Another major factor that must be considered in genotype-phenotype association studies: The Gut Microbiome

Genetic architecture” is a broad term defined as everything in the chromosomes of an individual organism that underlies and contributes to the genetic basis of a phenotypic trait and all variational properties. The “trait being studied” might include obesity, type-2 diabetes, schizophrenia, height or blood pressure, serum cholesterol or electrolyte levels, drug efficacy, drug toxicity or adverse reactions, drug-drug interactions, or any form of cancer.  “Everything in the chromosomes–– up to NOW –– has included DNA sequence alterations (genetics of the genome), patterns of pleiotropy, dominance and epistasis (gene-gene interactions), epigenetic effects (epigenetics of the genome), and environmental factors that are might cause mutations/chromosomal rearrangements but also are able to alter any of cell-type-specific epigenome.

Now, because it is realized that ~92% of all DNA in the human body is derived from gut bacteria, one must consider contribution(s) of the gut microbiome to each individual’s genetic architecture. Consequently, these three papers [attached] are mind-blowing to me, because I foresee that this topic will soon be required to be considered –– by anyone in the near future wishing to write grant proposals or perform experiments in genome-wide association studies (GWAS) and/or epigenome-wide association studies (EWAS), i.e. ‘human- or organism-wide’ microbiome-phenotype studies must be pondered.

These three papers plus the editorial [all attached], published in the same issue (Nov 2o16) of Nature Genetics, are among the first in a series of genetic analyses of gut microbiome composition in humans. These studies should be met with enthusiasm –– because the field of genomics continues to be appreciated as something far more complex than previously realized. These studies should also be interpreted with caution, because they are so rudimentary and we are just beginning to scratch the surface. Findings from these initial offerings demonstrate how population-scale approaches can provide deeper insights into host–microbiome interactions, while at the same time illustrating that our understanding of the genetic architecture of highly complex microbiome-associated ‘traits’ is still in an undeveloped stage.

Nat Genetic   Nov 2o16; 48: 1396-1406, 1407–1412, & 1413–1417 [THREE articles] plus 1301–1302 [News-N-Views editorial]

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