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

Abstract

Numerous common genetic variants have been linked to breast cancer (BCa) risk, but they only partially explain the total BCa heritability. Inference from Nordic population-based twin data indicates rare high-risk loci as the chief determinant of BCa risk. Here, we use haplotypes, rather than single variants, to identify rare high-risk loci for BCa. With computationally-phased genotypes from 181,034 white British women in the UK Biobank, a genome-wide haplotype-BCa association analysis was conducted using sliding windows of 5-500 consecutive array-genotyped variants. In the discovery stage, haplotype-BCa associations were evaluated retrospectively in the pre-study-enrollment data including 5,487 BCa cases. BCa hazard ratios (HRs) for additive haplotypic effects were estimated using Cox regression. The replication analysis included a prospective cohort of women free of BCa at enrollment, of whom 3,524 later developed BCa. This two-stage analysis detected 13 rare loci (frequency <1%), each associated with an appreciable BCa-risk increase (discovery: HRs=2.84-6.10, P-value<5x10-8; replication: HRs=2.08-5.61, P-value<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 BCa-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, six of the 13 rare-loci associations were found generalizable (odds ratio estimates: 1.48-7.67, P-value<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 datasets of germline whole-genome sequencing become available.

Haplotype blocks for genomic prediction: a comparative evaluation in multiple crop datasets

“…Therefore, haplotypes can assist in identifying rare variants that have a potential impact on phenotypic traits. ( Bloom et al., 2019 ; Wainschtein et al., 2022 ; Wang et al., 2023 ). Furthermore, especially in highly quantitative traits like yield where markers tend to have very small effects on traits, haplotype blocks can identify positive or negative chromosomal segments.…”

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

“…To improve the confidence in our chr11 discoveries, we next sought to apply Chromosome Overlap in a region known to contain a rare risk haplotype. Our recent genome-wide rare-haplotype analysis discovered by a sliding-window approach six loci containing rare haplotypes which were associated with increased breast cancer risk in both UKBB and DRIVE ( Wang et al, 2023 ). The lead 50-SNP haplotype (by P -value) discovered at chromosome 22q12, called h38, had a frequency of 10.6 per 10,000 chromosomes and an HR of 2.81 ( P = 1.2 × 10 −14 ).…”

“…FOXA1-binding occurred in a region devoid of any UKBB-typed SNPs, but without any coincident peaks belonging to other factors. A more intense Hi-C block occurred downstream of h1 and h38 in a region spanned by the original 250-SNP haplotype ( Wang et al, 2023 ). The comparative lack of features about h1 and h38 suggested that the binding events at the chr11 locus may have been specific to regulation of CCND1 and that some other biological mechanism would have to be sought at the chr22 locus, as explored in our previous study ( Wang et al, 2023 ).…”

“…Haplotype analysis has long been used as a method to improve power in genetic association studies ( Falk & Rubinstein, 1987 ; Schaid, 2004 ), but the idea that haplotypes themselves may tag or could themselves be the causal variants has received less attention. We recently explored the possibility in a genome-wide analysis that rare haplotypes with copy numbers on the order of tens per 10,000 chromosomes confer additional high risk for breast cancer ( Wang et al, 2023 ). That study identified five robustly replicated rare haplotypes defined by genotyped SNPs through a sliding-window analysis, but was necessarily constrained by the requirement that haplotypes be contiguous regions of chromosome of various sizes, each possibly bearing a rare causal variant.…”

“…We then compared the counts of (the closures of) these patterns in cases and controls on the hypothesis that the sharing of patterns by cases should be associated with their being cases. We apply Chromosome Overlap to computationally phased data from female breast cancer cases and controls in the UK Biobank (UKBB) ( Bycroft et al, 2018 ) to look for rare haplotypes in the vicinity of three of the strongest breast cancer (EFO_0000305) hits by P -value in the NHGRI-EBI GWAS Catalog ( Sollis et al, 2023 ), including: rs2981578 on chromosome 10q26 in an intron of FGFR2 ( Meyer et al, 2008 ); rs554219 on chromosome 11q13 upstream of CCND1 ( French et al, 2013 ); rs4784227 on 16q12 in an intron of CASC16 ( Long et al, 2010 ; Ulder et al, 2010 ); and also a locus at 22q12 containing a rare haplotype identified by our previous genome-wide haplotype analysis ( Wang et al, 2023 ). Subsequently, we replicated the 11q13 and 22q12 results in cases and controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, lending support to the hypothesis that rare haplotypes, or the rare variants they tag, underlie the synthetic association of breast cancer risk with at least some GWAS hits.…”