title: Mammographic breast density--evidence for genetic correlations with established breast cancer risk factors.
abstract: Previous twin and family studies indicate that the familial aggregation of breast density is due (in part) to genetic factors. Whether these genetic influences are shared with other breast cancer risk factors, however, is not known. Using standard film-screen mammography, we screened 550 women, including 611 pairs of sisters, from the Old Order Amish population of Lancaster County, Pennsylvania. We digitized mammograms and quantified the dense and nondense areas of the breast using a computer-assisted method. Information about other breast cancer risk factors was collected via questionnaires and a physical exam. Using pedigree-based variance component methods, we estimated the genetic contributions to several breast cancer risk factors, including breast density, and evaluated the evidence for shared genetic influences between them. After adjusting for covariates, genetic effects accounted for >33% of the total variance of each risk factor (P < 0.001), including breast density, and the dense and nondense areas of the breast were significantly genetically correlated with parity [genetic correlation (rho(G)) = -0.47; P = 0.013] and age at menarche (rho(G) = -0.38; P = 0.008), respectively. The nondense area of the breast and, in turn, breast density, expressed as a ratio of dense area to total area, were also genetically correlated with most measures of adiposity but in opposite directions (rho(G) > or = 0.75; P < 10(-7) for nondense area). We conclude that the genetic components that influence breast density are not independent of the genetic components that influence other breast cancer risk factors. This shared genetic architecture should be considered in future genetic studies of breast density.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Room 5912, Buhl Building, 1241 E. Catherine Street, Ann Arbor, MI 48109-5618, USA. jddoug@umich.edu
authors.forename: Julie A
authors.initials: JA
authors.lastname: Douglas
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Roy-Gagnon
authors.forename: Chuan
authors.initials: C
authors.lastname: Zhou
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Heang-Ping
authors.initials: HP
authors.lastname: Chan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Helvie
mesh_terms: D000273:Adipose Tissue / Q000000981:diagnostic imaging; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001940:Breast / Q000033:anatomy & histology*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008327:Mammography; D008875:Middle Aged; D015233:Models, Statistical; D010414:Pennsylvania / Q000453:epidemiology; D010808:Physical Examination; D011159:Population Surveillance; D012307:Risk Factors; D011795:Surveys and Questionnaires