Volumetric mammographic density: heritability and association with breast cancer susceptibility loci.
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 = 4025 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 < .001). Percent and absolute dense volume were associated with rs10995190 (ZNF365; P = 9.0 × 10(-6) and 8.9 × 10(-7), respectively) and rs9485372 (TAB2; P = 1.8 × 10(-5) and 1.8 × 10(-3), respectively). We also observed associations of rs9383938 (ESR1) and rs2046210 (ESR1) with the absolute dense volume (P = 2.6 × 10(-4) and 4.6 × 10(-4), respectively), and rs6001930 (MLK1) and rs17356907 (NTN4) with the absolute nondense volume (P = 6.7 × 10(-6) and 8.4 × 10(-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.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (JSB, KH, ME, PH, KC); Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Cambridge, UK (DJT); Human Genetics, Genome Institute of Singapore, Singapore, Singapore (JL). judith.brand@ki.se.
Judith S
JS
Brand
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (JSB, KH, ME, PH, KC); Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Cambridge, UK (DJT); Human Genetics, Genome Institute of Singapore, Singapore, Singapore (JL).
Keith
K
Humphreys
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (JSB, KH, ME, PH, KC); Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Cambridge, UK (DJT); Human Genetics, Genome Institute of Singapore, Singapore, Singapore (JL).
Deborah J
DJ
Thompson
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (JSB, KH, ME, PH, KC); Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Cambridge, UK (DJT); Human Genetics, Genome Institute of Singapore, Singapore, Singapore (JL).
Jingmei
J
Li
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (JSB, KH, ME, PH, KC); Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Cambridge, UK (DJT); Human Genetics, Genome Institute of Singapore, Singapore, Singapore (JL).
Mikael
M
Eriksson
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (JSB, KH, ME, PH, KC); Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Cambridge, UK (DJT); Human Genetics, Genome Institute of Singapore, Singapore, Singapore (JL).
Per
P
Hall
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (JSB, KH, ME, PH, KC); Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Cambridge, UK (DJT); Human Genetics, Genome Institute of Singapore, Singapore, Singapore (JL).
Kamila
K
Czene
D000328:Adult; D000368:Aged; D000071060:Breast Density; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016014:Linear Models; D042361:Mammary Glands, Human / Q000002:abnormalities*; D008327:Mammography; D008875:Middle Aged; D009929:Organ Size; D020641:Polymorphism, Single Nucleotide