Psychiatry: End of the Road for “Endophenotypes”?

By Neuroskeptic | December 4, 2014 3:39 pm

An important new study could undermine the concept of ‘endophenotypes’ – and thus derail one of the most promising lines of research in neuroscience and psychiatry.

The findings are out now in Psychophysiology. Unusually, an entire special issue of the journal is devoted to presenting the various results of the study, along with commentary, but here’s the summary paper: Knowns and unknowns for psychophysiological endophenotypes by Minnesota researchers William Iacono, Uma Vaidyanathan, Scott Vrieze and Stephen Malone.

In a nutshell, the researchers ran seven different genetic studies to try to find the genetic basis of a total of seventeen neurobehavioural traits, also known as ‘endophenotypes’. Endophenotypes are a hot topic in psychiatric neuroscience, although the concept is somewhat vague.

The motivation behind interest in endophenotypes comes mainly from the failure of recent studies to pin down the genetic cause of most psychiatric syndromes:


Essentially an endophenotype is some trait, which could be almost anything, which is supposed to be related to (or part of) a psychiatric disorder or symptom, but which is “closer to genetics” or “more biological” than the disorder itself. Rather than thousands of genes all mixed together to determine the risk of a psychiatric disorder, each endophenotype might be controlled by only a handful of genes – which would thus be easier to find.


Endophenotypes therefore offer researchers a “bridge” between biology and psychiatry. That’s the theory, anyway. But despite lots of talk, that theory has never really been tested – until now.

To try to link endophenotypes to genes, the Minnesota team performed a genome-wide association study (GWAS) analyzing the DNA of 4,900 subjects who underwent neurobehavioural testing, including EEG. That’s a moderate sample size by GWAS standards, but it’s absolutely gargantuan in neuroscience and psychology terms. I can’t think of another EEG study, genetic or otherwise, that had even 500 subjects, let alone nearly 5,000. This study is big.

The results were equally striking – but mainly by their absence. This table summarizes all of the genetic findings for each of the seventeen ‘endophenotypes’. Each column represents a different genetic ‘search strategy’. The key thing to notice are the dashes, each one of which represents a null result.


A dash means that no genetic variants were statistically significantly associated with the trait in question. Over 89% of the searches came up null in this way; for eight of the seventeen traits, the researchers found no associated genes using any strategy.

For the other nine traits, there were a handful of ‘hits’, however many of these raise more questions than they answer, i.e. they occur in genes that are not known to be involved in brain function. There were absolutely no hits in the set of candidate genes chosen because previous research suggested that they ought to be involved. This doesn’t mean that genetics has no influence on these traits, but it implies that the influence of any given genetic variant is tiny.

Iacono et al. conclude by saying that

Endophenotypes Will Not Simplify Gene-Finding for Psychiatric Disorder

The promise of endophenotypes has been oversold. Even if endophenotypes are conceptually simpler than DSM (Diagnostic and Statistical Manual of Mental Disorders) diagnoses and closer to underlying biology, endophenotype genetics are not sufficiently simpler genetically to aid in gene discovery in a sample the size of the Minnesota Twin Family Study. Consequently, the same challenges that make psychiatric genetics difficult are likely to make endophenotype genetics difficult.

In my opinion, these results ought to prompt a fundamental rethink not just of endophenotypes but also of an idea that lurks in the background of an awful lot of neuroscience. This is the idea that some brain phenomena are more “basic” than others.

One of the endophenotypes in the Minnesota study, for example, was brain alpha wave frequency as measured with EEG. Is alpha frequency “more basic” than, say, personality, or susceptibility to depression? To many people, it seems like it is. Alpha frequency is a measurable electrical phenomenon. It seems like “hard science” as opposed to personality which is “soft”. But does that mean that it is simpler?

After all, both alpha waves and personality are emergent properties of the whole human brain. Is it really a surprise, then, that alpha frequency turns out to be genetically complex? Or should we stop trying to divide the brain’s functions into “physical” and “mental”, “basic” and “complex” ones?

Maybe, but that’s idealistic thinking. In the real world, psychiatry has a lot of money, and a lot of hope, invested in the idea of endophenotypes. In Part II of this post, I’ll look at what the Minnesota results mean for the future of psychiatric research.

