Genetics of Mammographic Density in Ashkenazi Jews

描述(申请人提供)：乳房X光摄影密度(MD)是乳腺癌的强烈风险因素，也是一种高度可遗传的特征，基于双胞胎研究的遗传因素导致的变异约为60%-70%。在有强烈乳腺癌病史的家庭中，MD也更高。全基因组关联研究(GWAS)主要关注常见的遗传变异，已经发现了几个与MD相关的单核苷酸多态(SNPs)。然而，这些SNPs解释了MD的一小部分变异，这表明还有许多其他基因参与其中。连锁研究已经确定了一些可能与这种特征相关的基因座，但 目前还没有通过连锁分析定位到基因。因此，绝大多数乳房X光摄影密度的遗传性仍未得到解释，很可能是由于罕见的变异。我们最近发现了较高的乳房X光照相密度与德系犹太人血统之间的关联。由于德系犹太人是犹太人的创立者，因此在这一群体中绘制群体基因图谱可能有几个优势。特别是，由于创建者的数量很少，德系犹太人拥有大量相同的后代(IBD)染色体片段。我们建议利用IBD片段来帮助绘制乳腺X光检查密度的基因座图。特别是，我们计划搜索年龄和体重指数(BMI)调整后的乳房X线密度在年龄和体重指数(BMI)调整后的乳房X线密度中处于最高五分之一的德系犹太女性中的IBD区域，并将这些地区与年龄和BMI调整后的乳房X光密度最低五分之一的德系犹太女性进行比较。然后我们将选择最顶端的区域，并在高密度女性和低密度对照组中对它们进行排序，以确定最有可能与这一特征相关的遗传变异。

DESCRIPTION (provided by applicant): Mammographic density (MD) is a strong risk factor for breast cancer and is also a highly heritable trait with ~60-70% of the variance in due to genetic factors based on twin studies. MD is also higher in families with a strong history of breast cancer. Genome wide association studies (GWAS), which focus on common genetic variants, have identified several single nucleotide polymorphisms (SNPs) associated with MD. However, these SNPs explain a very small fraction of the variance of MD suggesting many other genes are involved. Linkage studies have identified some loci that may be associated with this trait, but no genes have been mapped yet by linkage analysis. Thus, the vast majority of the heritability of mammographic density remains unexplained and is likely due to rare variants. We have recently identified an association between higher mammographic density and Ashkenazi Jewish ancestry. Since Ashkenazi Jews are a founder population genetic mapping in this population may have several advantages. In particular, Ashkenazi Jews share extensive chromosomal segments that are identical by descent (IBD) due to a small number of founders. We propose to leverage the IBD segments to help map loci for mammographic density. In particular, we plan to search for regions that are IBD among Ashkenazi Jewish women in the top quintile of age and body mass index (BMI)-adjusted mammographic density for shared IBD segments and compare these to Ashkenazi Jewish women in the lowest quintile of age and BMI- adjusted mammographic density. We will then select the top regions and sequence them in the high density women and low density comparison group to identify the genetic variants most likely to be associated with this trait.