Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease which affects 1/350 individuals in the United Kingdom. The cause of ALS is unknown in the majority of cases. Two sample Mendelian randomisation (MR) enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study (GWAS) summary statistics for serum concentrations of 566 metabolites which were population matched with a GWAS study of ALS. For each metabolite we performed MR using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction our unbiased screen revealed three metabolites which were significantly linked to risk of ALS: Estrone-3-sulfate and bradykinin were protective, which is consistent with literature describing a male preponderance of ALS and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit breakdown of bradykinin. Serum isoleucine was positively associated with ALS risk. All three metabolites were supported by robust MR measures and sensitivity analyses; estrone-3-sulfate and isoleucine were confirmed in a validation ALS GWAS. Estrone-3-sulfate is metabolised to the more active estradiol by the enzyme 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1); further MR demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17β-HSD1, modify risk for ALS. Finally, in a zebrafish model of C9ORF72-ALS we present evidence that estradiol is neuroprotective. Isoleucine is metabolised via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction which consumes vitamin B12. Multivariable MR revealed that the toxic effect of isoleucine is dependent on depletion of vitamin B12; consistent with this, rare variants which reduce function of MMUT are protective against ALS. We propose that ALS patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12.

Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?

“…However, there are not many studies on this matter, although, interestingly, it has only been described that an increase in 17 β-estradiol enhanced autophagy and suppressed apoptosis to limit MN death in an NSC34 cell-like model that stably expresses the 25 kDa C-terminal fragment of TDP-43 [ 102 ]. 17 β-estradiol showed neuroprotector effects in a zebrafish model of C9ORF72-amyotrophic lateral sclerosis [ 103 ], which possibly confirms the 17 β-estradiol neuroprotective activity that is also in other protein alterations, such as C9ORF72.…”

Causal factors in primary open angle glaucoma: a phenome-wide Mendelian randomisation study

“…A conventional value for selection of instruments is p < 5E-08, but this can, in some cases, be problematic. For example, when the number of instruments exceeding this threshold is small, the analysis can be underpowered or, in certain cases of unbiased screens, the results can be inflated 40 . With this in mind, we have set the p value for instrument selection for each trait to the level where > 5 instruments are available for each analysis.…”

Phenome-wide Mendelian randomisation analysis identifies causal factors for age-related macular degeneration

“…For example, when the number of instruments exceeding this threshold is small, the analysis can be underpowered or, in certain cases of unbiased screens, the results can be inflated. (Boddy et al, 2022) With this in mind, we have set the p-value for instrument selection for each trait to the level where >5 instruments are available for each analysis. More specifically, for each trait, the analysis would first be conducted with a p-value for inclusion of 5E-8 and would sequentially increase by a factor of 10 each time until >5 eligible instruments are identified to a predefined maximum of p=5E-05.…”

“…This approach however can, in some cases, be problematic. For example, when the number of instruments exceeding this threshold is small, the analysis can be underpowered or, in certain cases of unbiased screens, the results can be inflated (Boddy et al, 2022). With this in mind, the p-value for instrument selection for each trait was set to the level where >5 instruments were available for each analysis.…”