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.

Public Health Relevance

Our proposal will search for novel genetic markers that are associated with high mammographic density among Ashkenazi Jewish women. We will map these genes using novel methods from population genetics and relying on the unique demographic history of Ashkenazi Jews. By identifying the genetic regions and particular genetic variants that underlie mammographic density in these patients, we will be able to help understand the biological mechanisms by which mammographic density causes breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA179442-01
Application #
8571075
Study Section
Special Emphasis Panel (ZCA1-SRLB-B (M1))
Program Officer
Nelson, Stefanie A
Project Start
2013-09-15
Project End
2015-08-31
Budget Start
2013-09-15
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$200,000
Indirect Cost
$72,611
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143