Large-scale genotyping identifies 41 new loci associated with breast cancer risk

Abstract

Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.

Figure 1

One-degree-of-freedom trend-test statistics for 29,807 iCOGS SNPs selected from the combined GWAS, excluding those occurring in known susceptibility regions. The red horizontal line represents P = 5 × 10⁻⁸. The blue horizontal line represents P = 1 × 10⁻⁵.

Figure 2

Distribution of normalized effect sizes (z scores) in the iCOGS stage, with the direction of effect determined by the direction in the combined GWAS. The blue curve represents the standard normal distribution. The green curve represents the best-fit normal distribution (mean = 0.19, s.d. = 1.22).