ResearchBlogging.orgIacono WG, Vaidyanathan U, Vrieze SI, & Malone SM (2014). Knowns and unknowns for psychophysiological endophenotypes: Integration and response to commentaries. Psychophysiology, 51 (12), 1339-1347 PMID: 25387720

  • Lynsey Hall

    What about the fact that psychiatric diagnosis is a binary classification (case, control) of a quantitative trait (genetic liability to psychiatric disorder)? A lot of explanatory power is lost by testing binary traits, therefore identifying quantitative traits which have a strong genetic correlation with the psychiatric disorder of interest may provide more statistical power to detect associated genetic variants, regardless of the “complexity” of the quantitative traits.

    • liam crapper

      I think that’s part of the hope of endophenotypes, they provide more of a range. I think all of what they tested here is continuous (at least what’s in that table) but they still didn’t find associations.

      Admittedly, trying to look for particular genes introduces a similar problem on the other end.

      • Neuroskeptic

        Right. Endophenotypes are continuous, which is one supposed advantage. Another is that they’re “directly measurable” as opposed to only being measurable with “soft” questionnaires and rating scales… although in fact there is a good deal of subjectivity in how you measure most of them!

        • Lynsey Hall

          It is not a supposed advantage, it is a statistical advantage. I take your point about 5000 being big for an imaging study, but you aren’t going to find anything in a genetic study of that size if you are looking for common variants with small effect sizes in psychiatric disorders which are notoriously heterogeneous and extensively polygenic in architecture. Schizophrenia only really started getting results once the sample was up to 50,000.

          The problem with the rating scales is that you are lumping everyone into one category as sharing the same illness, when most likely each psychiatric disorder is a collection of related illnesses unified by common symptoms. Stratification is the way forward, and if identifying endophenotypes can help with that, then I don’t think we should give up on the concept just yet.

          • waltinseattle

            not fluent in research analysis, but “related illnesses unified by common symptoms” certainly rings my “agree” bell. many of us comparing notes on family experience are getting more and more irritated with the whole concept of “behavioral medicine.” its seemms as if a simple chart lookup. as if : symptom a, drug 1. symptom b?, no, no drug. symptom c?….
            which is treating symptoms not causes. any failures are attributed not to diagnosis, but just not the “right drug combo” yet there seem to be a few common series of re-diagnoses from childhood to adulthood. maybe the presenting observables at any one time are not the same thing as the progressive illness. maybe categorizing at the beginning is just noise in the end? a moving expression that is searched by static means. noise out! null finding.
            then too, perhaps the wrong physiological measures are being used. have these not come to be trusted for ease of measurement? alpha rate? startle response? are they not of philosophical/theoretical significance rather than experimentally , “agnostically” (no prior beliefs or expectations) encountered measures? that is perhaps to say “these are not the beans you are looking to count”

    • vijay

      I don’t know how many researchers will agree with me on this, but I don’t know if seeing everything in terms of continuous traits isn’t part of the problem

      The trouble is that as we measure continuous traits, we’re losing sight of the illness, or that’s what it seems like. I know the effects of this on clinical care more than on research, but what generally happens is that research informs clinicians that there’s no real difference on a quantitative trait, when comparing between groups; thereafter, this trait is ditched, and gradually psychiatry moves away from the illness.

      What it does at the end of the day is create a situation where the phenotype itself is being lost, so that in the interest of having statistical power, the thing that is being correlated with the gene has less and less relevance. the case for this process is best exemplified by bipolarity where everyone with something that resembles an affective disturbance is now on the bipolar ‘spectrum’. it’s awful for psychiatric practice, in my opinion, but it might be equally the problem for research. I really don’t know.

      The line I liked most about this blog post was the idea of the emergent. psychiatric illnesses could well be the result of emergent processes in the brain, but in that case there are obvious constraints on this process, because the illnesses that are seen in practise do, quite often, resemble the archetypal (categorical) diagnosis. this is much more often true for some illnesses than others. schizophrenia is a case in point, and it’s a finding as old as the international pilot study. endophenotypes might be seen as the basis for those constraints.

