Identification of a novel percent mammographic density locus at 12q24.
Human Molecular Genetics 2012 ; 21: 3299-305.
Stevens KN, Lindström S, Scott CG, Thompson D, Sellers TA, Wang X, Wang A, Atkinson E, Rider DN, Eckel-Passow JE, Varghese JS, Audley T, Brown J, Leyland J, Luben RN, Warren RM, Loos RJ, Wareham NJ, Li J, Hall P, Liu J, Eriksson L, Czene K, Olson JE, Pankratz VS, Fredericksen Z, Diasio RB, Lee AM, Heit JA, DeAndrade M, Goode EL, Vierkant RA, Cunningham JM, Armasu SM, Weinshilboum R, Fridley BL, Batzler A, Ingle JN, Boyd NF, Paterson AD, Rommens J, Martin LJ, Hopper JL, Southey MC, Stone J, Apicella C, Kraft P, Hankinson SE, Hazra A, Hunter DJ, Easton DF, Couch FJ, Tamimi RM, and Vachon CM
DOI : 10.1093/hmg/dds158
PubMed ID : 22532574
PMCID : PMC3384385
Percent mammographic density adjusted for age and body mass index (BMI) is one of the strongest risk factors for breast cancer and has a heritable component that remains largely unidentified. We performed a three-stage genome-wide association study (GWAS) of percent mammographic density to identify novel genetic loci associated with this trait. In stage 1, we combined three GWASs of percent density comprised of 1241 women from studies at the Mayo Clinic and identified the top 48 loci (99 single nucleotide polymorphisms). We attempted replication of these loci in 7018 women from seven additional studies (stage 2). The meta-analysis of stage 1 and 2 data identified a novel locus, rs1265507 on 12q24, associated with percent density, adjusting for age and BMI (P = 4.43 × 10(-8)). We refined the 12q24 locus with 459 additional variants (stage 3) in a combined analysis of all three stages (n = 10 377) and confirmed that rs1265507 has the strongest association in the 12q24 region (P = 1.03 × 10(-8)). Rs1265507 is located between the genes TBX5 and TBX3, which are members of the phylogenetically conserved T-box gene family and encode transcription factors involved in developmental regulation. Understanding the mechanism underlying this association will provide insight into the genetics of breast tissue composition.