Genome Wide Association Analysis of a Founder Population Identified TAF3 as a Gene for MCHC in Humans

Giorgio Pistis, Shawntel U. Okonkwo, Michela Traglia, Cinzia Sala, So Youn Shin, Corrado Masciullo, Iwan Buetti, Roberto Massacane, Massimo Mangino, Swee Lay Thein, Timothy D. Spector, Santhi Ganesh, Nicola Pirastu, Paolo Gasparini, Nicole Soranzo, Clara Camaschella, Daniel Hart, Michael R. Green, Daniela Toniolo

Research output: Contribution to journalArticlepeer-review

Abstract

The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E-09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.

Original languageEnglish
Article numbere69206
JournalPLoS One
Volume8
Issue number7
DOIs
Publication statusPublished - Jul 31 2013

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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