Conflict of interest: Nothing to report.
Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study†
Article first published online: 23 OCT 2009
Copyright © 2009 Wiley-Liss, Inc.
American Journal of Hematology
Volume 85, Issue 1, pages 29–35, January 2010
How to Cite
Sebastiani, P., Solovieff, N., Hartley, S. W., Milton, J. N., Riva, A., Dworkis, D. A., Melista, E., Klings, E. S., Garrett, M. E., Telen, M. J., Ashley-Koch, A., Baldwin, C. T. and Steinberg, M. H. (2010), Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. Am. J. Hematol., 85: 29–35. doi: 10.1002/ajh.21572
- Issue published online: 22 DEC 2009
- Article first published online: 23 OCT 2009
- Accepted manuscript online: 23 OCT 2009 12:00AM EST
- Manuscript Accepted: 15 OCT 2009
- Manuscript Received: 14 OCT 2009
- NIH/NHLBI. Grant Numbers: R01 HL87681, R01 HL 068970
We conducted a genome-wide association study (GWAS) to discover single nucleotide polymorphisms (SNPs) associated with the severity of sickle cell anemia in 1,265 patients with either “severe” or “mild” disease based on a network model of disease severity. We analyzed data using single SNP analysis and a novel SNP set enrichment analysis (SSEA) developed to discover clusters of associated SNPs. Single SNP analysis discovered 40 SNPs that were strongly associated with sickle cell severity (odds for association >1,000); of the 32 that we could analyze in an independent set of 163 patients, five replicated, eight showed consistent effects although failed to reach statistical significance, whereas 19 did not show any convincing association. Among the replicated associations are SNPs in KCNK6 a K+ channel gene. SSEA identified 27 genes with a strong enrichment of significant SNPs (P < 10−6); 20 were replicated with varying degrees of confidence. Among the novel findings identified by SSEA is the telomere length regulator gene TNKS. These studies are the first to use GWAS to understand the genetic diversity that accounts the phenotypic heterogeneity sickle cell anemia as estimated by an integrated model of severity. Additional validation, resequencing, and functional studies to understand the biology and reveal mechanisms by which candidate genes might have their effects are the future goals of this work. Am. J. Hematol., 2010. © 2009 Wiley-Liss, Inc.