meia-Idade , Antagonistas Nicotínicos/farmacologia , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores Nicotínicos/metabolismo , Esquizofrenia/genética , Fatores de Tempo , Adulto Jovem
19.
Behav Genet ; 41(5): 680-90, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21748402

RESUMO

Twin and family studies have provided overwhelming evidence for the genetic basis of individual differences in tobacco initiation (TI), regular smoking (RS) and nicotine dependence (ND). However, only a few genes have been reliably associated with ND. We used a finite mixture distribution model to examine the significance and effect size of the association of previously identified and replicated specific variants in the CHRNA5 and CHRNA3 receptor genes with ND, against the background of genetic and environmental risk factors for ND. We hypothesize that additional phenotypic information in relatives who have not been genotyped can be used to increase the power of detecting the genetic variant. The nicotine measures were assessed by personal interview in female, male and opposite sex twin pairs (N = 4,153) from the population-based Virginia Twin Registry. Three SNPs in the CHRNA5 and CHRNA3 receptor genes, previously shown to be significantly associated with ND in this sample, were replicated in the augmented analyses; they accounted for less than one percent of the genetic variance in liability to ND, which is estimated to be over 50% of the phenotypic variance. The significance of these effects was increased by adding twins with phenotype but without genotype data, but gains are limited and variable. The SNPs associated with ND did not show a significant association with either TI or RS and appear to be specific to the addictive stage of ND, characterized by current smoking and smoking a large amount of cigarettes per day. Furthermore, these SNPs did not appear to be associated with the remaining items comprising the FTND scale. This study confirmed a significant contribution of the CHRNA receptor on different forms of tobacco dependence. However, the genetic variant only accounted for little of the total genetic variance for liability to ND. Including phenotypic data on ungenotyped relatives can improve the statistical power to detect the effects of genetic variants when they contribute to individual differences in the phenotype.


Assuntos
Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Receptores Nicotínicos/genética , Tabagismo/genética , Adulto , Doenças em Gêmeos , Meio Ambiente , Feminino , Interação Gene-Ambiente , Marcadores Genéticos , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fumar
20.
Schizophr Res ; 131(1-3): 43-51, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21752600

RESUMO

We conducted data-mining analyses of genome wide association (GWA) studies of the CATIE and MGS-GAIN datasets, and found 13 markers in the two physically linked genes, PTPN21 and EML5, showing nominally significant association with schizophrenia. Linkage disequilibrium (LD) analysis indicated that all 7 markers from PTPN21 shared high LD (r(2)>0.8), including rs2274736 and rs2401751, the two non-synonymous markers with the most significant association signals (rs2401751, P=1.10 × 10(-3) and rs2274736, P=1.21 × 10(-3)). In a meta-analysis of all 13 replication datasets with a total of 13,940 subjects, we found that the two non-synonymous markers are significantly associated with schizophrenia (rs2274736, OR=0.92, 95% CI: 0.86-0.97, P=5.45 × 10(-3) and rs2401751, OR=0.92, 95% CI: 0.86-0.97, P=5.29 × 10(-3)). One SNP (rs7147796) in EML5 is also significantly associated with the disease (OR=1.08, 95% CI: 1.02-1.14, P=6.43 × 10(-3)). These 3 markers remain significant after Bonferroni correction. Furthermore, haplotype conditioned analyses indicated that the association signals observed between rs2274736/rs2401751 and rs7147796 are statistically independent. Given the results that 2 non-synonymous markers in PTPN21 are associated with schizophrenia, further investigation of this locus is warranted.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Esquizofrenia/genética , Biologia Computacional/métodos , Biologia Computacional/estatística & dados numéricos , Bases de Dados Genéticas/estatística & dados numéricos , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Metanálise como Assunto , Proteínas Associadas aos Microtúbulos/genética
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