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

Abstract

BackgroundAccording 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.MethodsWe 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.ResultsGnRH1, 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).ConclusionsGnRH1 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.

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation

“…In addition, our findings are consistent with well-established evolutionary biology theory, that is reproductive success may be at the expense of longevity, possibly in a sex-specific manner, impling that central drivers of the reproductive axis, as well as androgen production and catabolism, and their environmental cues may be relevant to IHD ( Schooling, 2016 ; Schooling and Ng, 2019 ; Figure 2 ) encompassing the relations tested here ( Figure 1 ). Notably, upregulation of indicators of plentiful living conditions, such as insulin, appear to cause IHD, particularly in men ( Zhao et al, 2019 ), likely via gonadotropin releasing hormone (GnRH) ( Schooling and Ng, 2019 ). Similarly, fatty acids may affect GnRH ( Tran et al, 2016 ; Matsuyama and Kimura, 2015 ).…”

Day-night and seasonal variation of human gene expression across tissues

“…GNRH1, the gonadotropin-releasing hormone 1, which influences seasonal changes in other mammals (Hart et al 1984), is seasonal in two artery tissues: the aorta and the tibial one. Mutations in GNRH1 have been shown to be related to ischemic heart disease, which shows a seasonal pattern (Bhatia et al 2017;Schooling and Ng 2019). Interestingly, leptin (LEP), a hormone involved in seasonal food-seeking behaviour, thermoregulation (Fischer et al 2020), and obesity (Srivastava and Krishna 2007;Cahill et al 2013), was altered only in winter in three tissues: adipose visceral, nerve, and blood (Fig.…”

Causal association between mTOR-dependent EIF-4E and EIF-4A circulating protein levels and type 2 diabetes: a Mendelian randomization study

“…For the IVW estimate to be valid, all the SNPs should be valid instruments. To establish the validity of the SNPs as genetic instrumental variables (IV), we used the following tests: a weighted median and MR-Egger estimates 59 . The weighted median provides correct estimates when SNPs accounting for > 50% of the weight are valid 60 .…”