      • Lynsey Hall

        But if you are selecting an endophenotype on the basis of the criteria laid out by Gottesman and Gould (heritable in themselves, genetically and phenotypically correlated with the disorder, state independent, found in cases and unaffected relatives at a higher rate than in the general population) then you shouldn’t really be losing sight of the original trait. The caveat with psychiatry is that until recently the supposed main purpose of endophenotypes was that they would be “simpler” in genetic architecture, this has been proven to not be the case. However, just because these traits are not less complex doesn’t necessarily mean they are less tractable that the disorder itself.
        Also, having insufficient statistical power wastes money, time and hinders progress, as anything your study comes out with is most likely a false positive and sending people down blind alleys (as many candidate gene studies which then fail to replicate testify). In my mind this is more damaging to the progress of psychiatric research (and ultimately impeding the end goal of trying to identify improved treatment outcomes) than trying to find different methods of tapping into what is going on at the genetic level of these disorders.

        • vijay

          agreed. what I was trying to say is that the phenotype is simultaneously drifting away from any reasonable considerations, because of possibly different effects of the continuous-trait idea. without redefining the phenotypes more clearly, i think you might be seeking reliable, but essentially invalid traits for the illness. not that you won’t find traits.

          • Lynsey Hall

            Re: continuous trait idea. If you imagine schizophrenia in terms of height. The amount of variance and explanatory power you lose by thinking of height as small vs tall. You lose all of the variance between tall and very tall, small and very small, average height etc. This is essentially what we are doing by taking psychiatric disorders and going you’re a case, you’re a control. That is a phenomenal loss of information. I think you have hit the nail on the head with your point regarding the redefinition of phenotypes, and this is where a lot of effort is going just now with efforts to reduce heterogeneity through stratification of the disorders into subtypes.

          • vijay

            your analogy isn’t quite how i see it. you’re looking at marfan’s let’s say, and studying height. there is the archetypal marfan, who is preternaturally tall. but how tall, you don’t know. so you study height continuously, and marfanoid traits continuously. until the point where you study short people with one marfanoid traits, and try to extend that to the syndrome. at some point, that breaks down, but you’re so committed to the idea that this is the right way to go that you then hypothesise that marfan’s was an artificial construct anyway. and so on and so forth.

            and when i say redefine phenotypes, I mean the observable, as complex as it might be. that doesn’t seem the direction of RDoC–that seems more like an uninihibited embrace of the measurable continuous indirect trait. and the overall trend in psychiatry seems to be to jettison subtyping, as I see it.

          • Lynsey Hall

            In which case, the argument is never get too committed to an idea. Accept that any method and analysis has its limitations, be aware of what these are, do what you can to improve on said limitations.

        • Frank Lekstutis

          Gottesman’s main thing is just to say that everyone is wrong about everything. He’s a tiresome pain in the rear. He adds nothing to the discussion and helps no one.

          • Frank Lekstutis

            Is this your birthday?

  • Uncle Al

    If two or more variables are confounded, they can only be separated by working on them simultaneously (Theory of Experimentation). As usual, psychology-psychiatry have proven nothing. In “One Flew Over the Cuckoo’s Nest” (1975), the East Indian psychiatrist is a perfect depiction of profession(al dereliction): “Saepe errans, numquam dubitans”.

    A perfect experiment is telling two separated psychiatrists that the other is a nutcase who thinks he is a psychiatrist. Then…interface! Reality is much more abusive and obscene than that,

    • feloniousgrammar

      I’ve been acquainted with psychiatrists who I respect and like; but the field appears to me to be composed primarily of MDs who have learned to a large degree to completely ignore all diseases that cause psychiatric symptoms other than the diseases their field created. Anemia can be easily and often identified as “depression”, as can fatigue. A blow to the head can change a person’s personality so profoundly that it can turn a normal and attached person into a sociopath. Psychiatric labels should be a last resort, and should be tentative as should treatment plans.

      Oh, the big boys in the industry dismiss this as the whining of people who hate psychiatry for no real reason, but they need to have a look at what kind of treatment people who can’t afford to pay cash get from psychiatrists who can’t afford to subscribe to journals or further their education and take most of their cues from marketing and committees composed of people who are on the take with Pharma and for-profit hospital and clinic administrators with no training in medicine, but lots of training in raising profits at the expense of medical professionals, insurance companies, and patients.

      I’m becoming more and more convinced that we could do away with this specialization entirely, and make a whole lot more progress in solving the problems of mental/emotional/neurological and X kinds of disturbances that people suffer and how to resolve them with social scientists and counselors who listen, plus making allowances for long stays for people who need time to pull themselves together and helping them get the social assistance they need to stabilize.

