Oct 04 2010

ADHD and Genetics

A new study published in the Lancet purports to show a potential genetic link to ADHD (Attention Deficit Hyperactivity Disorder). While the genetic link found in this study has been somewhat overhyped in the media, the results are interesting.

The main problem with media reporting is that they tend to oversimplify the concept of a genetic disorder. The worst offenders speak of “the gene” for whatever is being discussed, like ADHD. There are purely genetic disorders that are the result of a mutation in a single gene, but more often diseases and disorders that have a genetic component are the complex result of multiple genes and their interaction with the environment. Therefore there is no single gene for ADHD, autism, migraines, obesity or other complex condition.

Saying that there is a “genetic link” to a disorder is more reasonable, but always must be put into context. What this study shows is an increased risk of copy number variants (CNVs) in people with a confirmed diagnosis of ADHD. A CNV is either a deletion or duplication of genetic material. The researchers found that 78 out of 1047 control had such CNVs (7%), while 57 out of 366 subjects with ADHD did (15%). This was a statistically significant increase. Further, CNV were more likely to occur on genes previous associated with both autism and schizophrenia (and therefore likely to be involved in brain development).

The authors conclude:

“Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct.”

That conclusion needs to be parsed very carefully – they are saying that this study is evidence that ADHD is not purely social. They are not saying that it is purely or even mostly genetic. In fact, only 15% of subjects with ADHD demonstrated increased CNVs. This study is a proof of concept more than anything, demonstrating that genetic makeup can contribute, at least in some cases, to the clinical syndrome of ADHD.

This makes sense in light of our understanding of similar neurological disorders. Many such disorders are defined clinically by a collection signs and symptoms, which in turn relate to some particular function or functions of the brain. However, there are likely to be many underlying causes (from a neuro-anatomical point of view) of such altered function. In other words, there may be many underlying alterations of brain function that lead to the final common pathway that results in the recognized signs and symptoms. Many neurological syndromes are defined by that final common pathway, not the underlying disorder that led to it.

And so complex syndromes like ADHD, autism, and schizophrenia are likely many underlying disorders all with a similar clinical manifestation that we recognize and name. It is helpful to understand what the nature of the clinical manifestation is, specifically with respect to whether it is mostly a construct of environment or an effect of brain development and hard-wiring.

This study supports the plausibility that ADHD can be a problem of brain development, genetically determined. The fact that only 15% of subjects showed the genetic changes the researchers were looking for does not mean that the other 85% have no genetic link – they could have other genetic changes that this study was not designed to detect.

Previous studies have also shown genetic alterations in some subjects with ADHD (for example). Researchers are also beginning to identify genetic subtypes that may respond better to certain medications.

We are still a long way from understanding the relevant genetics, but it is reasonable to say that genetic research into ADHD has been fruitful and is likely to continue to bear fruit. But the picture that is emerging (as with many other disorders) is that of a complex relationship among many genes and interaction with the environment. This makes it complex to talk about what “causes” ADHD (which itself is likely not a single discrete entity). This further means that accurately reporting about ADHD research requires some nuance and care – something which seems to be on the wane in science journalism.

19 responses so far

19 Responses to “ADHD and Genetics”

  1. HHCon 04 Oct 2010 at 11:29 am

    Is there an established link between gestational problems during the 266 days and increased likelihood of CNVs?

  2. Watcheron 04 Oct 2010 at 1:06 pm

    Hmm. Good question, probably not though. Would it be ethical to observe a mother in a poor state and compare it to a control woman?

  3. daedalus2uon 04 Oct 2010 at 1:23 pm

    Virtually all CNVs are thought to be de novo, and they occur during cell division. Probably they occur either during gamete formation or during very early division following fertilization.

    Maternal health during pregnancy might go both ways, it might increase survival of a fetus with CNVs, or it might decrease it by improving normal quality control mechanisms, i.e. spontaneous abortion.

    Parental health prior to fertilization might also have effects both ways.

  4. Calli Arcaleon 04 Oct 2010 at 2:02 pm

    Interesting thoughts on survival of a fetus with copy-number variations. What you mentioned, dadalus2u, about spontaneous abortions makes me wonder if one could look for increased rate of stillbirth/miscarriage in families with ADHD-diagnosed members?

  5. rhacodactyluson 04 Oct 2010 at 4:01 pm

    If nothing else, this is a great posting to throw in a family member’s face, who doesn’t believe in ADHD “kids are just hyper, parents just don’t know how to raise them.”

