Dataset Information

Genetic variation associated with circulating monocyte count in the eMERGE Network.

ABSTRACT: 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), ? = -0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(-7), ? = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(-16), ? = -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), ? = 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), ? = -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.

SUBMITTER: Crosslin DR

PROVIDER: S-EPMC3633369 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Genetic variation associated with circulating monocyte count in the eMERGE Network.

Crosslin David R DR McDavid Andrew A Weston Noah N Zheng Xiuwen X Hart Eugene E de Andrade Mariza M Kullo Iftikhar J IJ McCarty Catherine A CA Doheny Kimberly F KF Pugh Elizabeth E Kho Abel A Hayes M Geoffrey MG Ritchie Marylyn D MD Saip Alexander A Crawford Dana C DC Crane Paul K PK Newton Katherine K Carrell David S DS Gallego Carlos J CJ Nalls Michael A MA Li Rongling R Mirel Daniel B DB Crenshaw Andrew A Couper David J DJ Tanaka Toshiko T van Rooij Frank J A FJ Chen Ming-Huei MH Smith Albert V AV Zakai Neil A NA Yango Qiong Q Garcia Melissa M Liu Yongmei Y Lumley Thomas T Folsom Aaron R AR Reiner Alex P AP Felix Janine F JF Dehghan Abbas A Wilson James G JG Bis Joshua C JC Fox Caroline S CS Glazer Nicole L NL Cupples L Adrienne LA Coresh Josef J Eiriksdottir Gudny G Gudnason Vilmundur V Bandinelli Stefania S Frayling Timothy M TM Chakravarti Aravinda A van Duijn Cornelia M CM Melzer David D Levy Daniel D Boerwinkle Eric E Singleton Andrew B AB Hernandez Dena G DG Longo Dan L DL Witteman Jacqueline C M JC Psaty Bruce M BM Ferrucci Luigi L Harris Tamara B TB O'Donnell Christopher J CJ Ganesh Santhi K SK Larson Eric B EB Carlson Chris S CS Jarvik Gail P GP

Human molecular genetics 20130112 10

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 ...[more]

PMID: 23314186

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Project description:Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10-17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10-6, β = -0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = -0.09), VEGFA (rs11755845 p = 0.01, β = -0.13), and NFIA (rs334699 p = 1.50×10-3, β = -0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.

Project description:Background/objectivesMelanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus.Subjects/methodsThe sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping.ResultsTargeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m2. In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 (P = 5.36 × 10-25, Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties (P = 6.23 × 10-08, Beta = -0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI.ConclusionsMC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.

Dataset Information

Genetic variation associated with circulating monocyte count in the eMERGE Network.

Publications

Genetic variation associated with circulating monocyte count in the eMERGE Network.

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