RESUMEN
Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
Asunto(s)
Errores Innatos del Metabolismo , Metaboloma , Humanos , Metaboloma/genética , Metabolómica , Plasma/metabolismo , Fenotipo , Errores Innatos del Metabolismo/genética , Proteínas de la Membrana/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismoRESUMEN
The status of metallic sensations as a primary or basic taste category is controversial. Ferrous sulfate (FeSO4) has been suggested as a prototypical metallic chemosensory stimulus. At least part of the metallic sensation from FeSO4 arises from a metallic retronasal smell. The quality of this sensation was studied via multidimensional scaling (MDS) of taste similarities, with and without nasal closure to eliminate retronasal olfactory sensations. The metallic stimulus was embedded in a series containing classical "basic taste" stimuli, alum and monosodium glutamate. With olfaction available, the metallic stimulus plotted away from basic tastes and taste mixtures. Scaled ratings of sensory properties related to metallic taste (iron-nail, copper-penny-like, aftertaste) of FeSO4 decreased with nasal closure. Results are consistent with the idea that ferrous sulfate produces a distinctly different sensation from the traditional basic tastes, which includes both olfactory and oral sensations.
