Deconvoluting gene and environment interactions to develop an “epigenetic score meter” of disease

The title of this paper (“Deconvoluting gene and environment interactions to develop an “epigenetic score meter” of disease”) seemed “so relevant” to our GEITP email blog that one of our devoted GEITP-ers suggested that we consider it for discussion. As you can see, most of the coauthors are “Chairs” of one or another department or division, and “Chairs” notoriously write essays in a flowery manner — with a lot of handwaving, smoke and mirrors (i.e., phrases such as “deconvoluting, decoding, unraveling, reduction of dimensionality” are tossed around with impunity). 😉

One general criticism that we in GEITP have — is the emphasis (in many publications lately — throughout the world) on methylated DNA markers as THE Epigenome. It is best to keep in mind that “epigenetic processes” include not only DNA-methylation, but also RNA-interference (RNAi), histone-modifications, and chromatin-remodeling. [Each of these can affect gene expression, and genetic differences can influence each of these epigenetic processes.]

Human health is determined by both genetics (G) and the environment (E). This has been shown time-and-time again — in these GEITP email blogs — in which subsets of individuals, exposed to the same dose of an environmental toxicant, exhibit widely varying responses. Authors [see attached] propose a quantitative measure of the gene–environment interactions (GEI) effect — which, of course, has not yet been developed. [Many of us would say the GEI effect (currently) is too complex to “reduce it” to any simple equation. Maybe next year, maybe another decade — and we might change our minds.]

Examples that the authors chose to discuss [see attached] include the following.

[a] “How often does cancer occur randomly” versus “How often does cancer occur due to the patient’s lifestyle?” [Many of us would also add a 3rd category of “cancer-prone syndromes”.]

[b] Epigenetics is certainly highly likely to be involved in asbestos toxicity and cancer. An intriguing example is the BRCA1-associated protein-1 (BAP1), which has emerged as a suspect in the context of asbestos-related diseases. More than 200 families worldwide, carrying germline mutations of the BAP1 gene, have been found to develop a condition known as the “BAP1 cancer predisposition syndrome.”

[c] Liver toxicity disorders are associated with (among many other factors) reactive oxygen species (ROS) formation, aldehyde production, and genetic differences in aldehyde dehydrogenase expression. Additional factors include effects on genome integrity, and epigenetic control of aldehyde production.

[d] It is likely that differences (large variability) in genetics, epigenetics, and environmental exposure play a large role in the cause of autoimmune disorders.

[e] It is highly likely that epigenetics is a very substantial contributor to the etiology of autism spectrum disorder (ASD). The surge in the frequency of ASD — from one in 10,000 in 1970, to one in 36 in 2023 — is impossible to be blamed solely on DNA mutations (genetics), or changes in diagnostic practices, or increased awareness. Recently, one intriguing susceptibility locus implicated in ASD risk is the CHD8 gene (chromodomain helicase DNA-binding-8), which encodes a subunit of the SNF2H-like ATP-dependent chromatin-remodeling factor, CHD. Alterations in CHD8 expression have been shown to directly influence epigenetic regulation and the transcription of genes involved in neuronal development, and are associated with risk of ASD…!!

The authors’ idea assumes that all the relevant influences of genetics and environment are contained in the epigenome, and this information will someday be “decodified” and correlated with a quantitative measure of disease risk — which they suggest to be called the “epigenetic score meter.” Although this proposal appears “off-the-wall” at present, there is precedence for “the reproducible and quantitative decoding of extremely complex information,” (e.g., by the fast-Fourier transformation in the 1960s, which allowed monitoring of nuclear weapons’ tests, and is now an important basis of the science of earthquakes). The authors’ hypothesis suggests that future studies should be aimed at the “deconvolution ☹ of GxE Interactions” which will lead to the “quantification of all epigenetic effects.” 😊


EMBO Mol Med (2023) e18208

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