27 Genetic Variants Linked to ADHD | Hacker News Reader

27 Genetic Variants Linked to ADHD

neurosciencenews.com

62 pointsbookofjoe80 comments

Browsing ClinVar for ADHD-related variants shows that most of the correlations are very weak. That is to say, you can have several of these variants and your chances of having ADHD are only marginally increased. There is no “ADHD gene”. Contrary to what this headline might imply, genetics aren’t diagnostic for ADHD.

This is the challenge with communicating genetic testing results: People frequently get their test results, go searching for a specific condition like ADHD, find a couple variants linked to ADHD, and assume it’s proof that they have ADHD.

The truth is that when there are 27 variants linked to ADHD, chances are very good that everyone who goes looking will have at least one of these variants. That does not mean they have ADHD, though.

The article also buries this seemingly important point that the variants studied were also heavily correlated with psychiatric disorders in general:

> Bivariate Gaussian mixture modeling estimated that 84–98% of ADHD-influencing variants are shared with other psychiatric disorders.

When the correlation approaches 98% I’m confused as to why they chose ADHD as the headline instead of psychiatric conditions in general? I suspect they know that ADHD headlines are trending right now while psychiatric conditions and depressive disorders haven’t been normalized in the same way in social media and pop culture in 2023.

I also find this "gene for X" idea troubling. Suppose there are genetic factors that drive increased susceptibility to an environmental factor, for example. Biology is a complex interaction not easily reduced to single-step causal narrative.

I suppose it’s a consequence of cheap DNA sequencing flooding the market. Especially without any “genetic counseling” or other services to help them draw realistic conclusions about their data, it’s only natural that most would have a poor mental model for the nuances of genetic expression.

My mom has adhd. I have it. My kids have. My sister has it. Her kids have it. Her grandkids.

I’m talking full blow ADHD. Actual diagnosis

And we could say "oh this spate of cancer victims in this area must all be genetically related" until we find major chemical spills poisoned the ground water. Correlation is not causation.

Oh yes, but this particular mutation has been discovered at least 100,000 years ago and has been shown in anthropology throughout most societies. It is relatively new in this post-industrial hellscape that we pathologize and punish it.

Not only is this my experience as well, it represents the massive heritability of it and other disorders. Some studies have shown neurodivergence in 80% of offspring with 2 neurodivergent parents. Another amazing study recently revealed that neurodivergent friendships and romantic partners are 11X more likely to be with a fellow neurodivergent vs neurotypical person. It is theorized it comes down to patterns of behavior and communication- “she gets me like nobody else”.

"Another amazing study recently revealed that neurodivergent friendships and romantic partners"

Neurodivergent, as far as I know, is not a medical term.

Did this study use that term?

"Neurodivergent" is an umbrella term which describes a cluster of neurological disabilities with similar associated traits and experiences. See below:

"Neurodiversity" embraces and celebrates these traits as valuable in the right context.

These are the diagnosis's and related traits that tend to cluster (50-80% cooccurrence in many!)

ADHD Autism Spectrum Disorder ADHD Anxiety Bipolar Creativity Depression Diet Dyslexia Dysgraphia EDS (wobbly joints) Executive Dysfunction Gender expression Giftedness Gastrointestinal issues Insomnia OCD Pattern Recognition PTSD Sensory Processing Disorders Social Communication Disorder Tourette's & Tic Disorders

However diagnostic criteria and practice is weak and varied, and has been based on a mental model where its a physical difference in rear brain mass and shape. This article highlights the complexity:

https://www.planetneurodivergent.com/is-comorbid-specific-en...

Neurodivergence in context:

https://eric.ed.gov/?id=EJ1308646

Older metanalysis of comorbidities:

https://www.sciencedirect.com/science/article/abs/pii/S17509...

The research is coming hot and heavy with new brain scans, DNA, and physical diagnosis rather than mental. We will see a new diagnosis class within the next 5 years. Females, "normalish"-passing, and limited health access have only recently started to influence the data. We're in the midst of a revolution around how this is understood, and an emerging community of people that never could connect before because of social difficulties. Heady times, friends.

