DNA methylation and childhood adversity

This 2017 Georgia human review covered:

“Recent studies, primarily focused on the findings from human studies, to indicate the role of DNA methylation in the associations between childhood adversity and cardiometabolic disease in adulthood. In particular, we focused on DNA methylation modifications in genes regulating the hypothalamus-pituitary-adrenal axis as well as the immune system.”

Recommendations in the review’s Epigenetics inheritance and preadaptation theory section included:

“Twin studies offer another promising design to explore the mediation effect of DNA methylation between child adversity and cardiometabolic outcomes..which could rule out heterogeneity due to genetic and familia[l]r environmental confounding.”

As it so happened, the below 2018 study provided some evidence.

http://www.sciencedirect.com/science/article/pii/S0167527317352762 “The role of DNA methylation in the association between childhood adversity and cardiometabolic disease” (not freely available) Thanks to lead author Dr. Guang Hao for providing the full study.

This 2018 UK human study:

“Tested the hypothesis that victimization is associated with DNA methylation in the Environmental Risk (E-Risk) Longitudinal Study, a nationally representative 1994-1995 birth cohort of 2,232 twins born in England and Wales and assessed at ages 5, 7, 10, 12, and 18 years. Multiple forms of victimization were ascertained in childhood and adolescence (including physical, sexual, and emotional abuse; neglect; exposure to intimate-partner violence; bullying; cyber-victimization; and crime).

Hypothesis-driven analyses of six candidate genes in the stress response (

  1. NR3C1 [glucocorticoid receptor],
  2. FKBP5 [a regulator of the stress hormone system],
  3. BDNF [brain-derived neurotrophic factor],
  4. AVP [arginine vasopressin],
  5. CRHR1 [corticotropin-releasing hormone receptor 1],
  6. SLC6A4 [serotonin transporter]

) did not reveal predicted associations with DNA methylation.

Epigenetic epidemiology is not yet well matched to experimental, nonhuman models in uncovering the biological embedding of stress.”

One of the sad findings was that as the types of trauma inflicted by other people on the subjects increased, so did the percentage of subjects who hurt themselves by smoking. Two-thirds of kids who reported three or more of the seven adolescent trauma types also smoked by age 18. Self-harming behaviors other than smoking weren’t considered.

Another somber finding was:

“Childhood sexual victimization is associated with stable DNA methylation differences in whole blood in young adulthood.

These associations were not observed in relation to sexual victimization in adolescence.”

The researchers guided future studies regarding the proxy measurements of peripheral blood DNA methylation:

“The vast majority of subsequent human studies, including the present one, have relied on peripheral blood. This choice is expedient, but also scientifically reasonable given the aim of detecting effects on stress-related physical health systems that include peripheral circulating processes (immune, neuroendocrine).

But whole blood is heterogeneous, and although cell-type composition can be evaluated and controlled, as in the present study, it does raise the question of whether peripheral blood is a problematic surrogate tissue for research on the epigenetics of stress.

Comparisons of methylomic variation across blood and brain suggest that blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”

The comment on “epigenetic epidemiology” overstated the study’s findings because the epigenetic analysis, although thorough, was limited to peripheral blood DNA methylation. Other consequential epigenetic effects weren’t investigated, for example, histone modifications and microRNA expression.

One unstated limitation was that the DNA methylation techniques were constrained by a budget. Studies like The primary causes of individual differences in DNA methylation are environmental factors point out restrictions in the study’s approach:

“A main limitation with studies using the Illumina 450 K array is that the platform only covers ~1.5 % of overall genomic CpGs, which are biased towards promoters and strongly underrepresented in distal regulatory elements, i.e., enhancers.

WGBS [whole-genome bisulfite sequencing] offers single-site resolution CpG methylation interrogation at full genomic coverage.

Another advantage of WGBS is its ability to access patterns of non-CpG methylation.”

I’d expect that in the future, researchers with larger budgets would reanalyze the study samples with WGBS and other DNA methylation techniques.

The researchers started and ended the study presenting their view of human “embedding of stress” as a fact rather than a paradigm. Epigenetic effects of early life stress exposure compared and contrasted this with another substantiated view.

This was also a missed opportunity to advance science regarding intergenerational and transgenerational epigenetic inheritance. Wouldn’t it have been informative to provide the parents with the same questionnaires their twins answered at age 18, and to analyze the parents’ blood samples?

