Background:
Breast cancer diagnosed at a younger age is more aggressive and has a worse outcome. While rare pathogenetic variants and >200 common variants have been found to be implicated in disease risk, ~50% of the familial risk of early-onset breast cancer (EOBC) remains unexplained. We aimed to examine the genetic susceptibility and causal risk factors for EOBC.
Methods:
We conducted GWAS meta-analyses of 25,885 EOBC cases (<45 years) with 35,809 age-matched controls, and 116,067 late-onset breast cancer (LOBC) cases (≥45 years) with 245,054 age-matched controls, from the Breast Cancer Association Consortium and UK Biobank. LD score regression and two-sample Mendelian randomisation were used to evaluate genetic correlations and causal relationships across 50,055 traits.
Results:
We identified 104 susceptibility loci for either EOBC or LOBC. Across loci, effect estimates for LOBC were on average 0.79 times lower than those with EOBC (95% CI: 0.72, 0.85; P= 7.18E-09), with three loci having a Bonferroni-corrected significant difference between EOBC and LOBC. LDSC analyses found 18 traits with a significant genetic correlation with breast cancer; of them, schizophrenia was more strongly correlated with EOBC (rg=0.18; 95% CI: 0.11, 0.25), while cancer diagnosed by doctor was stronger in LOBC (rg=0.56; 95% CI: 0.46, 0.65). MR analyses found 93 traits with a casual effect on breast cancer, 61 of which were not reported previously. Four traits, including triglycerides in small high-density lipoprotein, calcium/calmodulin-dependent protein kinase type 1, histo-blood group ABO transferase, and age at menopause had significant different causal effects between EOBC and LOBC, with the former two having a greater effect for EOBC. Schizophrenia was the only significant trait commonly found by LDSC and MR that was associated with EOBC.
Conclusions:
We identified novel susceptibility loci and causal factors for EOBC, highlighting potential links with neurocognitive pathways and refining the understanding of EOBC aetiology.