Okay but you wrote "Another amazing study recently revealed that neurodivergent friendships and romantic partners are 11X more likely..."

My question was is this a study of neurodivergent people or autistic people or something else? These terms are not interchangable.

There are autosomal dominate conditions that have a comorbidity of ADHD. hEDS for example. The genetic cause for hEDS hasn’t been discovered but there are candidate genes. Clearly given the higher likelihood of having ADHD with hEDS the hEDS genes should show up in ADHD genetic surveys. But diagnosis for ADHD and hEDS are very noisy so it’s still hard to find.

Right, and I frankly don’t see that improving much sooner without cheaper and more objective diagnostic methods. UW eye dilation diagnosis is one example of a bright spot that could help affordably and reliably diagnose. The current diagnostic system is flawed and biased around unequal access to care.

My hope is the increasing availability of WGS data allows for citizen scientists to work around the institutions. hEDS being a good example, the HEDGE study has too strict of entry requirements and thus misses the much more common but less severe types of hEDS. This is possibly by design as maintaining a rare disease classification helps with funding. They also work crazy slow for seemingly no reason besides the obvious that more time means more funding.

Recently some more advanced machine learning techniques have been ported for use in DNA population studies so I’m hopeful that’ll improve research quality.

The title of the original Nature Genetics paper does the same thing:

>Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

> The truth is that when there are 27 variants linked to ADHD, chances are very good that everyone who goes looking will have at least one of these variants. That does not mean they have ADHD, though.

Yes! And vice versa. Lacking one of these variants doesn't mean you don't have ADHD.

It's refreshing to see more information identifying ADHD beyond the behaviors and traits shown on the surface. I've always felt my brain is incapable of doing things a NT can do effortlessly and it's hard to live in a world that thinks "everyone has a little ADHD. You just need to try to focus more."

I was diagnosed with ADHD as a kid and as an adult it makes me feel angry because we slap a label on kids, and now even adults so we can have something to point the finger at rather than acknowledge that people are stimulated by different things.

> so we can have something to point the finger at rather than acknowledge that people are stimulated by different things.

So what do you do for people like me who without medication can't even do things we want to do or have an interest in, no matter how hard we try? It's not always as simple as being stimulated by different things.

Call it ADHD or not, in extreme cases it can be absolutely debilitating for people and it's not simply because they're lazy, or not trying.

I'm not saying ADHD doesn't exist or that there are not people who need medication to assist them.

I just believe that its so overly diagnosed these days. It's similar to depression. It's very common to just throw drugs at the problem when some people don't need drugs, they need a lifestyle change, sometimes that means using drugs to begin with as a bridge to a lifestyle change.

But we are in this weird state where people go to a doctor and its like "oh you sneezed? here take these 15 drugs" "how do you feel, on can't focus, must be ADHD, take this" "oh you feel down, must be depression, take these 6 drugs"

Sometimes I feel like we treat a problem before we diagnose the problem.

Less feelings, more data.

Since you were diagnosed as a child you may not be aware, but getting a diagnosis for ADHD is not nearly as simple as you describe and doctors are not just throwing meds at you. If anything, you'll first be labeled a drug-seeker.

> But we are in this weird state where people go to a doctor and its like "oh you sneezed? here take these 15 drugs"

Many people say this, but where's the evidence? Probably the best quality article to date in support of overdiagnosis and overtreatment is [1], and that paper is incredibly weak. It does not give any concrete numbers as to the rate of overdiagnosis, only really claims that there are populations of less severe ADHD that have inferior reward/risk outcomes of pharmacotreatment, while also admitting ADHD is underdiagnosed and undertreated in subpopulations, especially girls and minorities.

In other words, it's likely all just misdiagnosis, due to limited sensitivity and specificity.

