Coupling of metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and resulting traits and diseases

Abstract

Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using WES-based rare variant aggregation testing to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene-metabolite associations, many previously unreported. Validation through genetic and new computational approaches (in silicogene knockouts in whole-body models of human metabolism) provided orthogonal evidence that population-based studies of rare, damaging variants in the heterozygous state permit inferences usually obtained from inborn errors of metabolism. Allelic series of functional variants in transporters responsible for transcellular sulfate reabsorption (SLC13A1, SLC26A1) exhibited graded effects on plasma sulfate and human height, and pinpointed alleles that strongly increased risk for dozens of musculoskeletal traits and diseases in the population. We present a powerful approach to identify new players in incompletely characterized human metabolic reactions, and to reveal metabolic readouts of disease risk to inform disease prevention and treatment.

Unraveling the metabolomic architecture of autism in a large Danish population-based cohort

“…Predicted loss-of-function variants in TMLHE associates with increased levels of TML and 5-AVAB and with decreased levels of hydroxytrimethyllysine and 4-trimethylammoniobutanoic, both downstream of TMLHE in the carnitine biosynthesis pathway. As expected, the effects of the loss-of-function variants are significantly larger in men compared to women 48 . Although endogenous production is likely an important source of circulating 5-AVAB, there is mounting evidence that the gut microbiome also is a major contributor 29,30 .…”

“…The exact production pathway and to what extent the total pool of circulating 5-AVAB originates from endogenous production is however not known. More evidence for an endogenous production of 5-AVAB comes from a recent study investigating the effects of predicted loss-of-function variants in the X-chromosome gene TMLHE 48 . TMLHE codes for the enzyme trimethyllysine dioxygenase, responsible for catalyzing the conversion of TML to hydroxytrimethyllysine, the first step in the carnitine biosynthesis.…”

Panera: An innovative framework for surmounting uncertainty in microbial community modeling using pan-genera metabolic models

“… 13 , 14 , 15 , 16 GSMMs have proved to be a valuable and standard resource for in-silico reconstruction of microbial communities 17 , 18 and are publicly available in databases such as AGORA, AGORA2, and BiGG. 19 The metabolic characterization of these microbial communities opened avenues for diverse applications, including biomarker identification, 20 disease classification, 21 , 22 host-microbiome interaction exploration, 23 and personalized treatment regimen development. 24 However, a significant limitation of these simulations lies in their reliance on GSMMs derived from whole genomes.…”