Genetics of Mammographic Density in Ashkenazi Jews

描述（由申请人提供）：乳腺摄影密度（MD）是乳腺癌的一个强风险因素，也是一种高度遗传的性状，根据双胞胎研究，遗传因素导致的变异约为60-70%。MD在有乳腺癌病史的家庭中也更高。全基因组关联研究（GWAS），其重点是常见的遗传变异，已经确定了几个与MD相关的单核苷酸多态性（SNP）。然而，这些SNPs解释了MD变异的一小部分，表明涉及许多其他基因。连锁研究已经确定了一些可能与这一性状相关的基因座，但 目前还没有通过连锁分析绘制基因图谱。因此，乳腺摄影密度的绝大多数遗传性仍然无法解释，很可能是由于罕见的变异。我们最近发现了较高的乳房X线摄影密度和德系犹太人血统之间的联系。由于德系犹太人是一个创始人群体，在这个群体中进行遗传图谱绘制可能有几个优势。特别是，德系犹太人共享广泛的染色体片段，由于少数创始人而具有相同的血统（IBD）。我们建议利用IBD片段来帮助绘制乳腺摄影密度的位点。特别是，我们计划在年龄和体重指数（BMI）调整的乳房X线摄影密度最高的五分之一的德系犹太妇女中寻找IBD的地区，并将这些地区与年龄和BMI调整的乳房X线摄影密度最低的五分之一的德系犹太妇女进行比较。然后，我们将在高密度女性和低密度对照组中选择顶部区域并对其进行测序，以确定最有可能与该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.