No genome-wide correlations and little shared genetic architecture between reproductive life-history traits and estrogen receptor-positive breast cancer risk.

Estrogen receptor-positive breast cancer (ER+ BC) is one of the most prevalent cancers, but the evolutionary processes shaping genetic variation in ER+ BC risk are poorly understood. Both evolutionary life-history theory and evidence from studies of individual ER+ BC risk variants suggest that increased genetic ER+ BC risk is associated with faster maturation, earlier reproduction, and/or increased reproductive success (i.e., there is a trade-off), but it is unclear how well this pattern is replicated when considering the polygenic architecture of these traits after controlling for potential biases. Here, we estimate genome-wide genetic correlations between ER+ BC risk and three reproductive traits (age at menarche, age at first birth, and the number of children) using genomic restricted maximum-likelihood analyses on Lifelines biobank data and linkage disequilibrium score regressions on population and family-based genome-wide association study data. Regardless of the data or method used, genetic correlations were low and not statistically significant. Further analyses decomposing genome-wide genetic variance into local regions detected only three loci exhibiting significant pleiotropy between ER+ BC risk and age at menarche, suggesting little shared genetic architecture between ER+ BC risk and reproductive traits. Thus, the role of life-history trade-offs in shaping ER+ BC risk in European populations appears, at most, small, and the evolutionary processes giving rise to this life-threatening disease remain unclear. Future studies could examine the impact of evolutionary mismatches in shaping ER+ BC risk, where conducting longitudinal studies on populations transitioning to reproductive patterns observed in contemporary European populations would be most useful.