Sperm DNA methylation epimutation biomarker for paternal offspring autism(doi.org)
doi.org
Sperm DNA methylation epimutation biomarker for paternal offspring autism
https://doi.org/10.1186/s13148-020-00995-2
54 comments
I agree with heterogeneous. But why do you think that auggests multiple causes. Commonalities across the neurodivergent spectrum intuitively lead me to suspect the opposite, that there is some common mechanism underlying all of them.
Because the same symptoms can be produced by very different brain structures.
Have you read this paper: https://www.nature.com/articles/s41398-019-0631-2
They find that the four-way distinction between ASD, ADHD, OCD and "typically developing" has poor correspondence to the observed interaction between cortical morphology and behavioural symptoms.
If you take their clusters – https://www.nature.com/articles/s41398-019-0631-2/figures/3 – as "what is really going on in the brain", then the same "what is really going on in the brain" can produce all four of ASD, ADHD, OCD and typical development, at different proportions (clusters 1-5). Whereas, conversely, there is a subgroup of ASD (cluster 10) which doesn't overlap with ADHD or OCD or typicality.
I'd also recommend reading https://link.springer.com/article/10.1007/s40489-016-0085-x
Have you read this paper: https://www.nature.com/articles/s41398-019-0631-2
They find that the four-way distinction between ASD, ADHD, OCD and "typically developing" has poor correspondence to the observed interaction between cortical morphology and behavioural symptoms.
If you take their clusters – https://www.nature.com/articles/s41398-019-0631-2/figures/3 – as "what is really going on in the brain", then the same "what is really going on in the brain" can produce all four of ASD, ADHD, OCD and typical development, at different proportions (clusters 1-5). Whereas, conversely, there is a subgroup of ASD (cluster 10) which doesn't overlap with ADHD or OCD or typicality.
I'd also recommend reading https://link.springer.com/article/10.1007/s40489-016-0085-x
I would turn the argument around and say that what we usually diagnose as ADHD or ASD are infact many different brain variations. Having for example ADHD doesn't mean your brain has any similiarity to another ADHD brain. The diagnosis does not involve physical brain measurements in any way
If the boundaries between neurodevelopmental disorders lack validity – certainly they lack biological validity, and it has been argued [0] that they lack construct validity as well – maybe we should respond by merging them? Merge ADHD, ASD, etc, into one single overarching disorder? That is one way of interpreting Christopher Gillberg's ESSENCE proposal. It is also, at least somewhat, the recommendation of Lynn Waterhouse's book Rethinking Autism: Variation and Complexity, which ends with the proposal to replace ASD with the much broader concept of "phenotypes of neurodevelopmental social impairment"
[0] See https://doi.org/10.1002/aur.1832 in particular the authors' claim that "our review of research has led us to conclude that using the ASD diagnosis in basic and translational research cannot provide valid conclusions because the diagnosis lacks both biological and construct validity" and also "The ASD diagnosis lacks boundary construct validity..."
[0] See https://doi.org/10.1002/aur.1832 in particular the authors' claim that "our review of research has led us to conclude that using the ASD diagnosis in basic and translational research cannot provide valid conclusions because the diagnosis lacks both biological and construct validity" and also "The ASD diagnosis lacks boundary construct validity..."
Yes, I read down to this point and stopped. What significance can you really draw from a sample size of 26? (Serious question to academics out there)
To answer your serious question, n=26 is more than sufficient depending on effect size and sampling method.
Think about it, if you have 26 people randomly sampled and you give half a pill and the other half a placebo and the first half dies moments after ingestion, how confident are you that the pill is poisonous?
If the effect size is small, you may fail to detect it with a small population. If the sampling is biased, then you’re going to have a problem even if you have a massive population studied.
Think about it, if you have 26 people randomly sampled and you give half a pill and the other half a placebo and the first half dies moments after ingestion, how confident are you that the pill is poisonous?
If the effect size is small, you may fail to detect it with a small population. If the sampling is biased, then you’re going to have a problem even if you have a massive population studied.
The "small sample size" has been drilled to most people as a knee jerk red flag indicating a statistically unreliable conclusion, but this is not always the case. Depending on the desired outcome, a small sample size may actually increase the reliability of the result. This seems like one of those cases.
Think of it like this. The aim is to show a statistically significant difference. With a large enough sample, you will eventually show significance (hence Fisher's famous anecdote of "get more data"), but the effect size may be trivial. Whereas, with a small sample, only non-trivial effect sizes will achieve significance, and therefore achieving significance with such a small sample tells you something about the nontrivial extent of the effect size.