My hypothesis is that ADHD detection, like any medical test, has limits to its accuracy, and considering even quantitative tests with 90% accuracy have quite large false positive populations, we are seeing a similar situation with the far more qualitative ADHD test system.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042533/#!po=9....

It's not that simple to get diagnosed and the drugs are not the first thing that will be tried. I'm sure there are some overprescribing doctors out there, but on the other hand it took me months to get a diagnosis+prescription and required changing who I'm seeing. And that's even before you go on the "let's figure out the correct dosage" ride that takes time, effort, and bad days. It's not your average vitamins.

On the other hand comments like that are among things that contributed to me not getting diagnosed for years, so consider what are the confirmed facts when talking about medical treatments, ok?

It could be more frequently diagnosed, but also under-diagnosed at the same time. More diagnosis are due to more awareness, but there isn't data to prove it's been overly diagnosed in people who don't have it.

I was of this mind at one point. I didn’t take ADHD medication through my teens or early 20s. It wasn’t until I got married and had a kid that I found myself struggling to provide for my family in a very real way that I saw a psychiatrist and started Adderall.

I’ve tried a few times over the years to stop, and each time my career has taken a tail spin. I go from being a top performer when taking a small amount of Adderall to having difficulties doing the most basic work tasks because they’re boring.

I can acknowledge all I want that I’m stimulated by different things, but without a diagnosis to give a professional an idea of the symptoms I face, I wouldn’t be a successful or happy member of society.

Before my diagnosis and treatment I was EXTREMELY depressed and anxious all the time. The diagnosis has been literally life changing in the best way possible.

Same here. I got okay grades in school, and I even managed a few semesters in college with excellent grades (comp sci major), but that was with the help of self medicating with stimulants (illicitly obtained.)

Now that I'm an adult with a diagnosis and proper, legal medication, it has helped immensely. It makes me wonder where I would/could be if I got on the right path earlier in life.

ADHD isn't just "stimulated by different things" though. It's lacking the executive function to maintain that stimulation. Someone with ADHD might be stimulated by a thing and then get bored very soon and move on to another new stimulus.

Hard no. We have decades of research establishing there are distinct differences in the brains of people with ADHD and real kinds of tasks in which they drastically underperform regardless of effort.

It might be nice to think it's really just part of a rainbowy spectrum of everyone is different and koombaya, but it's simply not true.

Similar to another commenter here, I told myself this story until my early thirties and suffered the whole time thinking I was using the ADHD "label" as a crutch.

ADHD and other mental illnesses get this "just a label" treatment because we don't walk around with missing limbs or eyeballs. Most people with ADHD mask their symptoms enough to feign normality. That normality is enough to make them functional while enough to fool others the stray from normal is akin to the occasional distractability of neurotypical brains.

The "everyone is a little ADHD" is particularly annoying because it's basically true but misses the problem. Everyone does get distracted at times. But people with ADHD have it to a much worse degree.

It's like height. Everyone has a height, but if you're 180cm tall you'll find the world caters to you well, but at 250cm you struggle to fit and basic tasks are difficult.

It's not "basically true" though. The whole point of the "disorder" designation is that it interferes with life activities. Everyone has attention deficits at times - that does not a disorder make. Otherwise I agree with the analogy.

Like all English statements, it depends on how you read it.

I read it as, "everyone experiences the symptoms of ADHD to some extent, including those who don't experience symptoms beyond the threshold of a disorder."

The big question is, do you see that fact as a tool for the average person to trivialize or to empathize with the ADHD experience?

Its the same as people saying "I'm a bit OCD". They aren't.

Having both OCD and ADHD I can tell you that people who say they are "a bit OCD" or "a bit ADHD" have never wished they were dead because their executive function is shot and their emotional regulation is so compromised, and that they're fed up of washing their hands until they bleed.

Everyone has some traits of most disorders from time to time. What marks a disorder is that it is constant, unrelenting, pathological and happiness destroying.

> "everyone has a little ADHD. You just need to try to focus more."

