Refining the genetic risk of breast cancer with rare haplotypes and pattern mining

Hundreds of common variants have been found to confer small but significant differences in breast cancer risk, supporting the widely accepted polygenic model of inherited predisposition. Using a novel closed-pattern mining algorithm, we provide evidence that rare haplotypes may refine the association of breast cancer risk with common germline alleles. Our method, called Chromosome Overlap, consists in iteratively pairing chromosomes from affected individuals and looking for noncontiguous patterns of shared alleles. We applied Chromosome Overlap to haplotypes of genotyped SNPs from female breast cancer cases from the UK Biobank at four loci containing common breast cancer-risk SNPs. We found two rare (frequency <0.1%) haplotypes bearing a GWAS hit at 11q13 (hazard ratio = 4.21 and 16.7) which replicated in an independent, European ancestry population at P < 0.05, and another at 22q12 (frequency <0.2%, hazard ratio = 2.58) which expanded the risk pool to noncarriers of a GWAS hit. These results suggest that rare haplotypes (or mutations) may underlie the "synthetic association" of breast cancer risk with at least some common variants.