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2017.17060693 “Analysis of DNA Methylation in Young People: Limited Evidence for an Association Between Victimization Stress and Epigenetic Variation in Blood” (not freely available) Thanks to coauthor Dr. Helen Fisher for providing the full study.


Can researchers make a difference in their fields?

The purpose and finding of this 2017 UK meta-analysis of human epigenetics and cognitive abilities was:

“A meta-analysis of the relationship between blood-based DNA methylation and cognitive function.

We identified [two] methylation sites that are linked to an aspect of executive function and global cognitive ability. The latter finding relied on a relatively crude cognitive test..which is commonly used to identify individuals at risk of dementia.

One of the two CpG sites identified was under modest genetic control..there are relatively modest methylation signatures for cognitive function.”

The review’s stated limitations included:

“It is, of course, possible that a reliable blood-based epigenetic marker of cognitive function may be several degrees of separation away from the biological processes that drive cognitive skills.

There are additional limitations of this study:

  • A varying number of participants with cognitive data available for each test;
  • Heterogeneity in relation to the ethnicity and geographical location of the participants across cohorts; and
  • Relating a blood-based methylation signature to a brain-based outcome.

A 6-year window [between ages 70 and 76] is possibly too narrow to observe substantial changes in the CpG levels.”

All of these limitations were known before the meta-analysis was planned and performed. Other “possible” limitations already known by the 47 coauthors include those from Genetic statistics don’t necessarily predict the effects of an individual’s genes.

The paper referenced studies to justify the efforts, such as one (cited twice) coauthored by the lead author of A problematic study of DNA methylation in frontal cortex development and schizophrenia:

“Epigenome-wide studies of other brain-related outcomes, such as schizophrenia, have identified putative blood-based methylation signatures.”

Was this weak-sauce meta-analysis done just to plump up 47 CVs? Why can’t researchers investigate conditions that could make a difference in their fields?

Was this meta-analysis done mainly because the funding was available? I’ve heard that the primary reason there are papers like the doubly-cited one above is that the US NIMH funds few other types of research outside of their biomarker dogma.

The opportunity costs of this genre of research are staggering. Were there no more productive topics that these 47 scientists could have investigated?

Here are a few more-promising research areas where epigenetic effects can be observed in human behavior and physiology:

I hope that the researchers value their professions enough to make a difference with these or other areas of their expertise. And that sponsors won’t thwart researchers’ desires for difference-making science by putting them into endless funding queues.

https://www.nature.com/articles/s41380-017-0008-y “Meta-analysis of epigenome-wide association studies of cognitive abilities”

Make consequential measurements in epigenetic studies

The subject of this 2017 Spanish review was human placental epigenetic changes:

“39 papers assessing human placental epigenetic signatures in association with either

  • (i) psychosocial stress,
  • (ii) maternal psychopathology,
  • (iii) maternal smoking during pregnancy, and
  • (iv) exposure to environmental pollutants,

were identified.

Their findings revealed placental tissue as a unique source of epigenetic variability that does not correlate with epigenetic patterns observed in maternal or newborn blood.

Each study’s confounders were summarized by a column in Table 1. Some of the reviewers’ comments included:

“33 out of 39 papers reviewed (85%) reported significant associations between either placental DNA methylation or placental miRNA expression and exposure to any of the risk factors assessed. However, the methodological heterogeneity present throughout the studies reviewed does not allow meta-analytic exploration of reported findings.

Heterogeneity regarding the origin of biological tissues analyzed confounds the replicability and validity of reported findings and their potential synthesis.”

Sponsors and researchers really have to take their work seriously if the developmental origins of health and disease hypothesis can advance to a well-evidenced theory. Study designers should:

  1. Sample consequential dimensions. “There were no studies examining histone modifications.” Why were there no human studies in this important category of epigenetic changes in the placenta, the “barrier protecting the fetus”?
  2. Correct methodological deficiencies in advance. Eliminate insufficiencies like “Once collected, processing and storage of placental samples also differed across studies and was not reported in all of them.”
  3. Stop using convenient but non-etiologic proxy assays such as global methylation. How can a study advance the DOHaD hypothesis if everyone knows ahead of time that its outcome will be yet another finding that epigenetic changes “are associated with” non-causal factors?
  4. Forget about non-biological measurements like educational attainment per Does a societal mandate cause DNA methylation?.

