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1.
Schizophr Res ; 198: 52-59, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29287625

RESUMO

Sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) has been proposed as one of the most promising electrophysiological endophenotypes of schizophrenia. During the past decade, a number of publications have reported significant associations between genetic polymorphisms and PPI in samples of schizophrenia patients and healthy volunteers. However, an overall evaluation of the robustness of these results has not been published so far. Therefore, we performed the first meta-analysis of published and unpublished associations between gene polymorphisms and PPI of ASR. Unpublished associations between genetic polymorphisms and PPI were derived from three independent samples. In total, 120 single observations from 16 independent samples with 2660 study participants and 43 polymorphisms were included. After correction for multiple testing based on false discovery rate and considering the number of analyzed polymorphisms, significant associations were shown for four variants, even though none of these associations survived a genome-wide correction (P<5∗10-8). These results imply that PPI might be modulated by four genotypes - COMT rs4680 (primarily in males), GRIK3 rs1027599, TCF4 rs9960767, and PRODH rs385440 - indicating a role of these gene variations in the development of early information processing deficits in schizophrenia. However, the overall impact of single genes on PPI is still rather small suggesting that PPI is - like the disease phenotype - highly polygenic. Future genome-wide analyses studies with large sample sizes will enhance our understanding on the genetic architecture of PPI.


Assuntos
Estimulação Acústica , Transtornos Neurológicos da Marcha/genética , Polimorfismo Genético/genética , Reflexo de Sobressalto/genética , Catecol O-Metiltransferase/genética , Transtornos Neurológicos da Marcha/etiologia , Estudo de Associação Genômica Ampla , Humanos , Prolina Oxidase/genética , Receptores de Ácido Caínico/genética , Esquizofrenia/complicações , Fator de Transcrição 4/genética , Receptor de GluK3 Cainato
2.
PLoS Genet ; 7(2): e1001300, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21347282

RESUMO

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Doença das Coronárias/genética , Estudo de Associação Genômica Ampla , Hipertensão/genética , Negro ou Afro-Americano/genética , Dessaturase de Ácido Graxo Delta-5 , Genoma Humano , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Estados Unidos , População Branca
3.
Nature ; 466(7307): 714-9, 2010 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-20686566

RESUMO

Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , LDL-Colesterol/metabolismo , Cromossomos Humanos Par 1/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Adaptadoras de Transporte Vesicular/biossíntese , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Sequência de Bases , Sítios de Ligação , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Células Cultivadas , LDL-Colesterol/sangue , Estudos de Coortes , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Europa (Continente)/etnologia , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Haplótipos/genética , Hepatócitos/metabolismo , Humanos , Lipídeos/sangue , Lipoproteínas VLDL/sangue , Lipoproteínas VLDL/metabolismo , Fígado/citologia , Fígado/metabolismo , Camundongos , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Fenótipo , Transcrição Gênica
4.
Circ Cardiovasc Genet ; 3(3): 267-75, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20400780

RESUMO

BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans. METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups. CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.


Assuntos
Estudos de Associação Genética/métodos , Negro ou Afro-Americano/genética , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Estudos de Coortes , Bases de Dados Genéticas , Genótipo , Humanos , Fenótipo , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Projetos de Pesquisa , Triglicerídeos/sangue , Triglicerídeos/genética , População Branca/genética
5.
J Virol ; 79(23): 14863-75, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16282486

RESUMO

Reverse transcriptases (RTs) of retroviruses and long terminal repeat (LTR)-retrotransposons possess DNA polymerase and RNase H activities. During reverse transcription these activities are necessary for the programmed sequence of events that include template switching and primer processing. Integrase then inserts the completed cDNA into the genome of the host cell. The RT of the LTR-retrotransposon Tf1 was subjected to random mutagenesis, and the resulting transposons were screened with genetic assays to test which mutations reduced reverse transcription and which inhibited integration. We identified a cluster of mutations in the RNase H domain of RT that were surprising because they blocked integration without reducing cDNA levels. The results of immunoblots demonstrated that these mutations did not reduce levels of RT or integrase. DNA blots showed that the mutations did not lower the amounts of full-length cDNA. The sequences of the 3' ends of the cDNA revealed that mutations within the cluster in RNase H specifically reduced the removal of the polypurine tract (PPT) primer from the ends of the cDNA. These results indicate that primer removal is not a necessary component of reverse transcription. The residues mutated in Tf1 RNase H are conserved in human immunodeficiency virus type 1 and make direct contact with DNA opposite the PPT. Thus, our results identify a conserved element in RT that contacts the PPT and is specifically required for PPT removal.


Assuntos
DNA Polimerase Dirigida por RNA/metabolismo , RNA/metabolismo , Ribonuclease H/metabolismo , DNA Viral/biossíntese , Repetição Terminal Longa de HIV , Transcriptase Reversa do HIV/metabolismo , RNA/química , RNA/genética , DNA Polimerase Dirigida por RNA/química , DNA Polimerase Dirigida por RNA/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Especificidade por Substrato , Moldes Genéticos
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