PT  - JOURNAL ARTICLE
AU  - Schooling, C M
AU  - Ng, Jack C M
TI  - Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease
AID  - 10.1101/472548
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 472548
4099  - http://biorxiv.org/content/early/2018/11/19/472548.short
4100  - http://biorxiv.org/content/early/2018/11/19/472548.full
AB  - Background According to well-established evolutionary biology theory reproduction trades-off against 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.Methods 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 using multiplicative random effects inverse variance weighted (IVW), weighted median, MR-Egger and MR-PRESSO estimates.Results 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).Conclusions 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.AbbreviationsCVDcardiovascular diseaseGWASgenome-wide association studyGnRHGonadotropin-releasing hormoneIHDischemic heart diseaseSNPsingle nucleotide polymorphism