Volumetric Mammographic Density: Heritability and Association With Breast Cancer Susceptibility Loci
Brand, Judith S
Journal of the National Cancer Institute
Oxford University Press
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Brand, J. S., Humphreys, K., Thompson, D. J., Li, J., Eriksson, M., & Czene, K. (2014). Volumetric Mammographic Density: Heritability and Association With Breast Cancer Susceptibility Loci. Journal of the National Cancer Institute, 106 (dju334)https://doi.org/10.1093/jnci/dju334
Background: Mammographic density is a strong heritable trait, but data on its genetic component are limited to area-based and qualitative measures. We studied the heritability of volumetric mammographic density ascertained by a fully-automated method and the association with breast cancer susceptibility loci. Methods: Heritability of volumetric mammographic density was estimated with a variance component model in a sib-pair sample (N pairs = 955) of a Swedish screening based cohort. Associations with 82 established breast cancer loci were assessed in an independent sample of the same cohort (N = 4,025 unrelated women) using linear models, adjusting for age, body mass index and menopausal status. All tests were two-sided, except for heritability analyses where one-sided tests were used. Results: After multivariable adjustment, heritability estimates (standard error) for percent dense volume, absolute dense volume and absolute nondense volume were 0.63 (0.06) and 0.43 (0.06) and 0.61 (0.06) respectively (all P < 0.001). Percent and absolute dense volume were associated with rs10995190 (ZNF365; P = 9.0x10-6 and 8.9x10-7 respectively) and rs9485372 (TAB2; P = 1.8x10-5 and 1.8x10-3 respectively). We also observed associations of rs9383938 (ESR1) and rs2046210 (ESR1) with the absolute dense volume (P = 2.6x10-4 and 4.6x10-4 respectively), and rs6001930 (MLK1) and rs17356907 (NTN4) with the absolute nondense volume (P = 6.7x10-6 and 8.4x10-5 respectively). Conclusions: Our results support the high heritability of mammographic density, though estimates are weaker for absolute than percent dense volume. We also demonstrate that the shared genetic component with breast cancer is not restricted to dense tissues only.
This work was supported by the Swedish Research Council (grant no. 521-2011- 3187) and Swedish Cancer Society (grant no. CAN 2013/469). The KARolinska MAmmography project for risk prediction of breast cancer study was supported by Märit and Hans Rausing’s Initiative Against Breast Cancer and the Cancer and Risk Prediction Center CRisP (http://ki.se/en/meb/crisp), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council. KH is supported by the Swedish Research Counsil (grant no. 521-2011-3205) and JL is a UNESCO-L’OREAL International Fellow.
External DOI: https://doi.org/10.1093/jnci/dju334
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246741