Reproduction and longevity: A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart...

According to well-established evolutionary biology theory there is a trade-off between reproduction and longevity, implying that upregulating the reproductive axis might drive major diseases. We assessed whether the central driver of reproduction gonadotropin-releasing hormone 1 (GnRH1) had a causal effect on the leading cause of global morbidity and mortality, i.e. ischemic heart disease (IHD). As a contrast we similarly examined the role of GnRH2 because it is more a driver of female sexual behavior.

We applied strong (p-value <5 × 10^-6) and independent genetic predictors of GnRH1 and GnRH2 to an extensively genotyped IHD case (n = 76,014) - control (n = 264,785) study and combined the genetic variant specific Wald estimates using inverse variance weighting (IVW) with multiplicative random effects, and as a sensitivity analysis used weighted median, MR-Egger and MR-PRESSO estimates, and repeated the analysis only using genome wide significant genetic predictors.

GnRH1, predicted by 11 genetic variants, was positively associated with IHD (IVW odds ratio (OR) 1.04 per effect size, 95% confidence interval (CI) 1.01 to 1.08), but GnRH2, predicted by 15 genetic variants, was not (IVW OR 0.98, 95% CI 0.95 to 1.02). Estimates from sensitivity analysis were similar.

GnRH1 is a potential IHD genetic target. Apart from demonstrating a central tenet of evolutionary biology in humans, our study suggests that existing treatments and environmental factors targeting GnRH1, its drivers or consequences could be re-purposed to prevent and treat IHD. Given, the importance of reproduction to the human species, many such exposures likely exist.