title: Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study.
abstract: 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.
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. sebas@bu.edu
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: Nadia
authors.initials: N
authors.lastname: Solovieff
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Hartley
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Milton
authors.forename: Alberto
authors.initials: A
authors.lastname: Riva
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Dworkis
authors.forename: Efthymia
authors.initials: E
authors.lastname: Melista
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Klings
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Garrett
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
authors.forename: Allison
authors.initials: A
authors.lastname: Ashley-Koch
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D003185:Complement C8 / Q000235:genetics; D019295:Computational Biology; D055106:Genome-Wide Association Study; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics; D012720:Severity of Illness Index; D038501:Tankyrases / Q000235:genetics; D055815:Young Adult
chemical_list: D003185:Complement C8; D020930:MAP Kinase Kinase Kinases; D024683:Potassium Channels, Tandem Pore Domain; D038501:Tankyrases; C118290:KCNK6 protein, human; C418109:TNKS protein, human; C109162:MAP3K13 protein, human