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The Relative Importance of Genetics and Environment on Mammographic Density

Departments of ¹ Preventive Medicine, ² Pathology, and ³ Radiation Oncology, University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California; ⁴ Department of Nutrition, University of Oslo, Oslo, Norway; Departments of ⁵ Medicine and ⁶ Psychiatry, University of California at San Diego, La Jolla, California; and ⁷ Medical Imaging, Mammoth Hospital, Mammoth Lakes, California

Requests for reprints: Giske Ursin, Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, PB 1046, Blindern, 0316 Oslo, Norway. Phone: 47-22-85-13-79; Fax: 47-22-85-15-31. E-mail: giske.ursin{at}medisin.uio.no or gursin{at}usc.edu

Background: Although several environmental factors predict mammographic density, estimates of its heritability have been quite high. We investigated whether part of the presumed heritability might be attributed to differential sharing of modifiable risk factors in monozygotic (MZ) and dizygotic (DZ) twins.

Methods: We measured percent and absolute mammographic density using mammograms from 257 MZ and 296 DZ twin pairs. The correlation of intrapair mammographic density was compared according to zygosity across strata of modifiable risk factors. Portions of variance attributable to additive genetic factors, shared environment, and individual environment were calculated using a variance component methodology in the entire set, and within twin pairs stratified by environmental trait similarity.

Results: Both percent density and absolute mammographic density were more highly correlated between MZ twins than DZ twins, but the correlations varied across strata. Body mass index (BMI) and parity strongly predicted differences in mammographic density within MZ twin pairs. After adjusting for covariates, 53% of the total variance in percent density and 59% of that in absolute density seemed attributable to genetic effects, but these estimates varied greatly by stratum. For twins dissimilar on BMI (difference >2.5 kg/m²), the additive genetic component of absolute density was estimated at only 20% (±19%), and the common and individual environment at 21% (±14%) and 49%, respectively (P value for heterogeneity across BMI = 0.0001).

Conclusion: Our results confirm that the genome is an important determinant of mammographic density but suggest that an unknown portion of the mammographic density effect attributed to the genome may be due to shared modifiable environmental factors. (Cancer Epidemiol Biomarkers Prev 2009;18(1):102–12)