UC San Diego

Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, in a pilot study with a retrospective cohort design, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of the BRCA1 185delAG pathogenic variant, an important group given their high risk of developing breast cancer. We performed targeted-capture to sequence VNTRs, called genotypes with adVNTR, tested the association of VNTRs and breast cancer risk using Cox regression models, and estimated the effect size using a retrospective likelihood approach. Of 303 VNTRs that passed quality control checks, 4 VNTRs were significantly associated with risk to develop breast cancer at false discovery rate [FDR] < 0.05 and an additional 4 VNTRs had FDR < 0.25. After determining the specific risk alleles, there was a significantly earlier age at diagnosis of breast cancer in carriers of the risk alleles compared to those without the risk alleles for seven of eight VNTRs. One example is a VNTR in exon 2 of LINC01973 with a per-allele hazard ratio of 1.58 (1.07-2.33) and 5.28 (2.79-9.99) for the homozygous risk-allele genotype. Results from this first systematic study of VNTRs demonstrate that VNTRs may explain a proportion of the unexplained genetic risk for breast cancer.