So you could argue that the extent of methylation change was so large, that it achieved significance in a sample even as small as n=13!
Think of it like this. The aim is to show a statistically significant difference. With a large enough sample, you will eventually show significance (hence Fisher's famous anecdote of "get more data"), but the effect size may be trivial. Whereas, with a small sample, only non-trivial effect sizes will achieve significance, and therefore achieving significance with such a small sample tells you something about the nontrivial extent of the effect size.
So you could argue that the extent of methylation change was so large, that it achieved significance in a sample even as small as n=13!
For some this opinion might be contentious/taboo, but mild autism is prevalent across much of the skilled labor pool in STEM - and I count myself within that statistic. So it'll be interesting in a couple of generations what might happen to this labor pool if the potential to screen for the broad autism phenotype affects who is born and/or affects sexual selection.
Since most STEM workers have fairly successful professional and personal lives and whatever behaviours you associate with Autism Spectrum Disorder don't lead to any harm in their lives, it's hard to accept that what they have is a 'disorder' in any sense any more than working hard is mild workaholism.
If you have some cluster of traits that don't hurt you, then imho they're just traits, not a disorder.
If you have some cluster of traits that don't hurt you, then imho they're just traits, not a disorder.
Some people have broad autism phenotype (BAP), which means they have many of the traits of ASD, but those traits are not sufficiently disabling to justify the label of a disorder. And BAP is more common among STEM workers than the general population.
However, the boundary between BAP and ASD is not fixed. Different clinicians draw the line at different places, and it is moving over time. And which side of the line one ends up on can be determined by external life experiences. A person with BAP who lives a life full of luck and supportive environments may never be disabled by their traits to the extent that an ASD diagnosis is warranted. Give the same person worse luck and a more adverse environment, and the same traits may become much more disabling, and they may end up with an ASD diagnosis as a result. So, fundamentally the same person, whether they had ASD was determined not by who they are but by what their environment is.
This is part of what annoys me about some of these popular lines that "autistic people" and "neurotypical people" are "wired differently". Are people with BAP "neurotypical" or not? And sometimes the label is determined, not by one's "wiring", but by stuff going on in the world outside one's head, by society and culture and family and friends and fate and fortune.
However, the boundary between BAP and ASD is not fixed. Different clinicians draw the line at different places, and it is moving over time. And which side of the line one ends up on can be determined by external life experiences. A person with BAP who lives a life full of luck and supportive environments may never be disabled by their traits to the extent that an ASD diagnosis is warranted. Give the same person worse luck and a more adverse environment, and the same traits may become much more disabling, and they may end up with an ASD diagnosis as a result. So, fundamentally the same person, whether they had ASD was determined not by who they are but by what their environment is.
This is part of what annoys me about some of these popular lines that "autistic people" and "neurotypical people" are "wired differently". Are people with BAP "neurotypical" or not? And sometimes the label is determined, not by one's "wiring", but by stuff going on in the world outside one's head, by society and culture and family and friends and fate and fortune.
> whatever behaviours you associate with Autism Spectrum Disorder don't lead to any harm in their lives
It doesn't appear that the op made this claim.
I think I understand your perspective. I think there are some ASD associated traits which may result in sort of a tradeoff for some STEM workers. E.g someone who has a difficulty forming interpersonal relationships (negative) may thus have more free time to pursue academics and outperform their more social peers (positive). This seems more like what the op was talking about being able to observe.
It doesn't appear that the op made this claim.
I think I understand your perspective. I think there are some ASD associated traits which may result in sort of a tradeoff for some STEM workers. E.g someone who has a difficulty forming interpersonal relationships (negative) may thus have more free time to pursue academics and outperform their more social peers (positive). This seems more like what the op was talking about being able to observe.
Do STEM workers have succesful personal lives relative to people in other fields?
I have no idea, but there are some sterotypes that they are below average. Would be interesting to see studies on that.
I have no idea, but there are some sterotypes that they are below average. Would be interesting to see studies on that.
Personal lives are complex things, certainly, and no single metric can capture 'success' or 'failure' on them. However, one piece of evidence is the per-occupation divorce rate: https://flowingdata.com/2017/07/25/divorce-and-occupation
Software folks are really good about not getting divorced. And they have money, so they could if they wanted to.
Software folks are really good about not getting divorced. And they have money, so they could if they wanted to.
