RESUMO
The feasibility of using imperfectly phenotyped "silver standard" samples identified from electronic medical record diagnoses is considered in genetic association studies when these samples might be combined with an existing set of samples phenotyped with a gold standard technique. An analytic expression is derived for the power of a chi-square test of independence using either research-quality case/control samples alone, or augmented with silver standard data. The subset of the parameter space where inclusion of silver standard samples increases statistical power is identified. A case study of dementia subjects identified from electronic medical records from the Electronic Medical Records and Genomics (eMERGE) network, combined with subjects from two studies specifically targeting dementia, verifies these results.
Assuntos
Biomarcadores/metabolismo , Demência/genética , Registros Eletrônicos de Saúde/estatística & dados numéricos , Estudo de Associação Genômica Ampla , Genômica , Polimorfismo de Nucleotídeo Único/genética , Idoso , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Simulação por Computador , Demência/epidemiologia , Humanos , Modelos Estatísticos , Fenótipo , Fatores de RiscoRESUMO
With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(-16), ß = -0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(-7), ß = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(-16), ß = -0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(-7), ß = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(-17), ß = -0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.
Assuntos
Aterosclerose/sangue , Aterosclerose/genética , Cromossomos Humanos/genética , Estudo de Associação Genômica Ampla , Contagem de Leucócitos , Adulto , Idoso , Cromossomos Humanos/metabolismo , Feminino , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Humanos , Integrina alfa4/genética , Integrina alfa4/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Monócitos , Mutação de Sentido Incorreto , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismoRESUMO
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.