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Analysis Highlights Plasma Metabolites With Roles in Common Diseases

NEW YORK — Researchers have homed in on metabolites that have causal effects on a dozen common diseases, presenting opportunities for therapeutic interventions.

Through a series of genome-wide association studies and Mendelian randomization analyses, a McGill University-led team identified dozens of metabolites and metabolite ratios that influence a number of common aging-, inflammation-, and metabolism-linked conditions. As they reported on Thursday in Nature Genetics, the researchers further confirmed in a separate cohort that increased levels of one of these metabolites — orotate, which they tied to bone mineral density — was associated with an increased risk of hip fracture.

"This study provides a valuable resource describing the genetic architecture of metabolites and delivers insights into their roles in common diseases, thereby offering opportunities for therapeutic targets," senior author Brent Richards, an endocrinologist at Jewish General Hospital in Montreal and McGill, and colleagues wrote in their paper. Richards is also the CEO and cofounder of 5 Prime Sciences, which offers services to biotech, venture capital, and pharmaceutical firms.

The researchers first conducted GWAS of metabolite levels, testing more than 1,000 plasma metabolites. Through this, they found 690 metabolites whose levels were associated with 248 genetic loci, of which 32 associations were new. They similarly conducted GWAS of more than 300 metabolite ratios to uncover associations between 143 metabolite ratios at 69 genetic loci, 63 of which were new associations.

Using two complementary approaches — a gene expression-based approach and one relying on existing evidence in three databases — the researchers further searched for the particular genes that affect those metabolite levels and ratios. The gene expression-based approach uncovered 454 expression relevant genes for 625 genetic variants, and the knowledge-based approach pinpointed 262 biologically relevant genes for 321 variants. Together, the two prioritized 94 genes as effector genes for metabolites, the vast majority of which are enzymes or transporters.

Based on data from three additional databases — the DrugBank, the International Mouse Phenotyping Consortium, and the Online Mendelian Inheritance in Man — the researchers found that 14 of their effector genes with associated metabolites had related murine knockouts that had been described, are linked with Mendelian disease, and have therapeutics targeting them. This suggests, the researchers said, that these genes could be explored as therapeutic targets to affect metabolite levels and manage disease.

Then in a two-sample Mendelian randomization analysis, the researchers also examined how these gene-metabolite associations affected three key processes: aging, metabolism, and immune response. Twenty-two metabolites and 20 metabolite ratios had causal effects on 12 traits, and 10 metabolites and 12 metabolite ratios had their genetic associations colocalize with their target traits.

For instance, they found orotate affected bone mineral density, an aging-related trait, while spermidine/ergothioneine was linked to type 1 diabetes, an immune-related trait, and phosphate/linoleoyl-arachidonoyl-glycerol ratio with coronary artery disease, a metabolism-related trait.

The researchers further validated their findings using data from the Umeå Fracture and Osteoporosis Study, particularly focusing on 2,225 cases with hip fracture and 2,225 matched controls. Circulating orotate, they found, was associated with risk of hip fracture, a related trait to bone density that their Mendelian randomization results had suggested the metabolite influenced.

"The findings may assist in understanding the genetic regulation of human metabolism, allow future prospectively planned meta-analysis, and provide a valuable resource for the identification of targets for behavioral and pharmaceutical interventions," Richards and colleagues wrote in their paper.

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