Genetics of Mammographic Density in Ashkenazi Jews

Mammographic density (MD) is a strong risk factor for breast cancer and is also a highly heritable trait with ~60-70% of the variance 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. Thus, the vast majority of the heritability of mammographic density remains unexplained and may be explained, at least in part, by rare variants. Ashkenazi Jewish women are a founder population; founder populations frequently have alleles affecting phenotypes which may be unique and/or extremely rare in other populations. Prior reports have identified an association between higher mammographic density and Ashkenazi Jewish ancestry. Therefore, we developed a study of mammographic density in AJ women. We combined datasets from several different cohorts including (a) the California Pacific Medical Center Research Institute (b) the Athena Breast Health Cohort and (c) the Marin Women's study. In each study, we identified women who reported AJ ancestry (determined by self-report or by genetic analysis). We identified mammograms by linking the women to the San Francisco Mammography Registry. We retrieved digital mammographic results and used software to infer volumetric density and percent volumetric density for each woman. We then performed genome-wide genotyping of the samples using the Illumina MEGA array.]]>
Women who participated in either the (a) Marin Women's Study (M. Powell et al., 2014, PMID: 24461459), (b) the Athena Breast Health Cohort (Elson et al., PMID: 23887672), or the (3) California Pacific Medical Center Research Institute (Shieh et al., PMID: 27565998). Women in the Marin Women's Study reported AJ ancestry (yes/no) and those who responded yes were included. Women in the Athena Breast Health Cohort were included if they reported at least one AJ parent. Women in the California Pacific Medical Center Research Institute were included if they had previously been included in a GWAS study of mammographic density and were inferred by genetic analysis to have 50% or greater AJ ancestry (Caswell et al., PMID: 23668689). Women had to have at least one mammogram that was taken on a digital mammography unit in the SFMR to be included in the analysis and to have contributed either a blood or saliva sample to any of the 3 cohorts named.]]>
In analyses of the California Pacific Medical Center Research Institute (CPMCRI) cohort, we identified an association between mammographic density and AJ ancestry (Caswell et al., PMID: 23668689). We subsequently identified women of self-reported AJ ancestry in 2 additional cohorts, the Marin Women's Study and the Athena Breast Health Cohort, and combined these datasets into a GWAS of mammographic density in AJ women.]]>