    Thanks Steve,

    ~Rhaco

  6. hgkelleyon 04 Oct 2010 at 4:12 pm

    ***Anecdotal evidence alert***
    I am surprised there is still doubt about ADHD having a genetic component. My mom taught EH elementary school students for many years. (All of the kids were on medication for their diagnosed hyperactivity.) There were approximately 10 new students each year (not counting those who returned to the multiyear classroom) and she taught 13 years, so the “sample size” is approximately 100 students. Among those students, there were two commonly shared attributes: the medicine (a form of speed, as I understand) calmed them down, rather than made them more excitable; and their fathers also exhibited signs of being hyperactive. Nearly all the students were boys, but I cannot say whether that is because hyperactivity is more linked to male chromosomes, or whether girls are just better able to mask the symptoms.

  7. daedalus2uon 04 Oct 2010 at 6:07 pm

    Calli, I think it is too complicated and not enough is known about what causes CNVs or how CNVs have effects. It isn’t even clear that CNVs are present in all cells. Usually they look at blood cells, but blood cells have divided a lot more times than brain cells. Testing for CNVs is destructive, so you can’t do biopsies of essential organs like the brain.

    Females are mosaic, with one X chromosome being inactivated pretty much, pretty much at random. Females with a deletion of the MeCP2 gene on one X chromosome have Retts Syndrome (males have one X chromosome and deletion of MeCP2 on it is lethal). The presence of MeCP2 in some cells rescues cells that don’t have it somehow. How that happens is not understood.

    I have a hypothesis as to how and why CNVs do cause a broad range of neurodevelopmental disorders that I am in the process of writing up.

  8. Draalon 04 Oct 2010 at 9:47 pm

    Sequencing of genomes is increasingly becoming inexpensive and faster. Just imagine when, say, 1,000 or 10,000 people have their genomes sequenced. It would really put to test these hypothesized links between disorders, diseases, behavior, cancers or whatever with genetics. At $31,000 a pop, a 1000 would cost $31 million, well within the capabilities of the NIH. Throw in a super computer and BAM! You could test for correlations to your hearts content.

  9. daedalus2uon 04 Oct 2010 at 10:12 pm

    Draal, and they will find nothing.

    The genome and how it results in development is so complicated that a mere 1,000 or 10,000 examples are insufficient to sample even a tiny fraction of its complexity.

    Here is a nice study where they looked at whole genome scan of 4683 individuals from 1558 families with a million plus SNP whole genome scan.

    http://hmg.oxfordjournals.org/content/19/20/4072.full

    What did they find?

    “Our findings appear to rule out a common allele increasing relative risk by 2-fold or more. Much larger samples will be required to detect subtle effects on relative risk (e.g. 1.2), which is more typical of risk loci for common diseases.”

  10. Draalon 05 Oct 2010 at 12:09 am

    Perhaps daedulus2u. Interesting paper and brings up some good points. However, I’d still like to see 1000 entire genomes sequenced. The assay they used in that study only looked at the alleles using just under 1,000,000 SNPs. That’s 1,000,000 nucleotides out of 3.4 billion base pairs in the human genome.

  11. micheleinmichiganon 05 Oct 2010 at 9:51 am

    “It is helpful to understand what the nature of the clinical manifestation is, specifically with respect to whether it is mostly a construct of environment or an effect of brain development and hard-wiring.”

    Great article. I enjoyed the gray scale approach.

    I wonder, if time allows, what would be some examples of “construct of environment” I’m not sure if I’m understanding the phrase.

    The example that occurred to me was the increased risk of ADHD in children that were born low birth weight or premature. But perhaps that’s more of a correlation than causation risk.

    Or was the use of “construct” meant to suggest more the expectation of parents or schools in desired performance.

    Or?

  12. theshortearedowlon 05 Oct 2010 at 1:58 pm

    @hgkelley

    “and their fathers also exhibited signs of being hyperactive.”

    Unfortunately, that could be evidence of an environmental link as much as a genetic one; is it being raised in an environment with one or more ADHD adults, or inheriting ADHD genes that does it? (Of course both probably contribute.)

  13. ccbowerson 05 Oct 2010 at 7:13 pm

    “Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct”

    I find this statement meaningless. Who said that ADHD is “purely a social construct?”

  14. hippiehunteron 05 Oct 2010 at 7:43 pm

    I have seen far more ADHD amongst the children of single mothers who live caravan parks than any other group.
    Perhaps its something in the aluminium ?

