Searching for new risk variants in known breast cancer risk loci in Asians

描述（由申请人提供）：遗传因素在乳腺癌的病因学中起重要作用，乳腺癌是一种复杂的多因素疾病。迄今为止，全基因组关联研究（GWAS）已经发现了大约67个与乳腺癌风险相关的常见遗传易感位点。然而，除了少数几个基因座外，所有其他基因座最初都是在对欧洲血统的女性进行的研究中确定的。在迄今报告的67个指数snp中，只有大约一半可以在亚洲人身上直接复制。鉴于不同种族人群遗传结构的差异，我们假设在亚洲血统人群中可能存在不同的风险变异，在一些位点上，指数snp在亚洲人中没有复制。多项研究表明，基于1000基因组计划的数据比基于HapMap的数据提供了更好的机会来识别新的风险变异，因为1000基因组计划的数据具有更密集的snp，特别是低等位基因频率snp和更大的样本量。在过去的几年中，我们使用Affymetrix 6.0 SNP阵列对约9400例乳腺癌病例和对照进行了基因分型。我们建议使用最新的1000基因组计划数据作为参考，对这些样本进行数据推算，以评估在亚洲人中没有复制指数snp的10个乳腺癌位点。有希望的snp将在一组8400例亚洲血统的独立病例和对照中进一步调查。通过强有力的方法学和非常经济有效的研究设计，我们预计在亚洲祖先人群的这些基因座中将发现新的遗传变异。这些新发现的变异可以显著提高我们对乳腺癌遗传学和生物学的认识，并可用于癌症筛查和风险评估，旨在识别高危妇女，以针对性地预防乳腺癌。

DESCRIPTION (provided by applicant): Genetic factors play an important role in the etiology of breast cancer, a complex, multifactorial disease. To date, genome-wide association studies (GWAS) have discovered approximately 67 common genetic susceptibility loci for breast cancer risk. However, with the exception of a few loci, all others were identified initially in studies conducted among women of European ancestry. Among the 67 index SNPs reported to date, only about a half of them could be directly replicated in Asians. Given differences in genetic architecture across different ethnic populations, we hypothesize that different risk variants may exist in Asian-ancestry populations in some of the loci in which the index SNPs were not replicated in Asians. Multiple studies have showed that imputation based on the 1000 Genomes Project data provides better chance to identify novel risk variants than that based on the HapMap data since data in the 1000 Genomes Project have much denser SNPs especially low allele frequency SNPs and a larger sample size. Over the past few years, we have genotyped ~9,400 breast cancer cases and controls of Asian ancestry using Affymetrix 6.0 SNP arrays. We propose to impute data for these samples using the most recent 1,000 Genomes Project data as reference to evaluate 10 breast cancer loci in which the index SNPs were not replicated in Asians. Promising SNPs will be further investigated in an independent set of 8,400 cases and controls of Asian ancestry. With strong methodology and very cost- efficient study design, we anticipate that novel genetic variants will be identified in these loci in Asian ancestry populations. These newly-identified variants could significantly improve our understanding of breast cancer genetics and biology and could be used for cancer screening and risk assessment aimed at identifying high- risk women for targeted breast cancer prevention.