RESUMEN
White blood cell count (WBC) is unique among identified inflammatory predictors of chronic disease in that it is routinely measured in asymptomatic patients in the course of routine patient care. We led a genome-wide association analysis to identify variants associated with WBC levels in 13,923 subjects in the electronic Medical Records and Genomics (eMERGE) Network. We identified two regions of interest that were each unique to subjects of genetically determined ancestry to the African continent (AA) or to the European continent (EA). WBC varies among different ancestry groups. Despite being ancestry specific, these regions were identifiable in the combined analysis. In AA subjects, the region surrounding the Duffy antigen/chemokine receptor gene (DARC) on 1q21 exhibited significant association (p value = 6.71e-55). These results validate the previously reported association between WBC and of the regulatory variant rs2814778 in the promoter region, which causes the Duffy negative phenotype (Fy-/-). A second missense variant (rs12075) is responsible for the two principal antigens, Fya and Fyb of the Duffy blood group system. The two variants, consisting of four alleles, act in concert to produce five antigens and subsequent phenotypes. We were able to identify the marginal and novel interaction effects of these two variants on WBC. In the EA subjects, we identified significantly associated SNPs tagging three separate genes in the 17q21 region: (1) GSDMA, (2) MED24, and (3) PSMD3. Variants in this region have been reported to be associated with WBC, neutrophil count, and inflammatory diseases including asthma and Crohn's disease.
Asunto(s)
Variación Genética , Estudio de Asociación del Genoma Completo/métodos , Recuento de Leucocitos , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Población Negra/genética , Sistema del Grupo Sanguíneo Duffy/genética , Femenino , Frecuencia de los Genes , Genoma Humano/genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Genotipo , Humanos , Masculino , Complejo Mediador/genética , Registros Médicos/estadística & datos numéricos , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple , Análisis de Componente Principal , Complejo de la Endopetidasa Proteasomal/genética , Receptores de Superficie Celular/genética , Población Blanca/genética , Población Blanca/estadística & datos numéricosRESUMEN
To characterize the genetic basis of spike-wave discharges (SWDs) detected by electroencephalography (EEG) in C3H/He mice, substrains of C3H mice were evaluated by EEG and sensitivity to ethosuximide. Crosses with the SWD-negative strain C57BL/6J were performed to map the underlying gene(s). C3H/He substrains exhibited a modest incidence (average of 19 SWDs per hour) of 7-8 Hz SWDs when at rest, compared with the C3HeB/Fe subline (four SWDs per hour). In the mapping backcross, however, many mice showed a very high incidence (50-220 SWDs per hour) throughout the recording period. SWDs were first detected at 3.5 weeks of age, were associated with behavioral arrest, were suppressed by ethosuximide, and were strongest in the cerebral cortex and thalamus. The major C3H determinant of SWDs, spkw1 (spike-wave 1), mapped to chromosome (Chr 9), and together with a C57BL/6J determinant on Chr 8, spkw2, accounted for more than one-half of the phenotypic variation in the backcross mice. The modest SWD incidence in C3H/He mice and the high incidence in backcrosses implies that SWD could be a confounding variable for other behaviors. Because C3H/He mice have no other brain abnormalities, they are an attractive alternative for studying idiopathic absence epilepsy.
Asunto(s)
Modelos Animales de Enfermedad , Epilepsia Tipo Ausencia/genética , Epilepsia Tipo Ausencia/fisiopatología , Endogamia , Modelos Genéticos , Análisis de Varianza , Animales , Anticonvulsivantes/uso terapéutico , Mapeo Encefálico/métodos , Mapeo Cromosómico/métodos , Epilepsia Tipo Ausencia/tratamiento farmacológico , Etosuximida/uso terapéutico , Ratones , Ratones Endogámicos C3H , Ritmo Teta/efectos de los fármacosRESUMEN
N-ethyl-N-nitrosourea (ENU) mutagenesis is presented as a powerful approach to developing models for human disease. The efforts of three NIH Mutagenesis Centers established for the detection of neuroscience-related phenotypes are described. Each center has developed an extensive panel of phenotype screens that assess nervous system structure and function. In particular, these screens focus on complex behavioral traits from drug and alcohol responses to circadian rhythms to epilepsy. Each of these centers has developed a bioinformatics infrastructure to track the extensive number of transactions that are inherent in these large-scale projects. Over 100 new mouse mutant lines have been defined through the efforts of these three mutagenesis centers and are presented to the research community via the centralized Web presence of the Neuromice.org consortium (http://www.neuromice.org). This community resource provides visitors with the ability to search for specific mutant phenotypes, to view the genetic and phenotypic details of mutant mouse lines, and to order these mice for use in their own research program.
Asunto(s)
Mutagénesis , Enfermedades del Sistema Nervioso/genética , Fenómenos Fisiológicos del Sistema Nervioso , Alquilantes , Animales , Etilnitrosourea , RatonesRESUMEN
The National Center for Biotechnology Information has created the dbGaP public repository for individual-level phenotype, exposure, genotype and sequence data and the associations between them. dbGaP assigns stable, unique identifiers to studies and subsets of information from those studies, including documents, individual phenotypic variables, tables of trait data, sets of genotype data, computed phenotype-genotype associations, and groups of study subjects who have given similar consents for use of their data.