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Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.

ABSTRACT: Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

SUBMITTER: Ganesh SK

PROVIDER: S-EPMC2778265 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.

Ganesh Santhi K SK Zakai Neil A NA van Rooij Frank J A FJ Soranzo Nicole N Smith Albert V AV Nalls Michael A MA Chen Ming-Huei MH Kottgen Anna A Glazer Nicole L NL Dehghan Abbas A Kuhnel Brigitte B Aspelund Thor T Yang Qiong Q Tanaka Toshiko T Jaffe Andrew A Bis Joshua C M JC Verwoert Germaine C GC Teumer Alexander A Fox Caroline S CS Guralnik Jack M JM Ehret Georg B GB Rice Kenneth K Felix Janine F JF Rendon Augusto A Eiriksdottir Gudny G Levy Daniel D Patel Kushang V KV Boerwinkle Eric E Rotter Jerome I JI Hofman Albert A Sambrook Jennifer G JG Hernandez Dena G DG Zheng Gang G Bandinelli Stefania S Singleton Andrew B AB Coresh Josef J Lumley Thomas T Uitterlinden André G AG Vangils Janine M JM Launer Lenore J LJ Cupples L Adrienne LA Oostra Ben A BA Zwaginga Jaap-Jan JJ Ouwehand Willem H WH Thein Swee-Lay SL Meisinger Christa C Deloukas Panos P Nauck Matthias M Spector Tim D TD Gieger Christian C Gudnason Vilmundur V van Duijn Cornelia M CM Psaty Bruce M BM Ferrucci Luigi L Chakravarti Aravinda A Greinacher Andreas A O'Donnell Christopher J CJ Witteman Jacqueline C M JC Furth Susan S Cushman Mary M Harris Tamara B TB Lin Jing-Ping JP

Nature genetics 20091011 11

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 indiv ...[more]

PMID: 19862010

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Project description:White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

Project description:Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health.The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers.We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts.Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (? = 0.0035, P = 4.90 × 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (? = 0.0053, P = 1.05 × 10(-6)) and Chinese Americans (? = 0.0028, P = 0.002) but not African Americans (? = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: ? = 0.0118, P = 4.05 × 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (?-coefficient reduced by 86%), with similar reductions in Hispanic Americans and Chinese Americans.Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat.

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Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.

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Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.

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