Common variations in BARD1 influence susceptibility to high-risk neuroblastoma

Abstract

We conducted a SNP-based genome-wide association study (GWAS) focused on the high-risk subset of neuroblastoma. As our previous unbiased GWAS showed strong association of common 6p22 SNP alleles with aggressive neuroblastoma, we restricted our analysis here to 397 high-risk cases compared to 2,043 controls. We detected new significant association of six SNPs at 2q35 within the BARD1 locus (P(allelic) = 2.35 x 10(-9)-2.25 x 10(-8)). We confirmed each SNP association in a second series of 189 high-risk cases and 1,178 controls (P(allelic) = 7.90 x 10(-7)-2.77 x 10(-4)). We also tested the two most significant SNPs (rs6435862, rs3768716) in two additional independent high-risk neuroblastoma case series, yielding combined allelic odds ratios of 1.68 each (P = 8.65 x 10(-18) and 2.74 x 10(-16), respectively). We also found significant association with known BARD1 nonsynonymous SNPs. These data show that common variation in BARD1 contributes to the etiology of the aggressive and most clinically relevant subset of human neuroblastoma.

Figure 1. Summary of the neuroblastoma GWAS results in the discovery set restricted to the high-risk group of patients

The y-axis represents the level of significance for each SNP (log transformed P-values) at the relative genomic position (Build 35) on each chromosome along the x-axis from short arm terminus (left) to long arm terminus (right). The horizontal line indicates our threshold for follow-up analysis (P-value < 1×10⁻⁷). The previously reported 6p22 signal is more significant in this discovery case series enriched for the subset of 397 high-risk patients compared to the 1032 unselected neuroblastoma cases previously studied, and a new chromosome 2q35 signal emerged.

Figure 2. Regional plot of the BARD1 locus associated with high-risk neuroblastoma

Single marker results (−log₁₀P-values) for association testing of all SNPs at the BARD1 locus with six SNPs showing P-values <1×10⁻⁷ indicated in relation to the BARD1 genomic structure (exons indicated by vertical boxes) and in relation to the r² linkage disequilibrium structure at all BARD1 SNPs with MAF>0.05 from HapMap CEU data, generated with the use of Haploview software. The position of five additional nsSNPs subsequently genotyped is also indicated (rs7585356 located 3′ downstream of BARD1 was also genotyped but is not shown).