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

Fan Wang, Wonjong Moon, William Letsou, Yadav Sapkota, Zhaoming Wang, Cindy Im, Jessica L. Baedke, Leslie Robison, Yutaka Yasui

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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 computationally phased genotypes from 181,034 white British women in the UK Biobank, a genome-wide haplotype–breast cancer association analysis 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 prestudyenrollment 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 prospective 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 ¼ 2.84–6.10, P < 5 × 10–8; replication: HRs ¼ 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 cisregulatory 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 haplotypes 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 sequencing become available.

Original languageEnglish (US)
Pages (from-to)332-345
Number of pages14
JournalCancer Research
Issue number2
StatePublished - Jan 15 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
©2022 American Association for Cancer Research.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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