Every human alive today has observable lasting epigenetic effects caused by environmental factors during the earliest parts of our lives. Isn’t this sufficient rationale to expect serious efforts by research sponsors and designers?

https://www.sciencedirect.com/science/article/pii/S0892036217301769 “The impact of prenatal insults on the human placental epigenome: A systematic review” (click the Download PDF link to read the paper)

Science and technology hijacked by woo

I’m an avid reader of science articles, abstracts, studies, and reviews. I tried a free subscription to Singularity Hub for a few weeks last month because it seemed to be a suitable source of articles on both science and technology.

I unsubscribed after being disappointed by aspects of science and technology hijacked almost on a daily basis into the realm of woo. Discovering scientific truths and realizing technologies is inspiring enough to stand on its own. It’s sufficiently interesting to publish well-written articles on the process and results.

I was dismayed that the website didn’t host a feedback mechanism for the authors’ articles. We shield ourselves from information incongruent with our beliefs. It’s a problem when a publisher of science and technology articles similarly disallows non-confirming evidence as a matter of policy.

An article may or may not advance knowledge of the subject, and Singularity Hub enables author hubris in presenting their views as the final word on the subject. Directing readers elsewhere for discussion is self-defeating in that every publisher’s goals include keeping visitors on their website as long as possible.

Here’s my feedback on two articles that inappropriately bent reality.

Regarding What Is It That Makes Humans Unique?:

“This trait [symbolic abstract thinking] not only gives us the ability to communicate symbolically, it also allows us to think symbolically, by allowing us to represent all kinds of symbols (including physical and social relationships) in our minds, independent of their presence in the physical world. As a result, internal associations of novel kinds become possible.”

Why limit discussion of our capability for symbolic representations? Other features to explore are:

  • What is a belief if not a symbolic representation?
  • What attributes of human behavior provide evidence for hopes and beliefs as symbolic representations?
  • What is the evolved functional significance that benefits humans of using symbolic abstract thinking to develop hopes and beliefs?

“Our revolutionary traits stand out even more when we take a cosmic perspective..We are not only in the universe, but the universe is also within us..Our brains, as an extension of the universe, are now being used to understand themselves.”

This article should be written well enough to inspire without resorting to unevidenced assertions about revolutions, the cosmos, and the timing of brain functionality.

“Some of us possess higher consciousness than others. The question that we now have to ask ourselves is, how do we cultivate higher consciousness, structural building, and symbolic abstract thinking among the masses?”

What is the purpose of steering an evolution topic into elitism?

How a Machine That Can Make Anything Would Change Everything received >53,000 views compared with <5,000 views of the above article. This was an indicator that readers of Singularity Hub are relatively more interested in the possible implications of future technology than those of our past biological evolution. Why?

“If nanofabricators are ever built, the systems and structure of the world as we know them were built to solve a problem that will no longer exist.”

Soon we will have the worldwide solution to limits in food supply, energy supply, medicine availability, income, knowledge – all of the elements needed for survival?

I was reminded of the chip-in-the-brain article referenced in Differing approaches to a life wasted on beliefs. Each of us needs to address the impacts of past threats to our survival that include producing our present hopes if we are ever going to individually break out of these self-reinforcing, life-wasting loops.

“Human history will be forever divided in two. We may well be living in the Dark Age before this great dawn. Or it may never happen. But James Burke, just as he did over forty years ago, has faith.”

Is it inspiring that the person mentioned has had a forty-year career of selling beliefs in technology?

Yes, future technologies have promise. Authors can write articles that provide developments without soiling the promise with woo.

Epigenetics research and evolution

This 2017 UK essay was a longish review of how epigenetics and other research has informed evolutionary theory:

“There are several processes by which directed evolutionary change occurs—targeted mutation, gene transposition, epigenetics, cultural change, niche construction and adaptation.

Evolution is an ongoing set of iterative interactions between organisms and the environment..Directionality is introduced by the agency of organisms themselves.”

A few takeaway items concerned:

“It is of course the functional phenotype that is ‘seen’ by natural selection. DNA sequences are not directly available for selection other than through their functional consequences.

..the comparative failure of genome-wide association studies to reveal very much about the genetic origins of health and disease. This is one of the most important empirical findings arising from genome sequencing.

Environmental epigenetic impacts on biology and disease include:

  • Worldwide differences in regional disease frequencies
  • Low frequency of genetic component of disease as determined with genome wide association studies (GWAS)
  • Dramatic increases in disease frequencies over past decades
  • Identical twins with variable and discordant disease frequency
  • Environmental exposures associated with disease
  • Regional differences and rapid induction events in evolution

The above list was from the cited 2016 review “Developmental origins of epigenetic transgenerational inheritance” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933018

I was especially interested in the points about behavior’s role in evolution:

“Differential mutation rates are not essential to enable organisms to guide their own evolution.

