Abstract 2778: Shared genetics of breast cancer risk factors across life stages
Authors: Gao Chi , Tamimi Rulla M. , Kraft Peter , Lindstrom Sara 
Published: August 2015

Abstract
Breast cancer clusters in families and many of its established risk factors are under strong genetic control. Understanding the genetic architecture shared by breast cancer risk factors highlight the causal pathways through which these risk factors affect breast cancer risk. Traditionally, pedigree studies are used to estimate genetic correlations between complex traits but such estimates can be confounded by shared environmental factors. Recent methodological developments make it possible to estimate disease heritability and genetic correlations using data from genome-wide association studies (GWAS). We used GWAS of unrelated individuals to estimate the proportion of variance in breast cancer risk factors that can be explained by GWAS SNPs. We also quantified the shared genetic contribution to all pairs of the following traits: body mass index (BMI), gender-specific BMI, height, age at menarche, age at natural menopause, and childhood body fatness.
We obtained GWAS and phenotypic information from a total of 20,769 subjects from the Nurses’ Health Study I & II, Health Professional Follow-up Study, and Physician Health study. Using linear mixed models, we estimated single trait heritability and genetic correlation between two traits. We observed a significant amount of phenotypic variation explained by genotyped SNPs for all traits except age at natural menopause (hg2 = 0.15, se = 0.09). Heritability ranged from 0.18 (se = 0.004) for childhood body fatness to 0.35 (se = 0.05) for age at menarche. We found significant negative genetic correlation between adult BMI and height (corr = -0.20; se = 0.07, pvalue = 0.005), BMI and age at menarche (corr = -0.50; se = 0.07, pvalue = 8.8×10e-8), and age at menarche and childhood body fatness (corr = -0.57, se = 0.12, pvalue = 2.8×10e-6). We observed a positive genetic correlation between adult BMI and childhood body fatness (corr = 0.59, se = 0.12, pvalue = 8.0×10e-8) and such correlation is statistically different from 0 and 1, implying only a partially shared genetic signature between these two traits. The genetics underlying BMI in men and women were highly correlated (corr = 0.84, se = 0.26, pvalue = 9.7×10e-4). In addition, we found no significant shared genetic components between age at natural menopause and any of the traits, suggesting a different genetic architecture underlying the mechanism of menopause in comparison with other breast cancer risk factors.
Using genome-wide SNP data in unrelated individuals to estimate heritability helps eliminate possible influence from unmeasured shared environmental factors that is commonly seen in family studies. Our findings improve the understanding of shared genetic architecture of breast cancer risk factors and provide important insights in breast cancer etiology.
Citation Format: Chi Gao, Rulla M. Tamimi, Peter Kraft, Sara Lindstrom. Shared genetics of breast cancer risk factors across life stages. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2778. doi:10.1158/1538-7445.AM2015-2778