That statistic could go both ways though. Can't get divorced if you never get married.
This information is in the Census data releases. You can test your hypothesis. Do share if you find anything interesting.
My guess is that a large part of it is social. In STEM you don't have to be as personable to succeed. I'm perfectly capable of bringing a face, but even though I'm an extrovert god damn is it exhausting. Thankfully, working in stem I don't have to, so I don't, and I save my energy for non-work socialization.
If you find it exhausting you're probably not an extrovert (extrovert/introvert is just about how much energy social stuff takes you, it has nothing to do with how much you socialize, how good you are at it, or how much you like it)
I mean what I said: I find it exhausting to bring a face. When I'm interacting with people in a more organic setting I gain energy. -- definitely an extrovert. My primary non-work activity is highly social (social dance).
STEM make more money, and more money is associated with happiness.
But you probably wanted something more conclusive.
But you probably wanted something more conclusive.
X correlates with Y & Y correlates with Z doesn't imply X correlates with Z.
Also money generally doesn't correlate with happiness past a certain very basic point.
Pretty sure there was recent research which says the opposite: people always have more appetite for money, just that the amount of money required is nonlinear with respect to wealth.
Rich people still get happy when they make money, and sad when they lose it.
It's kind of crazy to think otherwise.
Rich people still get happy when they make money, and sad when they lose it.
It's kind of crazy to think otherwise.
This was a widely shared and delightfully counterintuitive idea, but it’s not right. The first source that comes to mind is Dan Luu’s summary, but it’s been widely reported (though sadly hasn’t spread as wide as the original claim) https://danluu.com/dunning-kruger/.
Im not sure im totally convinced (based on that article, i didn't read the citations)
- that graph cuts off at a pretty low annual salary (200k). That's certainly a comfortable lifestyle, but that's still within the realm of what normal people on the high end of a good job make. Maybe the happiness cut off is further into the aristocracy
- even if the increase in happiness is logrithmic in the amount of money, and that contunues. Logs grow slowly, maybe at some point it effectively doesn't matter.
- that graph cuts off at a pretty low annual salary (200k). That's certainly a comfortable lifestyle, but that's still within the realm of what normal people on the high end of a good job make. Maybe the happiness cut off is further into the aristocracy
- even if the increase in happiness is logrithmic in the amount of money, and that contunues. Logs grow slowly, maybe at some point it effectively doesn't matter.
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Give me some so I can test that theory ;)
> If you have some cluster of traits that don't hurt you, then imho they're just traits, not a disorder
Even more relevant is that some things could be cliff disorders, where it is actually beneficial till it actually falls over some point.
Like Icarus flying, but takes him too close to the sun.
Being obsessive about details making things or being paranoid about what you eat are probably great things to start with, but overrides its own utility at some point.
Even more relevant is that some things could be cliff disorders, where it is actually beneficial till it actually falls over some point.
Like Icarus flying, but takes him too close to the sun.
Being obsessive about details making things or being paranoid about what you eat are probably great things to start with, but overrides its own utility at some point.
These traits are typically in clusters. You may have an amazing brain trait that accelerates your success and also have a sensory processing disorder which creates great discomfort.
The cliff question would seem to be a very personal question. Where does that cliff exist? What traits create a cliff? ( not really looking for answer )
I have two autists in my house. For them autism has created some substantial struggles when dealing with the world in general. However, their ( what I call super powers ) have allowed them great success in their given fields ( cs and research ).
Both see the world substantially different than their mom and I do. Their view is often, simple and more forgiving.
Autists have and continue to make great contributions to the neural typical world. My hope is that we are not on a road to eliminate these individuals from our world.[0]
[0]https://www.appliedbehavioranalysisprograms.com/historys-30-...
The cliff question would seem to be a very personal question. Where does that cliff exist? What traits create a cliff? ( not really looking for answer )
I have two autists in my house. For them autism has created some substantial struggles when dealing with the world in general. However, their ( what I call super powers ) have allowed them great success in their given fields ( cs and research ).
Both see the world substantially different than their mom and I do. Their view is often, simple and more forgiving.
Autists have and continue to make great contributions to the neural typical world. My hope is that we are not on a road to eliminate these individuals from our world.[0]
[0]https://www.appliedbehavioranalysisprograms.com/historys-30-...
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This is such a good point.
For example, there’s fastidious, which is a great to have in at least some members of a team, or to be able to draw on as a skill or trait for oneself; and then there’s the same taken to an extreme which manifests as disorders such as OCD, hoarding, etc.
