Barnholtz-Sloan Jill S, Raska Paola, Rebbeck Timothy R, Millikan Robert C
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine Cleveland, OH, USA.
Front Genet. 2011 Jul 1;2:37. doi: 10.3389/fgene.2011.00037. eCollection 2011.
In this study, we assessed association of genome-wide association studies (GWAS) "hits" by race with adjustment for potential population stratification (PS) in two large, diverse study populations; the Carolina Breast Cancer Study (CBCS; N total = 3693 individuals) and the University of Pennsylvania Study of Clinical Outcomes, Risk, and Ethnicity (SCORE; N total = 1135 individuals). In both study populations, 136 ancestry information markers and GWAS "hits" (CBCS: FGFR2, 8q24; SCORE: JAZF1, MSMB, 8q24) were genotyped. Principal component analysis was used to assess ancestral differences by race. Multivariable unconditional logistic regression was used to assess differences in cancer risk with and without adjustment for the first ancestral principal component (PC1) and for an interaction effect between PC1 and the GWAS "hit" (SNP) of interest. PC1 explained 53.7% of the variance for CBCS and 49.5% of the variance for SCORE. European Americans and African Americans were similar in their ancestral structure between CBCS and SCORE and cases and controls were well matched by ancestry. In the CBCS European Americans, 9/11 SNPs were significant after PC1 adjustment, but after adjustment for the PC1 by SNP interaction effect, only one SNP remained significant (rs1219648 in FGFR2); for CBCS African Americans, 6/11 SNPs were significant after PC1 adjustment and after adjustment for the PC1 by SNP interaction effect, all six SNPs remained significant and an additional SNP now became significant. In the SCORE European Americans, 0/9 SNPs were significant after PC1 adjustment and no changes were seen after additional adjustment for the PC1 by SNP interaction effect; for SCORE African Americans, 2/9 SNPs were significant after PC1 adjustment and after adjustment for the PC1 by SNP interaction effect, only one SNP remained significant (rs16901979 at 8q24). We show that genetic associations by race are modified by interaction between individual SNPs and PS.
在本研究中，我们在两个大型、多样化的研究人群中评估了全基因组关联研究（GWAS）“命中”结果与种族之间的关联，并对潜在的群体分层（PS）进行了校正；这两个人群分别是卡罗来纳乳腺癌研究（CBCS；总样本量为3693人）和宾夕法尼亚大学临床结局、风险与种族研究（SCORE；总样本量为1135人）。在这两个人群中，对136个祖先信息标记和GWAS“命中”结果（CBCS：FGFR2，8q24；SCORE：JAZF1、MSMB、8q24）进行了基因分型。主成分分析用于评估种族间的祖先差异。多变量无条件逻辑回归用于评估在对第一个祖先主成分（PC1）进行校正以及未校正的情况下，以及在PC1与感兴趣的GWAS“命中”结果（单核苷酸多态性，SNP）之间的交互作用存在与否的情况下，癌症风险的差异。PC1解释了CBCS中53.7%的变异以及SCORE中49.5%的变异。CBCS和SCORE中，欧洲裔美国人和非裔美国人在祖先结构上相似，病例组和对照组在祖先方面匹配良好。在CBCS的欧洲裔美国人中，9/11个SNP在经PC1校正后具有显著性，但在对PC1与SNP的交互作用进行校正后，只有一个SNP仍然显著（FGFR2中的rs1219648）；对于CBCS的非裔美国人，6/11个SNP在经PC1校正后具有显著性，在对PC1与SNP的交互作用进行校正后，所有6个SNP仍然显著，并且另外一个SNP现在也变得显著。在SCORE的欧洲裔美国人中，0/9个SNP在经PC1校正后具有显著性，在对PC1与SNP的交互作用进行进一步校正后未观察到变化；对于SCORE的非裔美国人，2/9个SNP在经PC1校正后具有显著性，在对PC1与SNP的交互作用进行校正后，只有一个SNP仍然显著（8q24处的rs16901979）。我们发现，种族间的遗传关联会因个体SNP与群体分层之间的相互作用而发生改变。
