Genetic and environmental causes of variation in an automated breast cancer risk factor based on mammographic textures.
BACKGROUND Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus. METHODS We measured Cirrus for 3195 breast-cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The single-nucleotide polymorphism (SNP)-based heritability was estimated for a subset of 2356 participants. RESULTS There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52(standard error[SE]=0.03) for MZ pairs and 0.16(SE=0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32%(SE=5%) of the variance, consistent with the SNP-based heritability of 36%(SE=16%). CONCLUSIONS Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to non-genetic factors operating in utero or in early life that are shared by MZ twins. IMPACT Early-life factors shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognised as a critical window of vulnerability to breast carcinogens.