Abstract Background: Breast parenchymal texture features capture the patterns of texture variation on a mammogram. One such texture feature is called V, which reflects the gray scale variation on the image. Recent studies have shown that texture features, including V, are associated with breast cancer risk, independent of mammographic density (MD). However, our knowledge on the genetic basis of texture features and the shared genetic components between these features, MD, and breast cancer is limited. Methods: We conducted a genome-wide association study (GWAS) of breast texture variation, including four different assessments of V, in 7,040 European-ancestry women within the Nurses’ Health Studies and Mayo Mammography Health Study cohorts. Genotype data were imputed to the 1000 Genomes Phase 3 version 5 reference panel. The four V assessments, differ by amount of breast edge erosion and image resolution, were generated from digitized film mammograms using fully automated methods. We used linear regression to test the single-nucleotide polymorphism (SNP)-phenotype associations adjusting for age, body mass index (BMI), MD phenotypes (percent density, dense area, and nondense area), and the top four principal components. Multivariate phenotype association tests were performed to estimate summary test statistics of the four V assessments. We compared our results to GWAS of breast cancer and MD phenotypes, and identified shared susceptibility loci. We calculated genetic correlations of V measures with MD phenotypes, breast cancer, overall and by estrogen receptor status, BMI, childhood body fatness, age at menarche, and age at natural menopause. Aggregate tests were performed to assess the relationship between V measures and the above traits using genome-wide significant SNPs for these traits. Results: We identified three novel genome-wide significant loci that are associated with V measures: rs79670367 (8q24.22) in LINC01591, rs113174754 (12q22) near PGAM1P5, and rs138141444 (6q24.1) in ECT2L. 12q22 is a known locus for both MD (nondense area) and breast cancer. 8q24.22 and 6q24.1 have not previously been associated with MD or breast cancer. We identified four additional loci that are associated with MD or breast cancer, or both and are significantly associated with the V measures at the Bonferroni-corrected thresholds accounting for the number of MD or breast cancer SNPs tested: rs335189 (5q23.2) in PRDM6, rs13256025 (8p21.2) in EBF2, rs11836164 (12p12.1) in LOC105369705, and rs17817449 (16q12.2) in FTO, the directions of association are consistent with MD or breast cancer for all four loci. We observed significant genetic correlations between V measures and dense area (rg = 0.79, p = 6.0 × 10-5), percent density (rg = 0.73, p = 1.0 × 10-4), and BMI (rg = -0.36, p = 3.9 × 10-7). Additional significant relationships were observed for nondense area (z = -4.14, p = 3.5 × 10-5) and childhood body fatness (z = -4.91, p = 9.1 × 10-7) from the aggregate tests. Conclusions: This is the first GWAS of breast parenchymal texture features. These findings provide new insights into the genetic basis of texture variation and their associations with MD, breast cancer risk, and other breast cancer risk factors. Citation Format: Yuxi Liu, Xia Jiang, Constance Turman, Celine M Vachon, Rulla Tamimi, Peter Kraft. A genome-wide association study of mammographic texture variation [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-02.