Genome-Wide Analysis of Rare Haplotypes Associated with Breast Cancer Risk

Numerous common genetic variants have been linked to breast cancer risk, but they only partially explain the total breast cancer heritability. Inference from Nordic population-based twin data indicates rare high-risk loci as the chief determinant of breast cancer risk. Here, we use haplotypes, rather than single variants, to identify rare high-risk loci for breast cancer. With computation-ally phased genotypes from 181,034 white British women in the UK Biobank, a genome-wide haplotype-breast cancer association anal-ysis was conducted using sliding windows of 5 to 500 consecutive array-genotyped variants. In the discovery stage, haplotype-breast cancer associations were evaluated retrospectively in the prestudy-enrollment data including 5,487 breast cancer cases. Breast cancer hazard ratios (HR) for additive haplotypic effects were estimated using Cox regression. The replication analysis included a prospec-tive cohort of women free of breast cancer at enrollment, of whom 3,524 later developed breast cancer. This two-stage analysis detected 13 rare loci (frequency <1%), each associated with an appreciable breast cancer-risk increase (discovery: HRs = 2.84-6.10, P< 5 x 10-8; replication: HRs = 2.08-5.61, P < 0.01). In contrast, the variants that formed these rare haplotypes individually exhibited much smaller effects. Functional annotation revealed extensive cis -regulatory DNA elements in breast cancer-related cells underlying the replicated rare haplotypes. Using phased, imputed genotypes from 30,064 cases and 25,282 controls in the DRIVE OncoArray case-control study, 6 of the 13 rare-loci associations were found generalizable (odds ratio estimates: 1.48-7.67, P< 0.05). This study demonstrates the complementary advantage of utilizing rare hap-lotypes to capture novel risk loci and suggests the potential for the discovery of more genetic elements contributing to cancer heritability as large data sets of germline whole-genome sequenc-ing become available.

Automated summary

This study identified 13 rare high-risk loci for breast cancer, which exhibit significant risk increase when combined as haplotypes. The individual variants forming these rare haplotypes have smaller effects. Functional annotation revealed extensive cis-regulatory DNA elements in breast cancer-related cells underlying these replicated rare haplotypes.