title: The association of copy number variation and percent mammographic density.
abstract: BACKGROUND
  Percent mammographic density (PD) estimates the proportion of stromal, fat, and epithelial breast tissues on the mammogram image. Adjusted for age and body mass index (BMI), PD is one of the strongest risk factors for breast cancer. Inherited factors are hypothesized to explain between 30 and 60% of the variance in this trait. However, previously identified common genetic variants account for less than 6% of the variance in PD, leaving much of the genetic contribution to this trait unexplained. We performed the first study to examine whether germline copy number variation (CNV) are associated with PD. Two genome-wide association studies (GWAS) of percent density conducted on the Illumina 660W-Quad were used to identify and replicate the association between candidate CNVs and PD: the Minnesota Breast Cancer Family Study (MBCFS) and controls from the Mayo Venous Thromboembolism (Mayo VTE) Case-Control Study, with 585 and 328 women, respectively. Linear models were utilized to examine the association of each probe with PD, adjusted for age, menopausal status and BMI. Segmentation was subsequently performed on the probe-level test statistics to identify candidate CNV regions that were associated with PD.
  
  
  RESULTS
  Sixty-one probes from five chromosomal regions [3q26.1 (2 regions), 8q24.22, 11p15.3, and 17q22] were significantly associated with PD in MBCFS (p-values <0.0001). A CNV at 3q26.1 showed the greatest evidence for association with PD; a region without any known SNPs. Conversely, the CNV at 17q22 was largely due to the association between SNPs and PD in the region. SNPs in the 8q24.22 region have been shown to be associated with risk of many cancers; however, SNPs in this region were not responsible for the observed CNV association. While we were unable to replicate the associations with PD, two of the five CNVs (3q26.1 and 11p15.3) were also observed in the Mayo VTE controls.
  
  
  CONCLUSIONS
  CNVs may help to explain some of the variability in PD that is currently unexplained by SNPs. While we were able to replicate the existence of two CNVs across the two GWAS studies, we were unable to replicate the associations with PD. Even so, the proximity of the identified CNV regions to loci known to be associated with breast cancer risk suggests further investigation and potentially shared genetic mechanisms underlying the PD and breast cancer association.
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. atkinson@mayo.edu.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Atkinson
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. eckelpassow.jeanette@mayo.edu.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Wang.Alice@mayo.edu.
authors.forename: Alice
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. greenberg.alexandra@gmail.com.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Greenberg
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. scott.christopher@mayo.edu.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Scott
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. vshanepankratz@yahoo.com.
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.affiliation: Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, MI, USA. purringk@karmanos.org.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Purrington
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA. thomas.sellers@moffitt.org.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. rider.david@mayo.edu.
authors.forename: David N
authors.initials: DN
authors.lastname: Rider
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, Mayo Clinic, Rochester, MN, USA. heit.john@mayo.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Heit
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. mandrade@mayo.edu.
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. cunningham.julie@mayo.edu.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. couch.fergus@mayo.edu.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. vachon.celine@mayo.edu.
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
mesh_terms: D000368:Aged; D000071060:Breast Density; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D042361:Mammary Glands, Human / Q000002:abnormalities*; D008875:Middle Aged