For example, there’s fastidious, which is a great to have in at least some members of a team, or to be able to draw on as a skill or trait for oneself; and then there’s the same taken to an extreme which manifests as disorders such as OCD, hoarding, etc.
Is it contentious? I thought it was pretty accepted. Pretty obvious too, even just looking at the people I know.
It hasn't really been studied or formalized in any way (at least that I know of). But I'm confident that it will be found to be the case if/when it is studied.
Yeah this is what I meant. I think that 'taboo' is also a big part of it. I think there are many high functioning autistic people that really don't want the label/perception, but also seem to be burning themselves out by constantly masking (to maybe little benefit). Seems like they could be happier if they accepted who they were
You say statistic. Is there a document regarding this?
https://journals.plos.org/plosone/article?id=10.1371/journal...
Autism Quotient (AQ) scores are generally accepted as a measure of Broad Autism Phenotype (BAP), which is subclinical ASD. That study produces the (entirely expected) conclusion that BAP is more common in men than women, and more common in STEM occupations than non-STEM occupations.
I'm not aware of any studies linking software engineering specifically to BAP, as opposed to STEM occupations in general. I think the evidence on that point is (thus far) based on anecdote and clinical experience.
Autism Quotient (AQ) scores are generally accepted as a measure of Broad Autism Phenotype (BAP), which is subclinical ASD. That study produces the (entirely expected) conclusion that BAP is more common in men than women, and more common in STEM occupations than non-STEM occupations.
I'm not aware of any studies linking software engineering specifically to BAP, as opposed to STEM occupations in general. I think the evidence on that point is (thus far) based on anecdote and clinical experience.
Also, ASD is massively underdiagnosed in girls and women for various reasons to do with societal expectations and a generally accepted better ability to mask autistic traits.
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> Autism spectrum disorder (ASD) has increased over tenfold over the past several decades
That should be "Diagnosis of ASD has increased tenfold..." because of a heap of factors including the medical criteria of diagnosis changing, a historical underdiagnosis of autism in girls and women, and improved public knowledge of the condition leading to more assessments and diagnoses.
EDIT:
Towards the end, it says
> The frequency of autism in the population has dramatically increased over tenfold the past several decades. This increase appears to be due in part to increased diagnosis efficiency from 1975 to the early 2000s, as well as greater public awareness of the disease [3]. The more recent increase in the last couple of decades suggests environmental factors, and exposures also have a critical role in autism prevalence.
That should be "Diagnosis of ASD has increased tenfold..." because of a heap of factors including the medical criteria of diagnosis changing, a historical underdiagnosis of autism in girls and women, and improved public knowledge of the condition leading to more assessments and diagnoses.
EDIT:
Towards the end, it says
> The frequency of autism in the population has dramatically increased over tenfold the past several decades. This increase appears to be due in part to increased diagnosis efficiency from 1975 to the early 2000s, as well as greater public awareness of the disease [3]. The more recent increase in the last couple of decades suggests environmental factors, and exposures also have a critical role in autism prevalence.
So are you saying our ability to detect it has not actually improved in the past several decades?
I'm saying an increase in diagnoses recently is in large part due to a historical underdiagnosis rather than an increasing frequency of children born with ASD. However, the paper hints at environmental factors being responsible for a proportion of the increase (but does not cite evidence to prove it).
Paper seems to refer to environment factors and paternal DNA. Is this established or just a hypothesis (the paternal part especially)?
It is kind of sad given the advances in sequencing and state of computing power that we cannot reliably diagnose this stuff with sequencing. I thought the promise of 23andme, and ilk was to gain large amounts of data and make progress on these problems (NIPT seems like a success though).
It is kind of sad given the advances in sequencing and state of computing power that we cannot reliably diagnose this stuff with sequencing. I thought the promise of 23andme, and ilk was to gain large amounts of data and make progress on these problems (NIPT seems like a success though).
“One of the control samples, IVI 14, had a very high sperm count of 396.62 million that was outside two standard deviations of the mean (2 ± SD), so the analysis was redone without this sample.”
Yeah having chuck norris in your study is going to skew any set of results.
Yeah having chuck norris in your study is going to skew any set of results.