      Fifteen minutes with a psychiatrist can easily lead to a decade or more of unnecessary and harmful drugging for a temporary problem, no really compelling problem, or a problem that would have resolved itself in a few months. And the person can be given a label that will follow them everywhere and do them no favors for the rest of their life.

      The obsession with and oversimplification of genetics, combined with a general neglect of environmental and social influences on mood and mindset might explain why psychiatrists have a suicide rate four times higher than the general population in the U.S.

      They’re doing it wrong.

      Sure, a lot of mental illness is very real, problematic on many levels, and disruptive, but so are a lot of other things that confound and harm persons and groups of persons. Genetics should be the last place to look, especially since genetic studies of the heredity of mental illnesses as defined by psychiatric taxonomies has historically been rife with fraud, confirmation bias, and a touch of eugenics.

      This manic drive to find biological causes for categories in psychiatric taxonomies has been happening since the field was first established— always around the corner and always they just need better tools and technology. The fact that these diseases can’t be identified with autopsy should have always been a big clue, and should be a bigger one now.

      Anyone who believes that 1 out of 4 or 1 out of 5 humans suffers from a genetically based mental illness needs to have their head checked.

  • menriquez

    totally not surprised at the results of this excellent study.

    i’ve been convinced for years that PD’s are caused by what-people-consider-trivial incidents in very early childhood that perhaps no one even recognizes at the time as trauma, much less deep trauma, and the results of this study almost guarantee that this has to be the correct hypothesis.

    if there is no nature component, it must be nurture.

  • Bernard Carroll

    Ever since Gottesman and Shields suggested the concept of
    endophenotype it has been enthusiastically adopted but not always with full
    understanding. In particular, enthusiasts tend to gloss over the requirement
    for a demonstrated genetic association (hopefully simpler than for the clinical
    phenotype) and the requirement for state-independence. Sometimes there even is
    a disconnect between a proposed endophenotype and the clinical facts. An
    example is the subtle impairment of reward mechanisms in at-risk relatives of
    depressed patients and in recovered depressives. These impairments can be shown
    in neurocognitive testing sessions but they don’t rise to a clinically obvious level.
    It’s then an issue of semantics whether to call those findings a potential
    endophenotype or rather simply to call them prodromal and residual features of
    reward disturbance. There also tends to be confusion or equivocation between
    the concept of a biomarker and that of an endophenotype.

    • Neuroskeptic

      Very true. In my second post I’ll be looking at how “endophenotypes” have often merged with “biomarkers” and how the resulting, vague concept has been sold as the future of psychiatry.

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  • Jespersen

    Fascinating stuff.

    Question: Is this yet another case of the ‘missing heritability problem’? As far as I can tell from the abstracts, it’s more or less established that the endophenotype candidates are at least partially heritable on their own (as evidenced from twins studies), or is this part controversial as well?

    (e.g. Mind Hacks recently drew attention to the enigmatic fact that congenital blindness prevents later development of schizophrenia, presumably due to visual pathways being involved in the latter… so there are instances where ‘environmental’ factors, or at least ones not immediately linked to the disorder in question, may affect development of mental disorders)

    • Neuroskeptic

      Yes – as you mention, this study also estimated heritability (because it was a twin study as well as a GWAS) and they found that most of the endophenotypes were moderately or strongly heritable.

      However, the heritability of the traits did not correlate with the number of GWAS ‘hits’ found for those traits.

      Overall, the ‘endophenotypes’ have a missing heritability problem just like other ‘complex traits’ (psychiatric disorders etc.)

