title: Trans-population analysis of genetic mechanisms of ethnic disparities in neuroblastoma survival.
abstract: BACKGROUND
  Black patients with neuroblastoma have a higher prevalence of high-risk disease and worse outcome than white patients. We sought to investigate the relationship between genetic variation and the disparities in survival observed in neuroblastoma.
  
  
  METHODS
  The analytic cohort was composed of 2709 patients. Principal components were used to assign patients to genomic ethnic clusters for survival analyses. Locus-specific ancestry was calculated for use in association analysis. The shorter spans of linkage disequilibrium in African populations may facilitate the fine mapping of causal variants in regions previously implicated by genome-wide association studies conducted primarily in patients of European descent. Thus, we evaluated 13 single nucleotide polymorphisms known to be associated with susceptibility to high-risk neuroblastoma from genome-wide association studies and all variants with highly divergent allele frequencies in reference African and European populations near the known susceptibility loci. All statistical tests were two-sided.
  
  
  RESULTS
  African genomic ancestry was associated with high-risk neuroblastoma (P = .007) and lower event-free survival (P = .04, hazard ratio = 1.4, 95% confidence interval = 1.05 to 1.80). rs1033069 within SPAG16 (sperm associated antigen 16) was determined to have higher risk allele frequency in the African reference population and statistically significant association with high-risk disease in patients of European and African ancestry (P = 6.42 × 10(-5), false discovery rate < 0.0015) in the overall cohort. Multivariable analysis using an additive model demonstrated that the SPAG16 single nucleotide polymorphism contributes to the observed ethnic disparities in high-risk disease and survival.
  
  
  CONCLUSIONS
  Our study demonstrates that common genetic variation influences neuroblastoma phenotype and contributes to the ethnic disparities in survival observed and illustrates the value of trans-population mapping.
authors.affiliation: Section of Genetic Medicine, University of Chicago, 900 E 57th St, Rm 3220F, Chicago, IL 60637, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Navin
authors.initials: N
authors.lastname: Pinto
authors.forename: Anuar
authors.initials: A
authors.lastname: Konkashbaev
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Im
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
mesh_terms: D001741:Black or African American / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D015999:Multivariate Analysis; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics*
chemical_list: D008869:Microtubule-Associated Proteins; C450619:SPAG16 protein, human