Genetic variation in life-history traits is not correlated with 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 studying individual ER+ BC risk variants suggest that increased genetic ER+ BC risk is indicative of life-history trade-offs, and is associated with faster maturation, earlier reproduction, and/or increased reproductive success, but how well this pattern is replicated across the full polygenic architecture of these complex traits is unclear. Here, we estimate genome-wide genetic correlations between ER+ BC risk and three reproductive life-history traits (age at menarche, age at first birth, and the number of children born) for Lifelines biobank women using genomic restricted maximum likelihood analyses. We complement these by performing linkage disequilibrium score regression on European population and family-based genome-wide association study data. Regardless of the data or method used, genetic correlations were low and not statistically different from zero. These results therefore suggest that while some important loci underlying ER+ BC risk may demonstrate antagonistic pleiotropy symptomatic of life-history trade-offs, the available genomic data suggests these findings are not replicated, on average, across the genome. Consequently, our results suggest that genetic variation does not overall shape the observed phenotypic relationships between these life-history traits and ER+ BC risk. Future studies incorporating local-genetic correlations or gene-network data could further our understanding how as to how genetic variation in these traits maps to phenotypic associations and aid our understanding of the evolutionary processes shaping this important disease.