Schizophrenia, Bipolar, Autism, Depression disorders share genes

February 9, 2018 12:01 PM

Second breakthrough in two years for humankind's commonest mental illnesses. Published in Science today, Gandal et al. show correlations in gene expression between Schizophrenia and three other major mental illnesses: 70% for Bipolar disorder, 45% for Autism spectrum disorder and 30% for Major Depressive disorder. This research comes exactly two years after Sekar et al. published an in-depth discovery that a known gene from the immune system was over expressed in the brains of Schizophrenics. 'Complement Component C4' gene flags connections between neurons for destruction in a late-adolescent process that called "synaptic pruning" and which is devastatingly overactive in Schizophrenia (previously). In the years ahead will these two findings merge into a scientific picture that our brains are profoundly shaped by our immune systems in late childhood?
posted by dongolier (29 comments total)

Interesting stuff. Possible new diagnostic tools and the possibility of a gene therapy?
posted by Samizdata at 12:08 PM on February 9, 2018 [1 favorite]

It would probably hinge on early detection and treatment - gene screening kids for mental illness and issuing therapy, how futuristic.
posted by Punkey at 12:29 PM on February 9, 2018 [1 favorite]

Can someone weigh in (who is better educated than me) on how PTSD and these disorders collide/combine/occur simultaneously?
posted by lextex at 12:35 PM on February 9, 2018 [3 favorites]

Not trying to be a party pooper, but it's worth noting that past research shows that very many gene associations with mental disorders (especially the variety examined in the Gandal et al. paper, i.e., single-nucleotide polymorphisms) tend not to be replicated by higher powered follow up studies, and so these results should be considered preliminary and suggestive until further research supports the findings.

NB: I am not a geneticist, but I am a clinical psychology researcher. The linked paper is about genetic findings for depression in particular.
posted by mister-o at 12:36 PM on February 9, 2018 [38 favorites]

lextex: The risk factors for developing Schizophrenia in some cases are surprisingly mild, we think of many of them as common experiences for a resilient person. Social defeat, cannabis use, nutrition, smoking, IQ, social cognition....these are the so-called 'second hits' that fall short of what we usually think of as trauma. The 'first hit' is a family history/genetic progeny.

Its very reasonable to infer that people with this gene(s) should never be in a combat setting, or serve as air traffic controllers or any stressful environment, they are the very definition of 'vulnerable' just based on their genes. It also worth pointing out that in identical twins where one has Schizophrenia, only half the time does the other twin. So childhood and young adulthood just has to run smoothly for children born into families with these histories. There's real positive evidence for immediate intervention upon the first episode of psychosis.
posted by dongolier at 1:08 PM on February 9, 2018 [10 favorites]

mister-o: The Gandal et al. paper studies gene expression in people with mental illness diagnoses (also alcoholism and irritable bowel syndrome!). They are studying the transcriptome which is not the same as the genome or SNP studies. They used 700 cortical samples (presumably from human cadavers).
posted by dongolier at 1:18 PM on February 9, 2018 [2 favorites]

For what it's worth, we have known in principle that there is a shared genetic link between these mental illnesses (and others) for awhile (but these are new developments, of course)—e.g. the Psychiatric Genomics Consortium has been around since 2007. I think the primary problem is not identifying that a relationship exists but pairing down which genes are related and how—the last I read, some 10,000 genes were collectively "responsible" for bipolar disorder, depression, and schizophrenia.
posted by koavf at 1:37 PM on February 9, 2018 [4 favorites]

So, does anyone (who is a reputable researcher) think that this sort of immune/autoimmune problem has any relation to other autoimmune diseases which seem to be more prevalent in western cultures? Could the rising prevalence of schizophrenia also be related to lack of parasite exposure as some have suggested for certain autoimmune responses? I have a at best a pop-sci understanding of genetics and biology, so please be gentle if I have asked profoundly stupid questions.
posted by runcibleshaw at 1:45 PM on February 9, 2018 [2 favorites]

I can't wait til they start doing deeper research on how environmental variables influence these epigenetic alterations over generations giving rise to what we call "genetic" illnesses that are reactions to environmental variables that family members have been dealing across generations.

And I can't wait for us to start being accountable for the overwhelming evidence that the majority of causes of mental illness are environmental variables that we have the power to prevent rather than focusing on the small influence of genetics in order to allow us to focus purely on the after effects and to promote the pharmaceutical market as the only possible way to view creating mental wellnes.
posted by xarnop at 2:06 PM on February 9, 2018 [13 favorites]

koavf: Its only very few genes that are responsible for these diseases...Schizophrenia being related to C4 was a late finding because (apparently) of the complexity of the genome responsibly for the recognizing 'flags' of typically foreign pathogens (the multi-histocompatibility complex)...they needed to build an advanced statistical model to account for variations that would still transcribe to a bland variant (for the two closely related genes: C4A has two, C4B has two). Here's a good paper which lists all the known neuropsychiatric genes...most don't cause mental illness but physical illness....but just in the brain. I took a look at the linked Excel spreadsheet, he's got 532 neuropsychiatric genes in total: Schizophrenia susceptibility is from 32 of them (because the internets deserve to know! DISC1, RGS4, SCZD9, DISC2, EPN4, EPNR, KIAA0171, SCZD1, TAAR6, TRAR4, SCZD5, DTNBP1, HPS7, SCZD6, SCZD11, DAO, DAMOX, HTR2A, SCZD7, G72, AKT1, CHRNA7, SCZD10, SCZD8, RTN4R, NOGOR, COMT, PRODH, PRODH2, SCZD4, APOL2, APOL4). But variations in these genes may not be very common. For a very common illness you would want to find a common gene variant responsible, which C4 is...but the list is from 2011. Bipolar susceptibility has two genes, Autism susceptibility has what looks like a couple dozen....


,
posted by dongolier at 2:15 PM on February 9, 2018

lextex: The risk factors for developing Schizophrenia in some cases are surprisingly mild, we think of many of them as common experiences for a resilient person. Social defeat, cannabis use, nutrition, smoking, IQ, social cognition....these are the so-called 'second hits' that fall short of what we usually think of as trauma. The 'first hit' is a family history/genetic progeny.

Yep, two factors I remember from a talk given by a guy who was sorta-ish in my research group were; "born in winter" and "emigrated to another country" which off the top of my head had the same 1-5% correlation as many of the ones you mentioned. A lot of them sound like definite stress factors, but yeah, it's complicated.
posted by kersplunk at 2:19 PM on February 9, 2018 [2 favorites]

A few years ago I read about some research that correlated bipolar disorder/schizophrenia with fever in late pregnancy, and then some later research that specifically called out influenza. I wonder if there's a connection or if any of that research has been continued. (I have treatment-resistant bipolar disorder and my mother had a fever so high while she was pregnant with me that she was hospitalized and given ice baths, so the research caught my attention due to confirmation bias.)

Like others here, I've also read that relatively minor stress/trauma can trigger schizophrenic episodes. I'm acquainted with a guy whose son watched the planes hit the WTC center and proceeded to have his first psychotic break within a few days. Now he's fully schizophrenic, avoiding meds and self-medicating with cannabis, nicotine, and alcohol. I wish that the early intervention mentioned by dangolier had been a factor for this guy; I had no idea that any progress had been made in this area.
posted by xyzzy at 2:46 PM on February 9, 2018 [2 favorites]

koavf: the last I read, some 10,000 genes were collectively "responsible" for bipolar disorder, depression, and schizophrenia.

That's about half of all genes, which makes me suspect that whoever came up with that number wasn't trying very hard to narrow it down.
posted by clawsoon at 3:23 PM on February 9, 2018

xarnop: And I can't wait for us to start being accountable for the overwhelming evidence that the majority of causes of mental illness are environmental variables that we have the power to prevent rather than focusing on the small influence of genetics in order to allow us to focus purely on the after effects and to promote the pharmaceutical market as the only possible way to view creating mental wellness.

