title: Genetic variants that confer resistance to malaria are associated with red blood cell traits in African-Americans: an electronic medical record-based genome-wide association study.
abstract: To identify novel genetic loci influencing interindividual variation in red blood cell (RBC) traits in African-Americans, we conducted a genome-wide association study (GWAS) in 2315 individuals, divided into discovery (n = 1904) and replication (n = 411) cohorts. The traits included hemoglobin concentration (HGB), hematocrit (HCT), RBC count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Patients were participants in the electronic MEdical Records and GEnomics (eMERGE) network and underwent genotyping of ~1.2 million single-nucleotide polymorphisms on the Illumina Human1M-Duo array. Association analyses were performed adjusting for age, sex, site, and population stratification. Three loci previously associated with resistance to malaria-HBB (11p15.4), HBA1/HBA2 (16p13.3), and G6PD (Xq28)-were associated (P ≤ 1 × 10(-6)) with RBC traits in the discovery cohort. The loci replicated in the replication cohort (P ≤ 0.02), and were significant at a genome-wide significance level (P < 5 × 10(-8)) in the combined cohort. The proportions of variance in RBC traits explained by significant variants at these loci were as follows: rs7120391 (near HBB) 1.3% of MCHC, rs9924561 (near HBA1/A2) 5.5% of MCV, 6.9% of MCH and 2.9% of MCHC, and rs1050828 (in G6PD) 2.4% of RBC count, 2.9% of MCV, and 1.4% of MCH, respectively. We were not able to replicate loci identified by a previous GWAS of RBC traits in a European ancestry cohort of similar sample size, suggesting that the genetic architecture of RBC traits differs by race. In conclusion, genetic variants that confer resistance to malaria are associated with RBC traits in African-Americans.
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Teri A
authors.initials: TA
authors.lastname: Manolio
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Rasmussen-Torvik
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Masys
authors.forename: Hayan
authors.initials: H
authors.lastname: Jouni
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pachecho
authors.forename: Abel N
authors.initials: AN
authors.lastname: Kho
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Rex
authors.initials: R
authors.lastname: Chisholm
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
mesh_terms: D001741:Black or African American / Q000235:genetics*; D060467:Disease Resistance / Q000235:genetics*; D057286:Electronic Health Records; D004906:Erythrocyte Count; D004909:Erythrocyte Indices / Q000235:genetics; D004912:Erythrocytes / Q000473:pathology*; D055106:Genome-Wide Association Study; D006400:Hematocrit; D006454:Hemoglobins / Q000235:genetics; D006801:Humans; D008288:Malaria / Q000097:blood / Q000235:genetics*
chemical_list: D006454:Hemoglobins
keywords: African-Americans; electronic medical record; genome-wide association study; informatics; natural selection; red blood cell (RBC) traits