  15. micheleinmichiganon 05 Oct 2010 at 8:42 pm

    # hippiehunteron 05 Oct 2010 at 7:43 pm
    I have seen far more ADHD amongst the children of single mothers who live caravan parks than any other group.

    Yes, many diagnoses are more apparent in our own neighborhoods. But I would guess if you moved out of the trailer park, you’d might see an equal number of kids with ADHD. Although it’s possible that they are getting better treatment from upscale docs and better supports in a higher mileage school district.

  16. ccbowerson 06 Oct 2010 at 10:08 am

    @micheleinmichigan

    Funniest comment I’ve seen in a long time.

  17. Calli Arcaleon 06 Oct 2010 at 12:17 pm

    hippiehunter — I used to work for a company that financed mobile homes. Contrary to the typical stereotype, they are not actually made of aluminum sheet metal. This is because aluminum is too expensive. If you can afford an aluminum mobile home, you can afford a HOUSE, and who’d get a mobile home that’ll be worthless in twenty years (assuming it even survives that long) when you could get an actual house on actual land that you actually own for the same money?

    Mobile homes are typically wood-frame construction, just like a regular house, but with a few unique traits. They are all long and narrow (or are built as two long and narrow pieces which must then be bolted together onsite), so they can fit down a road. They all have a steel trailer frame on the bottom (usually concealed with skirting after installation), which may or may not include wheels and axles (depending on customer and local zoning requirements — if wheels and axles are not retained, the customer typically pays a fee to rent them from the dealer).

    Siding was once usually aluminum, but nowadays it tends to be vinyl, a trend also seen in more conventional housing.

    Aluminum, of course, isn’t likely to be the source. However, I wouldn’t be too surprised if ADHD were more apparent among trailer communities, though probably less diagnosed than among the wealthy. There are threeo factors I can see. One: poorer communities are less likely to be able to afford psychiatric care for their children, so it is far less likely to be formally diagnosed and also far less likely to be actually treated. Thus, even given the same ADHD rate, you’d see it more because it would be less controlled. Two: though mileage varies widely, poorer communities present certain challenges for their children which affluent communities do not. It tends to be a much more stressful life, and the parents are more likely to need to work multiple jobs in order to make ends meet, or the poverty can be the result of a parent who is irresponsible or entirely absent (for any of many possible reasons), giving the child less assistance from the parents. Stress tends to aggravate ADHD symptoms, so even given the same incidence rate and even if all the children studied were untreated, the poorer ones would probably display more symptoms than the wealthy ones. Third: ADHD really is a disability. Though in nearly all cases, it is possible to learn to manage it and become a productive adult, the fact that it is possible does not make it certain. Consequently, ADHD sufferers, on average, will tend to earn less and be less successful than normal folks. This could lead to more ADHD sufferers becoming impoverished and requiring the low-cost shelter offered by a mobile home. Since ADHD is known to run in families, it may be reasonable to expect more ADHD children to be born into poverty than wealth for this reason. However, I would very much hope that this effect is weak, if it exists at all.

  18. Calli Arcaleon 06 Oct 2010 at 12:35 pm

    Addendum: I should point out that while I suspect the incidence rate of ADHD is the same among both rich and poor, it is certain that the actual numbers are quite different. Very few ADHD sufferers are wealthy. This is not because of ADHD itself; it is because very few people, period, are wealthy.

    For perspective, I’ve seen numbers from 1% to 7% for the actual rate of ADHD diagnosis among the population. Meanwhile, only 1.93% of US households in 2006 had an income above $250,000 (according to Wikipedia, which gets the data from US census data).

  19. Stuon 04 Apr 2011 at 12:09 am

    @ Calli, ADHD people also tend to have an inaccurate self-perception, which might explain the less successful population, even though many that have it are extremely creative and intelligent. Adding to your thoughts about the poverty stricken: the diets of the poor are usually made up of synthetic sugary fillers and poor quality anything else. I would infer that while this diet doesn’t “make” someone have ADHD, it certainly might aggravate it. Parents working long hours at low wages means more TV time for kids. TV’s not bad, but a constantly changing picture enjoyed with 3-4 Pepsi’s might also aggravate it.

    Are their cases of people who have never had the symptoms and suddenly, through somatic mutation, “get” it?

    I get frustrated at the last D in ADHD: Disorder. It’s only a disorder because it complicates society’s desire of “order”.

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