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

Keyue Ding, Mariza de Andrade, Teri A. Manolio, Dana C. Crawford, Laura J. Rasmussen-Torvik, Marylyn D. Ritchie, Joshua C. Denny, Daniel R. Masys, Hayan Jouni, Jennifer A. Pachecho, Abel N. Kho, Dan M. Roden, Rex Chisholm, Iftikhar J. Kullo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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 < 1 × 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.

Original languageEnglish (US)
Pages (from-to)1061-1068
Number of pages8
JournalG3: Genes, Genomes, Genetics
Volume3
Issue number7
DOIs
StatePublished - Jul 2013

Keywords

  • African-Americans
  • Association study
  • Electronic medical
  • Genome-wide
  • Informatics
  • Natural selection
  • Record
  • Red blood cell (RBC)
  • Traits

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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