This looks super interesting 👀 I had read about the idea that certain genetic variants contribute to both fertility and breast cancer. Seems like the data don’t support that (which tbh I don’t find that surprising)

Rather than a trade-off, these variants may have persisted due to the disease’s late age at onset and weak selection, but the role of evolutionary mismatches should also be tested. By integrating different methods, we provide a robust framework that future studies could extend to other diseases.

Finally, we searched for “local” regions shared between the traits that were missed in our genome-wide analyses. But this revealed only three regions shared between just age at menarche and ER+ breast cancer risk, suggesting largely independent genetic architectures.

And did this reveal the predicted genetic trade-offs?? Well, no. In fact, reassuringly, our estimates were fairly consistent with our first results, reaffirming that there was little evidence for a genetic trade-off shaping ER+ breast cancer risk.

BUT, these traits are highly influenced by social and environmental factors that may have biased our genetic correlations. To overcome this, we used family GWAS data, which leverages the random chance of children inheriting different alleles to remove this confounding.

We first used Lifelines biobank data and the latest and largest available GWAS data, and found no evidence in favor of our hypothesis across both of these approaches. (Our analysis of GWAS data had much more power!)

To do so, we estimated *genome-wide* genetic correlations between ER+ breast cancer risk and three human reproductive traits (age at menarche, age at first birth, and number of children) to examine evidence for genetic trade-offs underlying why we get sick.

Genetic studies have also flagged individual genes that influence *both* ER+ breast cancer risk *and* reproductive processes. However, both the disease and human reproduction are underpinned by many, many more genes. We wanted to know what you find when you take a deeper dive across the whole genome

Estrogen receptor-positive (ER+) breast cancer provides a good candidate for testing this theory: it is fairly common and is influenced by genetic factors. Moreover, epidemiological studies have identified a link with reproductive patterns.

Natural selection should remove mutations causing disease like cancer because carriers have lower survival. BUT evolutionary theory predicts that if such mutations also increase reproductive rates, fitness benefits may offset costs. Leading disease-causing mutations to persist thanks to a trade-off.