> Methods and results
> Sperm samples were obtained from fathers that have children with or without autism, and the sperm then assessed for alterations in DNA methylation. A genome-wide analysis (> 90%) for differential DNA methylation regions (DMRs) was used to identify DMRs in the sperm of fathers (n = 13) with autistic children in comparison with those (n = 13) without ASD children. The 805 DMR genomic features such as chromosomal location, CpG density and length of the DMRs were characterized. Genes associated with the DMRs were identified and found to be linked to previously known ASD genes, as well as other neurobiology-related genes. The potential sperm DMR biomarkers/diagnostic was validated with blinded test sets (n = 8–10) of individuals with an approximately 90% accuracy.
This has to be a preliminary study right? I mean n=13...
> Sperm samples were obtained from fathers that have children with or without autism, and the sperm then assessed for alterations in DNA methylation. A genome-wide analysis (> 90%) for differential DNA methylation regions (DMRs) was used to identify DMRs in the sperm of fathers (n = 13) with autistic children in comparison with those (n = 13) without ASD children. The 805 DMR genomic features such as chromosomal location, CpG density and length of the DMRs were characterized. Genes associated with the DMRs were identified and found to be linked to previously known ASD genes, as well as other neurobiology-related genes. The potential sperm DMR biomarkers/diagnostic was validated with blinded test sets (n = 8–10) of individuals with an approximately 90% accuracy.
This has to be a preliminary study right? I mean n=13...
Trying to reconstruct the title
Found a mutation in spermatozoa that can be used as a flag for higher probability of having autistic children. Correct?
Found a mutation in spermatozoa that can be used as a flag for higher probability of having autistic children. Correct?
More like "Found: an epigenetic change in sperm that seems to correlate with genes we know are involved in autism".
Methilation isn't a mutation. It's epigenetics - (potentially) persistent / heritable changes in phenotype (expressed genes) outside of genetic code (DNA).
It's used for many things, e.g. turning on/off specific genes in somatic cells, repairing DNA (when DNA is copied, the old strand is methilated; so you know how to fix any differences between old and new strand), and more recently, for measuring aging (Horvath epigenetic clock).
It's used for many things, e.g. turning on/off specific genes in somatic cells, repairing DNA (when DNA is copied, the old strand is methilated; so you know how to fix any differences between old and new strand), and more recently, for measuring aging (Horvath epigenetic clock).
We can substitute a mutation as a synonym for modification here then. It doesn't matter and would be still more clear.
We could say that the string of letters is not modified but the letters in the DNA string are "in cursive" now, so when we read the text we understand a different thing.
We could say that the string of letters is not modified but the letters in the DNA string are "in cursive" now, so when we read the text we understand a different thing.
Does anyone know of a similar study but involving mothers instead of fathers?
I haven't found one specifically on autism. Most of the mothers' risk in offspring seems to be gestational factors during brain development stages, and later on impacts on milk.
This gets close "Epigenetics in Families: Covariance between Mother and Child Methylation Patterns" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913850/
This gets close "Epigenetics in Families: Covariance between Mother and Child Methylation Patterns" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913850/
It's a lot more destructive to harvest eggs than sperm.
Fertility clinics harvest eggs from women every day. Some of those eggs could be donated for research.
Example: Clinics harvests 12 eggs from a layd, 1 egg needed for IVF, IVF is succesful (baby born), lady is now happy to donate the remaining 11 eggs to science.
Example: Clinics harvests 12 eggs from a layd, 1 egg needed for IVF, IVF is succesful (baby born), lady is now happy to donate the remaining 11 eggs to science.
Some nitpicks:
* IVF involves retrieval and then fertilization of eggs. There’s not usually leftover unfertilized eggs unless the woman is banking her eggs.
* The success rates my partner and I have been quoted mean that we want to keep as many embryos as possible in case we need to try again. I think it would be really unethical to ask a woman to give up any good eggs or euploid embryos as they can be hard to get in some cases.
The shots a woman has to give herself daily to stimulate follicle production are no joke. That would be a lot to put someone through purely for research. It’s not as simple as that. And it’s wishful thinking to expect any woman to do that.
The shots a woman has to give herself daily to stimulate follicle production are no joke. That would be a lot to put someone through purely for research. It’s not as simple as that. And it’s wishful thinking to expect any woman to do that.
Full title: Sperm DNA methylation epimutation biomarker for paternal offspring autism susceptibility
ASD is widely acknowledged to be a highly heterogeneous condition which is likely to have multiple independent causes, and which has unclear boundaries with other diagnoses (especially ADHD)
So a study which effectively treats ASD as a single undifferentiated condition, and has rather small sample sizes too, I think should be treated with a great deal of scepticism.