    • DietrichB

      First, those like Dr.Jay Joseph, author of The Missing Gene and The Gene Illusion, and many others have debunked the psychiatry “twin studies” because they ignored many environmental and other factors along with many other “errors.” Thus, there is no replication of their claims of bipolar and schizophrenia genes as is well known despite the constant lies to the public that these fake labels are “genetic.”
      Also, the claim that people with congenital blindness cannot be given a bogus DSM stigma like schizophrenia or any of the 300+ voted in labels to push the latest lethal drugs and other brain damaging “treatments” like ECT on patent is false. Dr. Thomas Insel, Head of NIMH, has finally admitted that DSM labels are fables in that they are totally invalid and lacking any science or evidence or what anyone doing the least amount of research has known for decades.
      The real major gene experts have admitted that very few illnesses, social status, emotional distress, poverty and human suffering in general now stigmatized by psychiatry’s DSM and other human characteristics are gene related while most are caused by environmental/relationship factors, home, work, school, community abuse, mobbing and bullying, which the scientific community and psychiatry wish to cover up by blaming the victims of growing inequality, environmental hazards, pollution, toxic food, toxic drugs, inadequate pay, dangerous health care and inadequate housing/schools for a growing majority or the 99% the 1% continues to rob and prey on at the same time.
      It’s sad that psychiatry continues to push the same deadly eugenics “theories” they used to justify sterilizing and then gassing to death those they stigmatized as “mentally ill” in the 1930’s that led to them moving their apparatus to the concentration camps to administer the further eugenics ethnic cleansings of the Jews in Nazi Germany and in more recent ethnic cleansings in our times. Hitler gave psychiatry much credit for these eugenics theories in his Mein Kampf BEFORE he came to power though he is often blamed for the Holocaust while psychiatry deserves all the credit since they were gassing their victims to death before Hitler came to power as well and hid it from him when he tried to stop it due to complaints by Catholics. Psychiatrists continued the gassing even after Germany lost the war and the allies were preparing for the Nuremburg Trials. Those presiding over those trials said that without psychiatry, the Holocaust would probably never have happened. Many articles have been coming out recently including the NYTon the old eugenics office to remind us of the horrors that can result from such theories. But, those theories are alive and well under such names as genetics, biomarkers, endophenotypes, faulty brain circuits and on and on for the same purposes.
      Another reason for pursuing this known fraudulent and very harmful approach to most human suffering is that the biopsychiatry/Big Pharma cartel has made billions for themselves with corrupt politicians. However, due to exposure of so much corruption in this old boy network and billions in fines for Big Pharma not to mention their sullied reputation thanks to associating with biopsychiatry, Big Pharma has mostly abandoned psychiatry though they continue to sell their current useless poisons. The NIMH and biopsychiatry are eager to get the drying psychiatric drug and other “treatment” pipelines going again at the usual horrific cost to their targets as long as they can keep the billions rolling in for the psychiatric industry and their government enablers.
      Again, this ongoing pursuit of eugenics started by the robber barrons like Rockefeller to justify their theft of so much wealth with unfair practices due to their supposed superior genes as wealthy, powerful whites continues unabated by the latest global robber barons and their enablers in psychiatry and other industries.
      I do give Neuroskeptic much credit for debunking the poor studies and never ending claims of genetic or other bad brain theories promoted by psychiatry. However, I think it would be better to look at the big picture and the ethics of the ongoing eugenics agenda by psychiatry, the government and the psychopathic global rulers served by it as much now as in the past to blame the victims of their crimes against humanity.
      I think the work of Dr. Robert Hare, world authority on psychopaths and consultant to the FBI, and author of Snakes in Suits and Without Conscience, is more applicable here. Very interesting that psychiatry all but ignores psychopathy and narcissism that harms so many people while there are now tons of books and web sites to help the growing number of their targets who have been greatly harmed by them. Dr. Hare helped start the web site, Aftermath, to help the greatly damaged targets of psychopaths who are totally ignored by psychiatry other than to blame and stigmatize the victims per usual. Another enlightening source is the web site and related book, Political Ponerology, that explain why there is so much global suffering throughout human history despite the good intentions of the majority of people.

      • waltinseattle

        oh my god, another partisan misinterpretation of Dr Insel. i can hardly rise to making reply. i think everyone(else) here is far beyond one gene one trait, one gene “defect” one “disease”. to deny one to one magic genes is far far different than denying genetic involvement. holistics is no longer a foreign, airy fairy concept to scientists. nor non linear outcomes, nor saddle points where convergences may or not go into behavioraly diagnosable conditions, maybe a branching tree of “related” ones.

        • DietrichB

          I have no illusions about Dr. Insel’s motives for admitting voted in DSM stigmas are bogus invalid junk science. The uproar over the absurd DSM 5 along with Big Pharma leaving psychiatry in droves was his inspiration to come up with the new blame the victims faulty brain circuits fraud to bring Big Pharma/Business back to their ongoing eugenics fold to continue to prey on vulnerable people targeted by the psychopaths in power around the globe to make more billions for these intraspecies predators. Insel will continue his evil eugenics agenda as a patsy enabler like most of the mental death profession and especially the KOL’s for the 1% in power to give them ammo to use against the 99% as they continue to destroy the world and kill more people with their lethal agendas for greed, profit, power and sadism. Just as with the case in Nazi Germany with psychiatry catering to the robber barons of that time to justify their world predation on humanity in the guise of science and “eugenics” now just called genetics, but meaning the same thing for the most part. There are some noble scientists working on the very rare cases where genes play a role in disease/illness who deserve much credit. But, the pseudoscientists using genetics as eugenic ideology deserve nothing but contempt for covering up the fact that inequality, racism, sexism, poverty, pollution, toxic junk food, bogus medicine and other poisons cause human suffering and rarely their genes! And major genetics experts have blown the whistle on this despicable eugenics ideology that continues today to enable the psychopathic corporations per the movie and book that Dr. Robert Hare dissects and “diagnoses” along with predatory corporations and people he covers in his books, Snakes in Suits and When Psychopaths Go to Work.

    • Endomantwin

      The death knell for endophenotype strategies is premature IMHO. Although one of the 1972 introducers to the concept is deceased (James Shields), I understand the other is alive, although an octogenarian and still writing (see Google Scholar).
      The latter site shows more than 3,500 citations for the 2003 paper by Gottesman & Gould that reintroduced the construct with suggested criteria. Virtually all are not pessimistic.
      The distinction between biomarkers and endophenotypes is easily explained by the attached schematic figure: all endophenotypes are biomarkers, but not all biomarkers are endophenotypes. Yes heritability is a key criterion.
      The special issue referred to in the intro to this blog was specific to psychophysiology and must be accepted as facts to reckon with. However, there are hundreds of other kinds of candidate endophenotypes from other domains such as neuroimaging, etc. spelled out with references and examples in recent papers by David Glahn, Mark Lenzenweger, Miller & Rockstroh. Further, the concept is endorsed by Insel and Cuthbert as compatible with their RDoC program of research.

      • Neuroskeptic

        Thanks for the comment – I’ll be discussing these issues in my next post!

        Just one point: while the Minnesota study was limited to electrophysiological endophenotypes, I see no reason a priori to expect neuroimaging phenotypes to be any closer to genetics than electrophysiological ones.

        • Endomantwin

          Let us all pause for a minute to remember Pearl Harbor, a “date that will live in infamy”.

          Your implied query is taken up empirically in the 2011 paper by Glahn et al. in Biological Psychiatry dealing with major depressive disorder and using inputs from various domains including imaging, psychological tests, as to rank order the usefulness and research potential of candidate endophenotypes.

          “Results: Top-ranked endophenotypes included the Beck Depression Inventory, bilateral ventral diencephalon volume, and expression

          levels of the RNF123 transcript. To illustrate the utility of endophentypes in this context, each of these traits were utlized along with disease

          status in bivariate linkage analysis. A genome-wide significant quantitative trait locus was localized on chromsome 4p15 (logarithm of

          odds 3.5) exhibiting pleiotropic effects on both the endophenotype (lymphocyte-derived expression levels of the RNF123 gene) and

          disease risk.”

          Thank you for a stimulating discussion on a topic near to my heart. Extensions of the concept are provided in the extensive research program of David Braff and colleagues, and in the theoretical additions by Kendler & Neale, Flint & Munafo (2014 in Nature commenting on a major effort to find genes for schizophrenia:Nature http://dx.doi.

          org/10.1038/nature13595 (2014).

        • waltinseattle

          but perhaps closer to symptoms! see petrossa above, and my rather rambly even earlier above.

          again, ease of measure, first to be utilized. i will not say dynosaur, just over rated. i prefer functional imaging, maybe its related to my “dynamic” gene….but i prefer process to “things”. many of those Insel abusers are still locked to what can be seen on autopsy! talk of dynosaurs!
          an aside into modern merridian theory. the bon hoc ducts were not found in autopsy. blood system is. the ducts exist only in a dynamic flow system, much like extraneuronally there are salts and proteins , ions in motion, seeking ballance, either dynamic or static ballance. when the spark is turned off, the blood quits flowing but the system remains, whereas the not so constrained extracellulars have no glow snd the aggregated flows disperse. a smoke ring becomes a smoky room. at a higher set levrl, emergent mind exists with subtle traces in gross anatomy but is not explained at that level. ….you can explain baseball at the level of mechanics..ball meets bat physics, or by the rules and regulations. which level describes strategy best? where the ball is thrown, the why its batted at. we are still looking at mechanics striving to divine emergent, darwinian strategies

    • waltinseattle

      “presumably involved” screams hubris level of self certainty. what if they are related merely by some as yet unnamed lack/excess of network formation/prunning enzymes? ie the blindness has no “later effect” but is a separate effect of a common cause, and merely observable earlier.

  • Skeletor Farnsworth

    Honestly, this should be expected of an organ that has been put together piece-meal, through trial and error, over hundreds of millions of years of evolution. If we consider that the modern life of a human being is full of a seemingly infinite number of atypical events, most of which our brains were not designed to process, then we can’t expect the micro world of our neural network to fully map the macro world of our everyday experiences. That is to say, expecting to find a gene or set of genes that phenotypically results, specifically, in agoraphobia is almost as futile as looking for a gene that results specifically in preferrence of Coke over Pepsi. There are simply too many moving parts and, most importantly, the structure of our neural processes are built atop such primordial foundations, that the underlying mechanisms behind our more complex neural processes are a tangled web of slapped together contingency modules. Consider for one second what OCD would mean to a bacteria. Then ponder the fact that we are descended from bacteria. The long chain of evolutionary pressures and selections, over the course of billions of years, has gone from a one-celled organism that doesn’t need to worry about missing its flight to a complex multi-cellular organism, which, at some point in its evolutionary history, became susceptible to panic attacks. Does a bacteria have panic attacks? Good question. But bacteria don’t have brains, so whether they do or do not have panic attacks certainly opens up a lot of questions about psychological disorders in situ.

    • waltinseattle

      bacteria dont set on the same darwinian plateau as great apes. their variations cant reflect ours, not the variance of ours. it has nothing to do with gene quantity. a potato, i understand, has more than we do. its just those “simple” genetic rules give us emergent qualities …some things no potao will ever dream of.

  • liam crapper

    Great post, but I have a couple questions:

    This is very interesting for EEG data, but what about using traits that have had fairly strong genetic associations like impulsivity or aggression?

    Part of the idea is that the underling cause of the syndrome either drives or is otherwise related to the endophenotype, so people with a syndrome may have more homogeneous genetic associations, could the design of the study actually be washing out the effects they’re looking for?

    I was going to ask about biomarkers but I will wait until part 2 for that.

  • Allan V Kalueff

    The approach used by Iacono et al. seems to ignore the possibility that GWAS is insensitive to compex genetics – e.g., genetics behind the potential endophenotypes’ linkage (see for details) – another aspect that may underlie the spectrum nature of brain disorders, in addition to showing the limitations of GWAS analyses

  • James Kohl

    Excerpt: “…should we stop trying to divide the brain’s functions into “physical” and “mental”, “basic” and “complex” ones?”

    I thought serious scientists had already done that by linking feedback
    loops from nutrient-uptake to pheromone-controlled behaviors during the life history transitions of species from microbes to man via conserved molecular mechanisms.

    Has anyone not accepted these facts:
    “The honeybee already serves as a model organism for studying human immunity, disease resistance, allergic reaction, circadian rhythms, antibiotic resistance, the development of the brain and behavior, mental health, longevity, and diseases of the X chromosome (Honeybee Genome Sequencing Consortium, 2006). Included among these different aspects of eusocial species survival are learning and memory, as well as conditioned responses to sensory stimuli (Maleszka, 2008; Menzel, 1983).” — Kohl (2012)

    Nutrient-dependent RNA-directed DNA methylation and RNA mediated events link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man via amino acids substitutions that differentiate cell types. See for review: Kohl (2013)

    That fact links everything currently known about nutrigenomics and
    pharmacogenomics to evidence-based personalized medicine based on a 10,000 patient study that linked metabolic networks to gene networks.

    What were researchers expecting to learn about psychophysiological
    endophenotypes without linking metabolic networks to genetic networks via epigenetically-effected RNA-mediated events that differentiate all cell types in all tissues of all organs of all human organ systems via the gene-cell-tissue-organ-organ system pathway, which starts with epigenetically-effected gene activation?

  • petrossa

    This doesn’t work because it’s bass ackwards. It’s trying to find the root system of a tree by tracing all the leaves. The mere assumption psychiatric constructs of ‘disorders’ are correct makes this an exercise in futility.
    Work the other way around…. Take genetic tracers and see what comes out at the other end. Then build a proper DSM from that that actually represents reality.

    • waltinseattle


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  • Frank Lekstutis

    The study is highly flawed. So no wonder it got a lot of dashes in the results. The study just isn’t structured properly. And the whole concept of endophenotypes is problematic. Unfortunately people like ‘Mad In America’ will use this study simply to further discredit psychiatry and biological models(their especial pet disorder being schizophrenia), which have nothing to do with this study, and which this study does not disprove.

    • Neuroskeptic

      What is highly flawed about this study?

      I agree that axe-grinders will misinterpret this study but that doesn’t mean the study itself is bad.

  • stmccrea

    A lot of this genetic research seems misdirected to me. For one thing, the DSM disorders are constructed from almost purely social variables, regarding things that we as a culture find difficult or disturbing. Why would they necessarily all have the same or similar genetic underpinnings? Sure, there may be “vulnerabilities,” but so far, research has suggested that such vulnerabilities, if they are in fact genetic in origin, only come into play under certain kinds of psychological or physiological stress, like child abuse or substance ab use, and that many with the same vulnerabilities would not become “ill,” as the term “vulnerability” suggests. Additionally, the assumptions underlying much of this research ignore the “hardware/software” dilemma, by which I mean that there may be nothing whatsoever wrong with the brain (hardware), but the training received (software) has resulted in chronic miscalculations and bad outputs. For instance, a child who learns early in life that throwing tantrums is an effective way to get his parents to do what he wants may through lots of tantrums, and qualify for diagnoses of “ADHD”, “ODD” or “Bipolar Disorder.” And yet there may be nothing whatsoever wrong with his brain – he has just learned that this works for him and so continues to do it. This would be quite a contrast to a child who was, say, exposed prenatally to drugs and ignored and not fed by his/her parents and develops similarly intense tantrums, or a child who is treated well but develops intense tantrums despite appropriate parenting and low overall stress. All three of the above examples could lead to the diagnoses I named, but the causes would be completely different. The third is more likely to have some physiological and perhaps even genetic problem. The second may have both bad hardware and bad software, whereas in the first case, bad programming is clearly the most likely cause. How could these three cases ever be distinguished objectively using DSM diagnostic criteria? I think the clear answer is that they can not be.

    Given these two observations, how on earth could we expect that a purely genetic or neurological explanation could exist for behaviors/emotions that could be generated by a plethora of unrelated internal and external conditions? I think any attempt to find genetic causes for any DSM diagnosis (except perhaps Alzheimers) is simply never going to bear any fruit, because the definitions of the disorders group together tons of people who will inevitably have vastly different internal and external variables that vary widely within the group.

    —- Steve

  • Julie O’Toole

    You talk as if somethings were “biology” and somethings not. It’s all biology, of course, as we are material beings. And mind, as Eric Kandel says, is a range of functions carried out by the brain.

    • stmccrea

      Not everyone shares this view. It is not a view proven by science, but a set of assumptions.

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  • Robert Jensen

    In his reference book ‘Genes and Behavior:Nature-Nurture Interplay Explained’, Sir Michael Rutter correctly argues,
    referencing the work of Kendler, that ‘the strong, clear and direct causal relationship implied by the concepts of a ‘a gene for’ does not exist for psychiatric disorders. Although we may wish it to be true, we do not have and are not likely ever to discover ‘genes for’ psychiatric illness’. Page 13)

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  • gettingwell

    Part II of this post?

    • Neuroskeptic

      That’s an excellent question! I’m still working on it… hopefully soon!

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  • big bang dissertation

    It’s a good thing that there are a lot of people who were able to learn this kind of matter that might help a lot of people who suffered from illness due to that kind of thing.



No brain. No gain.

About Neuroskeptic

Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.


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