This reminds me of research on the SERT gene which found that the allele which leads to higher rates of depression after a traumatic childhood also leads to greater happiness than average after a positive childhood.

Siddhartha Mukherjee discusses schizophrenia and genetics in The Gene: An Intimate History. Google Books has a preview that's worth a read.
posted by clawsoon at 3:39 PM on February 9, 2018 [7 favorites]

I was going to mention that in the tiny bit of press that followed Sekar et al. (Nature Feb 2016), Siddhartha Mukherjee wrote a fascinating piece for the New Yorker.
posted by dongolier at 4:14 PM on February 9, 2018 [2 favorites]

Its very reasonable to infer that people with this gene(s) should never be in a combat setting, or serve as air traffic controllers or any stressful environment, they are the very definition of 'vulnerable' just based on their genes.

As an autistic person with mental illness, I find this kind of paternalism chilling. "Your genes are bad, therefore we will not allow you to do [this], [that], or [the other thing]" is very problematic. It's not saying "give people the best information possible about their genetics and let them make what they perceive to be the best choice", it's saying "don't let people with these genetics do these things".

I've found that people seem to get prickly when one points out that this kind of thinking is awfully close to eugenics, as long as nobody has gone so far as to actually call for sterilizing people against their will. I still think it quacks like a duck.
posted by Lexica at 4:44 PM on February 9, 2018 [32 favorites]

Lexica: Here is a really tasteful account of a bipolar woman's final months after being released from hospital. The New Yorker article leaves open the question of the rights of mental health patients vis-a-vis what everyone else, including their loved ones, think is in their best interest. Im with you though in that I think about the worst thing you can do to someone is take away their freedom, to use the broadest possible sense of the word...even their freedom to live without pharmacological intervention within a delusion that feels real.
posted by dongolier at 5:01 PM on February 9, 2018 [3 favorites]

Lexica: As an autistic person with mental illness, I find this kind of paternalism chilling. "Your genes are bad, therefore we will not allow you to do [this], [that], or [the other thing]" is very problematic. It's not saying "give people the best information possible about their genetics and let them make what they perceive to be the best choice", it's saying "don't let people with these genetics do these things".

There's a similar-ish debate around insulin-dependent diabetics being commercial pilots. We're allowed to do it in Canada, but it took decades of fighting for it, and you have to demonstrate that you've been able to keep your blood sugar levels stable for months at a time. In the U.S., I believe that insulin-dependent diabetics still can't become commercial pilots, though they're allowed to become private pilots if they demonstrate a similar level of blood sugar control.

I can see the sense in the rules. When my blood sugar goes low, I'm not in a state to be trying to land a 747. But if I'm able to demonstrate that I can reliably prevent my blood sugar from going low, then my medical condition is no longer a factor preventing me from reliably performing the job.
posted by clawsoon at 5:10 PM on February 9, 2018 [1 favorite]

(One thing that changed the debate about insulin-dependent diabetics being pilots was portable blood glucose meters, since they replaced subjective and often faulty guessing about one's blood sugar levels with an objective measurement. I've had Type I diabetes for 20 years, but there are still times when I don't feel low blood sugar coming on, or think that it's coming on when it isn't. The blood glucose meter removes doubt and tells me exactly what I need to do: Medicate, or sugarize. We don't yet have anything similar for mental health disorders, which makes any comparisons a little weaker.)
posted by clawsoon at 5:17 PM on February 9, 2018

As someone who has been a specialist in autism for over thirty years, there is a new genetic finding about autism every week now. Sometimes the findings contradict each other and as noted above, the findings aren't often replicated. When I do training in Autism 101, I list over 90 supposed causes of autism. None of which have been proven to be definitive.

Autism is complex disorder and becomes more complex the more you know. There has long been thought that there may be different types of what we classify as autism and that different types may have different causes. Kids who are identified as autistic at 18 months are very different from the person with Aspergers who is identified at age eight.