Like telling an alcoholic that everyone enjoys drinking, you just need to control yourself.

For reference, these are the established "12 steps" of overcoming alcoholism:

1. We admitted we were powerless over alcohol — that our lives had become unmanageable.

2. Came to believe that a Power greater than ourselves could restore us to sanity.

3. Made a decision to turn our will and our lives over to the care of God as we understood Him.

4. Made a searching and fearless moral inventory of ourselves.

5. Admitted to God, to ourselves, and to another human being the exact nature of our wrongs.

6. Were entirely ready to have God remove all these defects of character.

7. Humbly asked Him to remove our shortcomings.

8. Made a list of all persons we had harmed, and became willing to make amends to them all.

9. Made direct amends to such people wherever possible, except when to do so would injure them or others.

10. Continued to take personal inventory and when we were wrong promptly admitted it.

11. Sought through prayer and meditation to improve our conscious contact with God as we understood Him, praying only for knowledge of His will for us and the power to carry that out.

12. Having had a spiritual awakening as the result of these Steps, we tried to carry this message to alcoholics, and to practice these principles in all our affairs.

This, under some atheist/agnostic worldviews, is roughly equivalent to "you just need to control yourself".

I have friends who work in the recovery field: The “12 steps” are from one program, but they’re not any sort of established treatment protocol.

That program works for some people, doesn’t work for others. It’s not any sort of standard that gets handed out universally by treatment programs, though.

Yes. The parallel being that "you just need to focus more" would work for some people but not others.

First time I took medication for ADHD. It was absolutely shocking to experience focus on something I didn’t find highly interesting. I normally associate boring to being worse than almost all physical pain. Maybe just below when I had a kidney stone.

Having that “pain” taken away was amazing. I can focus better without meds now that I know what it’s like. No where near as with meds. But still a big improvement.

These "12 steps" are established by definition of throwing out anyone that they don't work for. Not exactly a ringing endorsement of a process, all told.

For the record, the 12 steps were established by a group of long-term, hard-core alcoholics who were literally dying from their decades of excessive consumption and still could not stop. "Giving it up to God" helped that specific group.

And now we call every guy who goes on a bender an alcoholic and send them to AA though most people drink less as they get older without any intervention of any kind.

Its also a load of shit.

Same thing with anxiety/panic disorders

> and it's hard to live in a world that thinks "everyone has a little ADHD

Ironically, headlines like this contribute to the idea that “everyone has ADHD”. Once you identify 27 different variants as being linked to ADHD, a lot of people are going to have at least one of those variants. That doesn’t mean they have ADHD, because the correlation to any singular variant is insignificant. But a lot of people are going to find one or two or three of these variants and assume, wrongly, that it means they have ADHD.

The more variants that are “linked to” a condition, the more people will have at least one of those variants and get confused. When you have as many as 27 variants linked, it could be the case that virtually everyone has at least one of those variants, depending on how common they are.

These aren’t diagnostic for ADHD in any way. They’re more of loose correlational hints for further research.

Can somebody who knows statistics explain something for me?

They report (https://www.nature.com/articles/s41588-022-01285-8/tables/1, https://doi.org/10.1038/s41588-022-01285-8) e.g. the C allele of rs114142727 to have an OR of 1.285, yet they also report the frequency of said allele to be similar in the case and control group (both ~0.988). Is this a rounding issue (i.e. frequency in the case group must always be higher to report an OR>1) and the frequency is only slightly higher in the case group and the OR becomes so large simply because of the large sampling size? (40K case, 200K controls)

When they report 1.285 OR with a standard error of 0.04 at N=38691, does this roughly translate to a 95% CI of [1.207,1.363]?

I think it's a copy paste error. The minor allele frequency of rs114142727 is around 1%.

The reported frequency is with respect to A1, which in this case appears to be the major allele C. According to https://www.ncbi.nlm.nih.gov/snp/?term=rs114142727, the minor allele is G with MAF (ALFA) ~0.013, this would make C the major allele with frequency of ~0.987 which seem to be in line with the report.

