title: Identification of two novel mammographic density loci at 6Q25.1.
abstract: BACKGROUND
  Mammographic density (MD) is a strong heritable and intermediate phenotype for breast cancer, but much of its genetic variation remains unexplained. We performed a large-scale genetic association study including 8,419 women of European ancestry to identify MD loci.
  
  
  METHODS
  Participants of three Swedish studies were genotyped on a custom Illumina iSelect genotyping array and percent and absolute mammographic density were ascertained using semiautomated and fully automated methods from film and digital mammograms. Linear regression analysis was used to test for SNP-MD associations, adjusting for age, body mass index, menopausal status and six principal components. Meta-analyses were performed by combining P values taking sample size, study-specific inflation factor and direction of effect into account.
  
  
  RESULTS
  Genome-wide significant associations were observed for two previously identified loci: ZNF365 (rs10995194, P = 2.3 × 10(-8) for percent MD and P = 8.7 × 10(-9) for absolute MD) and AREG (rs10034692, P = 6.7 × 10(-9) for absolute MD). In addition, we found evidence of association for two variants at 6q25.1, both of which are known breast cancer susceptibility loci: rs9485370 in the TAB2 gene (P = 4.8 × 10(-9) for percent MD and P = 2.5 × 10(-8) for absolute MD) and rs60705924 in the CCDC170/ESR1 region (P = 2.2 × 10(-8) for absolute MD). Both regions have been implicated in estrogen receptor signaling with TAB2 being a potential regulator of tamoxifen response.
  
  
  CONCLUSIONS
  We identified two novel MD loci at 6q25.1. These findings underscore the importance of 6q25.1 as a susceptibility region and provide more insight into the mechanisms through which MD influences breast cancer risk.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden. Judith.brand@ki.se.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Brand
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden. Jingmei.Li@ki.se.
authors.forename: Jingmei
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden. Keith.Humphreys@ki.se.
authors.forename: Keith
authors.initials: K
authors.lastname: Humphreys
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden. Robert.Karlsson@ki.se.
authors.forename: Robert
authors.initials: R
authors.lastname: Karlsson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden. Mikael.Eriksson@ki.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Eriksson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden. Emma.Ivansson@ki.se.|Swedish eScience Research Centre (SeRC), Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden. Emma.Ivansson@ki.se.
authors.forename: Emma
authors.initials: E
authors.lastname: Ivansson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden. Per.Hall@ki.se.
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden. Kamila.Czene@ki.se.
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
mesh_terms: D000328:Adult; D000071060:Breast Density; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002896:Chromosomes, Human, Pair 6; D005260:Female; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D042361:Mammary Glands, Human / Q000002:abnormalities*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci