title: A genome-wide linkage study of mammographic density, a risk factor for breast cancer.
abstract: BACKGROUND
  Mammographic breast density is a highly heritable (h2 > 0.6) and strong risk factor for breast cancer. We conducted a genome-wide linkage study to identify loci influencing mammographic breast density (MD).
  
  
  METHODS
  Epidemiological data were assembled on 1,415 families from the Australia, Northern California and Ontario sites of the Breast Cancer Family Registry, and additional families recruited in Australia and Ontario. Families consisted of sister pairs with age-matched mammograms and data on factors known to influence MD. Single nucleotide polymorphism (SNP) genotyping was performed on 3,952 individuals using the Illumina Infinium 6K linkage panel.
  
  
  RESULTS
  Using a variance components method, genome-wide linkage analysis was performed using quantitative traits obtained by adjusting MD measurements for known covariates. Our primary trait was formed by fitting a linear model to the square root of the percentage of the breast area that was dense (PMD), adjusting for age at mammogram, number of live births, menopausal status, weight, height, weight squared, and menopausal hormone therapy. The maximum logarithm of odds (LOD) score from the genome-wide scan was on chromosome 7p14.1-p13 (LOD = 2.69; 63.5 cM) for covariate-adjusted PMD, with a 1-LOD interval spanning 8.6 cM. A similar signal was seen for the covariate adjusted area of the breast that was dense (DA) phenotype. Simulations showed that the complete sample had adequate power to detect LOD scores of 3 or 3.5 for a locus accounting for 20% of phenotypic variance. A modest peak initially seen on chromosome 7q32.3-q34 increased in strength when only the 513 families with at least two sisters below 50 years of age were included in the analysis (LOD 3.2; 140.7 cM, 1-LOD interval spanning 9.6 cM). In a subgroup analysis, we also found a LOD score of 3.3 for DA phenotype on chromosome 12.11.22-q13.11 (60.8 cM, 1-LOD interval spanning 9.3 cM), overlapping a region identified in a previous study.
  
  
  CONCLUSIONS
  The suggestive peaks and the larger linkage signal seen in the subset of pedigrees with younger participants highlight regions of interest for further study to identify genes that determine MD, with the goal of understanding mammographic density and its involvement in susceptibility to breast cancer.
authors.affiliation: Program in Genetics & Genome Biology, The Hospital for Sick Children, 101 College Street, East Tower, Toronto, ON M5G 1L7, Canada.
authors.forename: Celia M T
authors.initials: CM
authors.lastname: Greenwood
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Linda
authors.initials: L
authors.lastname: Linton
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Carmel
authors.initials: C
authors.lastname: Apicella
authors.forename: Apostolos
authors.initials: A
authors.lastname: Dimitromanolakis
authors.forename: Valentina
authors.initials: V
authors.lastname: Kriukov
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Ayesha
authors.initials: A
authors.lastname: Salleh
authors.forename: Elena
authors.initials: E
authors.lastname: Samiltchuk
authors.forename: Rashmi V
authors.initials: RV
authors.lastname: Parekh
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Norman F
authors.initials: NF
authors.lastname: Boyd
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
mesh_terms: D015502:Absorptiometry, Photon; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000453:epidemiology / Q000235:genetics*; D005191:Family Characteristics; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D008126:Lod Score; D008327:Mammography; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors
chemical_list: D005819:Genetic Markers