The Nature paper in question: https://doi.org/10.1038/s41588-022-01285-8

Tad frustrating that the SNPs aren't listed; I'd very much like to see how many in question I have.

What are the genetic variants? I can’t access the paper, but I assume if anyone can we’d be able to run our DNA results (from 23andme, etc.) through this to see how high we score.

Unlikely as those services barely scrape the surface of genetic coding, if I recall they only sample from specific regions of the DNA to generate their data.

But I am also likely wrong, so I am hoping someone can challenge/confirm this thought.

Direct to consumer Whole Genome Sequencing is pretty affordable now, I had mine done at 30x coverage for $200 with Dante Labs.

Dante labs is actually a curious case.

People working in this field don't quite get how they could offer such a low price given cost of equipment and reagents.

The $200 is their sales price but it happens frequently enough that it’s not hard to get. The regular price is $600 and they do try to upsell with running disease specific tests against your genome. I thought the current wholesale cost of the genome sequencing was $75. After shipping costs there wouldn’t be much profit out of $200 So it is cutting things pretty lean but AFAIK still should be doable.

The cost of whole genome sequencing claimed by manufacturers is around $200 for the latest Illumina tech and sub 100$ for the latest MGI tech. All this assumes full load on max throughput machines - e.g. enough samples to sequence (otherwise the price invariably goes up).

These are not reference points for the pricing over the last couple years since these products were only announced last/this year respectively. 600$ WGS seems reasonable price for the last couple years in Europe, $200 is not. See this spreadsheet by @AlbertVilella who's a very useful source for his kind of stuff:

https://docs.google.com/spreadsheets/d/1GMMfhyLK0-q8XkIo3Yxl...

There is also Element and Ultima which I don't know much about except that Ultima tech seems to have noticeably higher sequencing error rate.

EDIT: @AlbertVilella corrected

It was actually €200 but at the time I did it the exchange rate was pretty close to 1:1, so a recent exchange rate drop could explain some of the discount. There is an added delay of 6 weeks to the special so I guess if they’re running under max utilization it could make sense to fit these in at above the cost of the reagent. There is also competition from Nebula Genomics so there is a market share and mind-space component to denying a competitor potential customers. I think I read something somewhere about cheaper bootleg reagent being used to get around patents. I think Nebula Genomics was hit by a lawsuit around that. Plus there is the potential outsourcing to less scrupulous countries that may go on to sell access to data. I think there was a rumor that Nebula Genomics was using a Hong Kong lab and later a Russian lab. I’m not worried about my DNA getting out, I already consider my DNA privacy defeated which was confirmed by my ability to find second cousins with it.

Correct, they genotype using a microarray.

https://customercare.23andme.com/hc/en-us/articles/202904600...

A professional psychiatrist once told me “It’s the screens, stupid.” This guy worked in a lot of different places and he noticed urban areas where the kids were always on the iPad and tv had noticeably worse and more cases of ADHD than remote areas he worked. It’s only anecdotal but thought worth sharing.

It makes sense both logically and intuitively, and there's research to back up his claim. The question is what conclusion to draw from it. It's pretty easy to dismiss children who's parents didn't give a shit about enforcing proper screen times at that then subsequently developed an attention deficit by rigorous conditioning as lazy. And it's a convenient avenue for gatekeeping in education.

It just makes sense: if you condition a developing brain to never expect anything other than instant gratification, you obviously have no neural pathways that can deal with a regular workload. There's a reason the chinese government is so harsh in terms of policing kids screentime nationally. Kids show similar symptoms to ADHD after consuming TikTok for a while.

To be clear, I'm not advocating for any archaic educational policies, like not giving your kids a smartphone until they get bullied by their peers for not having one. I'm just pissed that boomers completely missed teaching this generation some media literacy (because they don't know it either) and now act suprised when their kids grow up with this kind of deficit.

