ABSTRACT Mammographic density (MD) is a strong risk factor for breast cancer and family studies suggest it is highly heritable. Genome wide association studies (GWAS) have identified a modest number of loci for MD, some of which overlap with breast cancer risk. However, most of the heritability of breast cancer remains unexplained and the underlying biology that explains the overlap between density and breast cancer risk remains poorly understood. This proposal will support Dr. Elad Ziv to continue scientific work on the genetics of mammographic density and to continue to mentor clinician investigators in translational genetic studies of cancer. As part of the current cycle of this K24, Dr. Ziv and his colleagues have investigated the genetics of breast cancer and MD in Latina women. They have identified, via admixture mapping and GWAS, a very strong association for a single nucleotide polymorphism (SNP) on chromosome 6q25. The minor allele at of this SNP is associated with substantially reduced risk of breast cancer (Odds ratio of 0.6 for heterozygotes and 0.2 for homozygotes). They also found that the minor allele is associated with a substantial reduction of mammographic density; comparing women homozygous for the common allele vs. women homozygous for the low risk minor allele, the median percent mammographic density is reduced from 16% to 8%, respectively. This SNP is found almost exclusively in Latina women since this it originates in the Indigenous American populations from that region. These results demonstrate the value of genetic studies in non-Caucasian populations for complex traits. As part of the renewal for this project, they aim to extend these studies. They will focus on Latinas, a relatively understudied population, where they have developed unique resources including a large GWAS and whole exome sequencing data. First, they will investigate the possibility that rare variants at the 6q25 locus are associated with MD in Latina women. They will perform targeted capture and sequencing of the region they have previously found to be associated with breast cancer and density and they will perform rare variant association tests. Second, they will use GWAS data from Latina women with breast cancer and controls to determine what genes and pathways might be involved in the overlap between breast density and breast cancer risk. Third, they will use data from their exome sequencing project (R01CA184545) to investigate whether rare variants in coding regions in genes might underlie the shared heritability between MD and breast cancer. Dr. Ziv will also continue to mentor junior faculty, post-doctoral fellows, residents and students in research. Mentees will work on the aims listed in this proposal and on several other large projects on genetic susceptibility to breast cancer, genetics of mammographic density and genetics of multiple myeloma.