A genome-wide association study of mammographic texture variation

BackgroundBreast parenchymal texture features, including gray scale variation (V), capture the patterns of texture variation on a mammogram and are associated with breast cancer risk, independent of mammographic density (MD). However, our knowledge on the genetic basis of these texture features is limited. MethodsWe conducted a genome-wide association study of V in 7,040 European-ancestry women. Four V assessments representing different amounts of breast edge erosion and image resolutions were generated from digitized film mammograms. We used linear regression to test the single-nucleotide polymorphism (SNP)-phenotype associations adjusting for age, body mass index (BMI), MD phenotypes, and the top four genetic principal components. Multivariate phenotype association tests combining all four V assessments were performed. We further calculated genetic correlations and performed SNP-set tests of V with MD, breast cancer risk, and other breast cancer risk factors. ResultsWe identified three genome-wide significant loci associated with V: rs138141444 (6q24.1) in ECT2L, rs79670367 (8q24.22) in LINC01591, and rs113174754 (12q22) near PGAM1P5. 6q24.1 and 8q24.22 have not previously been associated with MD phenotypes or breast cancer risk, whilst 12q22 is a known locus for both MD and breast cancer risk. Among known MD and breast cancer risk SNPs, we identified four variants that were associated with V at the Bonferroni-corrected thresholds accounting for the number of SNPs tested: rs335189 (5q23.2) in PRDM6, rs13256025 (8p21.2) in EBF2, rs11836164 (12p12.1) near SSPN, and rs17817449 (16q12.2) in FTO. We observed significant genetic correlations between V and mammographic dense area (rg = 0.79, P = 5.91 x 10-5), percent density (rg = 0.73, P = 1.00 x 10-4), and adult BMI (rg = -0.36, P = 3.88 x 10-7). Additional significant relationships were observed for nondense area (z = -4.14, P = 3.42 x 10-5), estrogen receptor-positive breast cancer (z = 3.41, P = 6.41 x 10-4), and childhood body fatness (z = -4.91, P = 9.05 x 10-7) from the SNP-set tests. ConclusionsThese findings provide new insights into the genetic basis of mammographic texture variation and their associations with MD, breast cancer risk, and other breast cancer risk factors.