Children in front of a screen are essentially alone. It doesn't have to be a surplus in instant gratification but could as well be a deficit in human interaction.

> and there's research to back up his claim

That's a good chance to link it.

> you obviously have no neural pathways that can deal with a regular workload

And that's a really bad description for ADHD where, no, you absolutely do. And it's not about "regular workload".

Correlation is not causation. It's also likely that there was more awareness in urban areas, access to mental healthcare, schools that could look for ADHD synonyms.

Moreover, ADHD was also a thing 30 years ago when there weren't any screens; it just wasn't diagnosed.

There are many people who got diagnosed in adulthood. One of the key diagnostic criteria for adults is: the symptoms should have been present since childhood. Let me tell you this, many adults who got diagnosed late, absolutely had these symptoms as kids and have a lot of secondary psychological conditions due to undiagnosed ADHD.

'What I can't build, I don't understand'.

ADHD and the rest of the DSM will be viewed in the future with the same amount of credibility as we give to the Salem Witch Trials.

If you want some real science, check out Minsky's Society of Mind and Hawkins' 1,000 Brains for starters.

I am shocked at how quick doctors are today to prescribe medicine to treat psychological conditions. They’ve told me “if we don’t give them what they want, they’ll just go somewhere else” how to deal with this conflict of interest? What about other non pharmaceutical ways to treat these conditions, get fresh air, go to the gym, put down the phone, etc etc.

My experience has been that it is difficult to get treatment from primary care because they are hesitant to prescribe stimulants. The amount of times a doctor has treated me as drug seeking, a risk to go sell stimulants on the street, or prescribed me a stern talking that I lack life skills and need to buy a planner is frankly insulting.

I do go out to get fresh air, use my phone for 1-2 hours a day including work Slacks, exercise, meditate etc. Nothing helps like a well dosed stimulant and the drug shortages do not help.

On top of that, the "Adderall shortage" isn't from a lack of supply: it's from the DEA arbitrarily deciding to constrain the amount that drugmakers may legally manufacture; despite a significant increase in diagnosis.

It's all bullshit politics driven by the same thoughtless sentiment we see here.

I don't think you mean to be, but saying these disorders can be fixed with some fresh air and exercise doesn't match with reality.

I have ADHD, exercise and fresh air didn't fix it. I even got rid of my smartphone and home internet connection for 6 months to try to improve my focus. That didn't help either. After years of dead ends, getting a diagnosis and medication is more or less the only thing that has allowed me to hold down a job and live life.

That's a reach. Yes, we don't have biological testing methods for these conditions yet, but that doesn't mean DSM is like "Salem Witch Trials".

> these conditions

You are assuming these are real biological things in an individual, and not normal reactions to flaws in society/environment.

I've spent a decade trying to write in silico brains to simulate some of these conditions. I couldn't figure out how to map the DSM to reality. When I became open to the possibility that the DSM really is a weapon to be used against behaviors some people don't like, things started to make more sense.

You are also assuming these are purely linked to environment/society. Some DSM symptoms are likely based on environment and coping mechanisms developed. I do think that current lifestyle makes ADHD worse, but there hasn't been any research which shows it's purely due to society.

ADHD has been observed across the world in different lifestyles and societies - rich and poor, different parenting styles, now and when computers weren't a thing. It doesn't seem to purely be related to environment/society.

We don't understand a lot about brain, yet to definitively say ADHD is not biological. I don't really know how you mimicked chemical imbalances in silico brain, but just because you couldn't simulate them doesn't prove it's not biological.

As annoying as ADHD /can/ be. I am glad I have it. I do take meds to help “control it” but I also happily forgo them when I don’t need to crunch time focus on something.

There’s a lot of pros to it and most of the negatives that people run into are because the NTs have designed this world for a few certain “ types” of people and personalities and make everything else hard as fuck because it’s “wrong”.

Annoys the piss out of me.

Anyways, haven’t actually read the article yet. Just wanted to put that out there lol

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