If organisms have agency and, within obvious limits, can choose their lifestyles, and if these lifestyles result in inheritable epigenetic changes, then it follows that organisms can at least partially make choices that can have long-term evolutionary impact.”

These discussions provided support for the central question of The PRice “equation” for individually evolving: Which equation describes your life?:

“Applying the “How does a phenotype influence its own change?” question to a person:

How can a person remedy their undesirable traits – many of which are from their ancestral phenotype – and acquire desirable traits?”

http://www.mdpi.com/2079-7737/6/4/47/htm “Was the Watchmaker Blind? Or Was She One-Eyed?”

The pain societies instill into children

The human subjects of this 2017 Swiss study had previously been intentionally traumatized by Swiss society:

“Swiss former indentured child laborers (Verdingkinder) were removed as children from their families by the authorities due to different reasons (poverty, being born out of wedlock) and were placed to live and work on farms. This was a practice applied until the 1950s and many of the Verdingkinder were subjected to childhood trauma and neglect during the indentured labor.

DNA methylation modifications indicated experiment-wide significant associations with the following complex posttraumatic symptom domains: dissociation, tension reduction behavior and dysfunctional sexual behavior.”

Imagine being taken away from your family during early childhood for no other reason than your parents weren’t married.

Imagine just a few of the painful feelings such a child had to deal with then and ever since. I’m unloved. Alone. No one can help me.

Imagine some of the ways a child had to adapt during their formative years because of this undeserved punishment. How fulfilling it would be to believe that they were loved, even by someone they couldn’t see, touch, or hear. How fulfilling it would be to get attention from someone, anyone. How a child became conditioned to do things by themself without asking for help.

The study described a minute set of measurements of the subjects’ traumatic experiences and their consequential symptoms. The researchers tried to group this tiny sample of the subjects’ symptoms into a new invented category.

https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-017-3082-y “A pilot investigation on DNA methylation modifications associated with complex posttraumatic symptoms in elderly traumatized in childhood”

Another example was provided in Is IQ an adequate measure of the quality of a young man’s life?:

“During this time period [between 1955 and 1990], because private adoptions were prohibited by Swedish law, children were taken into institutional care by the municipalities shortly after birth and adopted at a median age of 6 mo, with very few children adopted after 12 mo of age.”

Swedish society deemed local institutional care the initial destination for disenfranchised infants, regardless of whether suitable families were willing and able to adopt the infants. What happened to infants who weren’t adopted by age 1?

Did Swedish society really need any further research to know that an adoptive family’s care would be better for a child than living in an institution?

A third example of the pain instilled into children by societies was related to me last year by two sisters. During the Chinese Cultural Revolution, 1966-1976, among other things, parents were required to be out of their households from dawn to late night, leaving the children to fend for themselves.

One of the daily chores for the sisters at ages 6 and 7, after attending school, was to buy food for dinner and the next day’s breakfast and lunch with ration coupons, and prepare the family’s evening meal. They never knew their four grandparents, who had died in ways the sisters either didn’t know or weren’t willing to express to me.

It wasn’t difficult to infer that traumatic childhood events still impacted the women’s lives 50 years later. My empathetic understanding of their histories, though, didn’t improve their current situations. I’ll highlight one of their many affected areas – accepting other people’s assistance.

One of the younger sister’s adaptations at ages 6 to 16 was – and still is – that she feels compelled to do everything herself. Her initial reaction is to reject help, no matter the circumstances. Her thoughts, feelings, and behavior impacted by childhood trauma have also included the opposite reaction of forcing family members – at their prolonged inconvenience and discomfort – to help others.

The older sister, on the other hand, accepts other people’s assistance, maybe too readily. She also lives alone, and sometimes has trouble providing for herself without excessive prompting from her sister. Her societal experiences apparently either taught her or reinforced helplessness.

It’s a challenge for each of us to recognize when our thoughts, feelings, and behavior are evidence of our own continuing responses to childhood pain that’s still with us, influencing our biology.

Let’s not develop hopes and beliefs that the societies we live in will resolve any adverse effects of childhood trauma its members caused. Other people may guide us, but each of us has to individually get our life back.

Europe, Asia, Africa, Australia, North and South America: every society has its horror stories, and there are people still living who can document last century’s events and circumstances. What evidence can be presented to show that traumatic effects on children from societal policies have ceased?