title: Genome wide association study identifies a novel putative mammographic density locus at 1q12-q21.
abstract: Mammographic density (MD) is an intermediate phenotype for breast cancer. Previous studies have identified genetic variants associated with MD; however, much of the genetic contribution to MD is unexplained. We conducted a two-stage genome-wide association analysis among the participants in the "Determinants of Density in Mammographies in Spain" study, together with a replication analysis in women from the Australian MD Twins and Sisters Study. Our discovery set covered a total of 3,351 Caucasian women aged 45 to 68 years, recruited from Spanish breast cancer screening centres. MD was blindly assessed by a single reader using Boyd's scale. A two-stage approach was employed, including a feature selection phase exploring 575,374 SNPs in 239 pairs of women with extreme phenotypes and a verification stage for the 183 selected SNPs in the remaining sample (2,873 women). Replication was conducted in 1,786 women aged 40 to 70 years old recruited via the Australian Twin Registry, where MD were measured using Cumulus-3.0, assessing 14 SNPs with a p value <0.10 in stage 2. Finally, two genetic variants in high linkage disequilibrium with our best hit were studied using the whole Spanish sample. Evidence of association with MD was found for variant rs11205277 (OR = 0.74; 95% CI = 0.67-0.81; p = 1.33 × 10(-10) ). In replication analysis, only a marginal association between this SNP and absolute dense area was found. There were also evidence of association between MD and SNPs in high linkage disequilibrium with rs11205277, rs11205303 in gene MTMR11 (OR = 0.73; 95% CI = 0.66-0.80; p = 2.64 × 10(-11) ) and rs67807996 in gene OTUD7B (OR = 0.72; 95% CI = 0.66-0.80; p = 2.03 × 10(-11)). Our findings provide additional evidence on common genetic variations that may contribute to MD.
authors.affiliation: Cancer and Environmental Epidemiology Unit, National Center for Epidemiology, Carlos III Institute of Health, Madrid, Spain; Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública-CIBERESP), Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fernandez-Navarro
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: Ramón
authors.initials: R
authors.lastname: Díaz-Uriarte
authors.forename: Leticia
authors.initials: L
authors.lastname: Tais Moreno
authors.forename: María
authors.initials: M
authors.lastname: Ederra
authors.forename: Carmen
authors.initials: C
authors.lastname: Pedraz-Pingarrón
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Contador
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Vázquez-Carrete
authors.forename: Pilar
authors.initials: P
authors.lastname: Moreo
authors.forename: Carmen
authors.initials: C
authors.lastname: Vidal
authors.forename: Dolores
authors.initials: D
authors.lastname: Salas-Trejo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stone
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pérez-Gómez
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
authors.forename: Marina
authors.initials: M
authors.lastname: Pollan
mesh_terms: D000328:Adult; D000368:Aged; D001315:Australia; D000071060:Breast Density; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003430:Cross-Sectional Studies; D010450:Endopeptidases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D015810:Linkage Disequilibrium; D042361:Mammary Glands, Human / Q000002:abnormalities*; D008327:Mammography; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D013030:Spain; D018433:Twin Studies as Topic
chemical_list: D011506:Proteins; D010450:Endopeptidases; C476458:OTUD7B protein, human
keywords: DDM-Spain; GWAs; MTMR11; OTUD7B; mammographic density