Rare and common genetic determinants of metabolic individuality and their effects on human health

[helvella]

Just noticed this new Nature paper.

Page 6 (PDF page number) has some thyroid details.

Rare and common genetic determinants of metabolic individuality and their effects on human health

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.

Paper freely accessible here:

nature.com/articles/s41591-...

[radd]

Thank you for posting helvella,

Still very much the investigation of genetic mutations is for a future standard practice sadly but its value is slowly becoming recognised in certain circles, ie haemochromotosis.

[helvella Administrator Thyroid UK in reply to radd]

At this stage, simple recognition that there is quite a number of variations which have their impacts - alone and in combination - is important.

For example, we don't need to know the precise genetic sequence which means patient A does better on T3-only. But we allow the hypothesis that there is, or could be, such a sequence. Thus possible need for T3-only cannot be high-handedly rejected.

After all, Mendel could not explain the genetics as to why some pea plants grew tall or short, or some peas yellow or green, wrinkled or smooth. Nor did he need to. He simply claimed some factor! (Whether he faked his results (as alleged) or not!)

[radd in reply to helvella]

🤔 ... theory of segregation.

Well, we're certainly segregated, left on fence and then hung out to dry 🤣