Also, autism is a PSYCHIATRIC diagnosis, not a medical diagnosis. Prior to May of 2013 there were five types of autism, then the American Psychiatric Society decided there was only one type of autism, with three different levels. In 2012, Rhett's syndrome was an autism spectrum disorder and now it's not. That kind of "science" makes it hard for some of us to believe that there is one single genetic cause for ALL types of autism.
posted by ITravelMontana at 5:33 PM on February 9, 2018 [16 favorites]

Its very reasonable to infer that people with this gene(s) should never be in a combat setting...

Throughout history famous military commanders often had complex personalities and intense mood swings. Emotional intensity is the valor in our soldiers, until they come home with PTSD. But soon our wars will all be fought by robots.
posted by ovvl at 9:08 PM on February 9, 2018 [2 favorites]

fyi autism is not actually a mental illness
posted by frantumaglia at 10:34 PM on February 9, 2018 [11 favorites]

Its very reasonable to infer that people with this gene(s) should never be in a combat setting, or serve as air traffic controllers or any stressful environment, they are the very definition of 'vulnerable' just based on their genes.

Yep, that's some Gattaca shit.
posted by inexorably_forward at 3:19 AM on February 10, 2018

The whole field of genetic research is often used to define us vs them and to give power over a group of people supposedly labelled "mentally ill" for functioning differently or having different needs. I find it highly suspect at it's entire ideological base and very money and power driven. There are entire fields of research that could help us better meet human developmental needs without othering and labeling people or genes as "mentally ill" and other.

The entire idea of chasing a bad gene to eliminate or modify instead of chasing all the known environmental variables that cause poor outcomes in humans- the very idea we should label people who react badly to poor variables as the factor to change instead of the factors themselves- is very suspect.
posted by xarnop at 7:37 AM on February 10, 2018

Mod note: A couple comments deleted. xarnop, you've made your point that's relevant to this thread, and we've talked to you before about not bringing every thread around to be about your own situation.
posted by LobsterMitten (staff) at 8:03 AM on February 10, 2018 [3 favorites]

Meta-analyses of transcriptomes are really, really, really hard (I should know, it's my third chapter) and batch effects are rampant. To the point that if you sequence samples from two different species on one lane of a flow cell, they'll look more like each other than samples from their own species sequenced on another flow cell. And we've only really recently begun to respect how much of a big deal this can be in your data output. They say they've rigorously normalized, though. So, I'm going to sift through this pretty carefully (because I need their methods yo) but I'm only very tentatively accepting these results.
posted by Made of Star Stuff at 10:46 AM on February 10, 2018 [6 favorites]

yessssssss, these people are my new favorite people for putting ALL of their scripts up on Github!
posted by Made of Star Stuff at 10:55 AM on February 10, 2018 [2 favorites]

The other thing is that the transcriptome is highly plastic and can change a lot in a very short amount of time (minutes, in some circumstances), which makes cadaver samples kind of problematic. It's a real pity there's no way of monitoring transcriptomes that's non-destructive. Not saying this invalidates their results, just that time since death could be an important source of batch effects and to some extent you can't really know what exactly the alive state was, not that there even necessarily was only one alive state for that cell type. Haven't read it yet so I'd be curious to see how they dealt with this.
posted by en forme de poire at 11:13 AM on February 11, 2018 [4 favorites]

And yeah, batch effects are tough. Using ComBat scares me a little since that kind of two-step process (find and adjust for noise covariates, then fit the model) can lead to anticonservative p-values in some cases. They're also making comparisons across microarray platforms, which is tough even when you have controls to compare against, and it looks like there's some fairly aggressive outlier removal going on, which troubles me because of the potential for overfitting. On the plus side, while the "modules" lingo is very mid-00s Broad (lol), looking for groups of functionally-related genes changing together is probably more robust than looking for individual genes, though there's always the risk of unmeasured covariates driving those differences (like the proportion of cell types varying).

Still, this is based on a skim of the paper, not an in-depth analysis, and it's so hard to do anything of this sort of work in humans that I'm still impressed. I'd be curious to get the real hard core stats take on this work from someone like Gelman.
posted by en forme de poire at 7:24 PM on February 11, 2018 [1 favorite]