Simple SummaryIn the US, Black women are disproportionately affected by higher breast cancer mortality rates and later-stage tumor diagnoses compared with White women. Breast density, the ratio of dense fibroglandular breast tissue to overall breast tissue area, has previously been identified as an important breast cancer risk factor. Most current genome-wide association studies for breast density have been performed in participants of European ancestry, which have yielded important insights into genetic etiology of breast density. However, little is known about the influence of common genetic variants on breast density in African ancestry populations. Our study aimed to determine genetic factors associated with breast density in African ancestry populations using a Genome-Wide Association Study (GWAS) and post-GWAS analyses on a cohort of genomic data available through the Penn Medicine BioBank. Results of this study elucidate potential genetic mechanisms associated with breast density, and thus cancer risk, among women of African ancestry.AbstractBreast density, the amount of fibroglandular versus fatty tissue in the breast, is a strong breast cancer risk factor. Understanding genetic factors associated with breast density may help in clarifying mechanisms by which breast density increases cancer risk. To date, 50 genetic loci have been associated with breast density, however, these studies were performed among predominantly European ancestry populations. We utilized a cohort of women aged 40–85 years who underwent screening mammography and had genetic information available from the Penn Medicine BioBank to conduct a Genome-Wide Association Study (GWAS) of breast density among 1323 women of African ancestry. For each mammogram, the publicly available “LIBRA” software was used to quantify dense area and area percent density. We identified 34 significant loci associated with dense area and area percent density, with the strongest signals inGACAT3,CTNNA3,HSD17B6,UGDH, TAAR8, ARHGAP10,BOD1L2,andNR3C2. There was significant overlap between previously identified breast cancer SNPs and SNPs identified as associated with breast density. Our results highlight the importance of breast density GWAS among diverse populations, including African ancestry populations. They may provide novel insights into genetic factors associated with breast density and help in elucidating mechanisms by which density increases breast cancer risk.