title: Previous GWAS hits in relation to young-onset breast cancer.
abstract: Genome-wide association studies (GWAS) have identified dozens of single-nucleotide polymorphisms (SNPs) associated with breast cancer. Few studies focused on young-onset breast cancer, which exhibits etiologic and tumor-type differences from older-onset disease. Possible confounding by prenatal effects of the maternal genome has also not been considered.
  
  
  
  Using a family-based design for breast cancer before age 50, we assessed the relationship between breast cancer and 77 GWAS-identified breast cancer risk SNPs. We estimated relative risks (RR) for inherited and maternally mediated genetic effects. We also used published RR estimates to calculate genetic risk scores and model joint effects.
  
  
  
  Seventeen of the candidate SNPs were nominally associated with young-onset breast cancer in our 1296 non-Hispanic white affected families (uncorrected p value <0.05). Top-ranked SNPs included rs3803662-A (TOX3, RR = 1.39; p = 7.0 × 10-6), rs12662670-G (ESR1, RR = 1.56; p = 5.7 × 10-4), rs2981579-A (FGFR2, RR = 1.24; p = 0.002), and rs999737-G (RAD51B, RR = 1.37; p = 0.003). No maternally mediated effects were found. A risk score based on all 77 SNPs indicated that their overall relationship to young-onset breast cancer risk was more than additive (additive-fit p = 2.2 × 10-7) and consistent with a multiplicative joint effect (multiplicative-fit p = 0.27). With the multiplicative formulation, the case sister's genetic risk score exceeded that of her unaffected sister in 59% of families.
  
  
  
  The results of this family-based study indicate that no effects of previously identified risk SNPs were explained by prenatal effects of maternal variants. Many of the known breast cancer risk variants were associated with young-onset breast cancer, with evidence that TOX3, ESR1, FGFR2, and RAD51B are important for young-onset disease.
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, Durham, NC, 27709, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, Durham, NC, 27709, USA.
authors.forename: Katie M
authors.initials: KM
authors.lastname: O'Brien
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences, 111 TW Alexander Fr, Research Triangle Park, Durham, NC, 27709, USA.
authors.forename: Dale P
authors.initials: DP
authors.lastname: Sandler
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences, 111 TW Alexander Fr, Research Triangle Park, Durham, NC, 27709, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Taylor
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, Durham, NC, 27709, USA.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Zaykin
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, Durham, NC, 27709, USA. weinber2@niehs.nih.gov.
authors.forename: Clarice R
authors.initials: CR
authors.lastname: Weinberg
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
keywords: Family-based genetic methods; Genetic risk score; Genome-wide association study; Log-linear models; Single-nucleotide polymorphism; Young-onset breast cancer