title: Mammographic breast density and breast cancer: evidence of a shared genetic basis.
abstract: Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer. The signed per-allele effect estimates of single-nucleotide polymorphisms (SNP) were multiplied with the respective allele counts in the individual and summed over all SNPs to derive the risk score for an individual. These scores were included as the exposure variable in a logistic regression model with breast cancer case-control status as the outcome. This analysis was repeated using 10 different cutoff points for the most significant density SNPs (1%-10% representing 5,222-50,899 SNPs). Permutation analysis was also conducted across all 10 cutoff points. The association between risk score and breast cancer was significant for all cutoff points from 3% to 10% of top density SNPs, being most significant for the 6% (2-sided P = 0.002) to 10% (P = 0.001) cutoff points (overall permutation P = 0.003). Women in the top 10% of the risk score distribution had a 31% increased risk of breast cancer [OR = 1.31; 95% confidence interval (CI), 1.08-1.59] compared with women in the bottom 10%. Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants.
authors.affiliation: Department of Public Health and Primary Care, Addenbrooke's NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Jajini S
authors.initials: JS
authors.lastname: Varghese
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Thompson
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Michailidou
authors.forename: Sara
authors.initials: S
authors.lastname: Lindström
authors.forename: Clare
authors.initials: C
authors.lastname: Turnbull
authors.forename: Judith
authors.initials: J
authors.lastname: Brown
authors.forename: Jean
authors.initials: J
authors.lastname: Leyland
authors.forename: Ruth M L
authors.initials: RM
authors.lastname: Warren
authors.forename: Robert N
authors.initials: RN
authors.lastname: Luben
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Loos
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Johanna
authors.initials: J
authors.lastname: Rommens
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Scott
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Atkinson
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Carmel
authors.initials: C
authors.lastname: Apicella
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stone
authors.forename: Jingmei
authors.initials: J
authors.lastname: Li
authors.forename: Louise
authors.initials: L
authors.lastname: Eriksson
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.forename: Norman F
authors.initials: NF
authors.lastname: Boyd
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Rulla M
authors.initials: RM
authors.lastname: Tamimi
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
mesh_terms: D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008327:Mammography; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause / Q000235:genetics; D012306:Risk; D006113:United Kingdom / Q000453:epidemiology