The Frontal Cortex

The Genetics of Mental Illness

Nature has a really interesting article on the sheer difficulty (impossibility?) of finding the genetic underpinnings of mental illness:

Finding genes involved in psychiatric conditions is proving to be particularly intractable because it is still unclear whether the various diagnoses are actually separate diseases with distinct underlying genetics or whether, as the DISC1 [a gene implicated in shcizophrenia] story suggests, they will dissolve under the genetic spotlight into one biological continuum. Indeed, some researchers suggest that it would be better to abandon conventional clinical definitions and focus instead on ‘intermediate phenotypes’, quantifiable characteristics such as brain structure, wiring and function that are midway between the risk genes involved and the psychopathology displayed.

In the past two years, researchers have pulled out a host of genes involved in other multifactorial diseases, such as diabetes and obesity, by use of genome-wide association studies. These use powerful new genomic tools to scan for variations in the DNA sequence called single nucleotide polymorphisms (SNPs) that tend to occur in individuals with a particular condition. They allow scientists to see which gene variants pop up more frequently in people who have a disorder.

Finding small genetic signals is a question of statistics: a weak association between a gene and a disease may stray into significance only when a study has hundreds or thousands of participants. But instead of helping to firm up which genes might be candidates, the largest population studies completed so far in psychiatric genetics seem to be eliminating them. A study this year led by Patrick Sullivan, a geneticist at the University of North Carolina at Chapel Hill, involved nearly 750 patients with schizophrenia and a similar number of controls, and analysed almost half a million SNPs. But not one gene met the rigorous statistical requirements needed to show it was a risk factor3 — not even DISC1.

Vaughan is exactly right: one of the real stumbling blocks of such studies is that they are forced to find subtle connections across very different levels of description. The genome is a biological text, a long alphabet full of quantifiable variation. The diagnosis of mental illness, on the other hand, is a squishy and subjective process. (This isn’t a criticism: there’s simply no other way.) As a result, doctors are forced to render a verdict based on phenomenological reports, even though the same condition will often manifest itself quite differently in different people. And then, of course, there’s the influence of society and culture. If geneticists had been around during Freud’s time, they would have been looking for the SNP’s underlying hysteria, searching for the confluence of genes that triggered such a bizarre set of symptoms. As Foucault famously pointed out, the definition of madness has always been mercurial, precisely because it has traditionally been defined against something else. Madness, in other words, is not necessarily a consistent set of symptoms caused by a particular genetic mishap: it’s just the opposite of “reason,” whatever that is.

Comments

  1. #1 Jim Fortune
    July 10, 2008

    Thanks for highlighting this article. In pathogen/pest related genetics we have the “gene for gene” hypothesis which at its most general has a combination of resistance genes (host) and virulence genes (pathogen). Why raise this point – its a strong reminder that genes and illness will be “2-way traffic” and that the current hunt in the human arena is focussed on the susceptible expression (eg can I develop a diagnostic and a treatment – the latter preferably tablet form). The environmental (eg lifestyle etc) impacts may be more important in discovering the “resistant response in an apparently susceptible genotype” but horrendously complex to unravel.

    Plant and animal breeders have been traversing this ground experimentally with classical genetics for a long time and know the joys of interactions. The opening note of the Nature article is a salutory reminder of the value of the human cytogenetics work and the need for the molecular “adventure” to travel with the classical genetics and statistics.

  2. #2 Dean Loomis
    July 11, 2008

    This research program has logical defects that will make it largely a waste of money that could be more effectively spent elsewhere. In addition to hysteria, the same approach could be used to find the genetic basis of Communism or Creationism, or even mathematical intuitionism. Why not, given a large enough sample size?

    Think about how any gene would lead to a behavioral effect. The gene dogmatically codes for an enzyme, which affects how neurons and neurite growth and migration directions find their predetermined paths through the dynamically reorganizing neural tissues to create the wiring diagram of the brain during the first dozen years or so of life, or find paths that are redirected according to the ongoing experience of the person. And then in the mature brain some of those enzymes may have structural or functional properties that independently of the wiring affect the dynamics of the turbulent waves of activity that surface in the muscle activity that we call behavior. In schizophrenia, the disorder doesn’t surface for 25 or 30 years, so the concept of “maturity” needs to be thought about carefully itself.

    Geneticists like Weinberger seem to be naively proposing a “one gene, one phenotype” model. Didn’t they learn their lesson at “one gene, one enzyme” long ago? The top-down approach that starts with diagnosed human patients is such a waste of effort. They should at least focus on pathologies with animal models where there’s some hope of following gene product developmentally. And if your definition of the mental disorder isn’t in terms that can be applied to animal models, then you’ve got some definitional issues to work through before even thinking about heading for the lab.

  3. #3 ala
    July 11, 2008

    There is childhood schi. /You seem to be baby of clinical science that does not even know that. If you dispute that childhood digneses are wrong that give the fast input to the APOA to correct thta in the next edition of the DSM/

    You need good clinical, full exposure intership.

    Stop misinformation and biases.

    Genes all right; aren’t they flexible though? How many functional cycles does it take to modify or form a gine.
    ( how mfast did you become phylogeneticaly/)

    You genues need to get that straight yourself before you start preaching others.

    The clinicians are not to make the bogy blob of science
    that confuses general public.

    The genetic disease a lot of times is the prejudice in your mind alone. Schi is deemed not genetic by the John Hapkins comprehensive reseach.
    Are you genetically affected by any chance? If that continues, I am promissing the functional analyses of what you are doing here. (Cause is realy transparent but I am withelding the comment on it)

    Go to school under the good and woilling clinician guidlines ( hard to get), instead of going all ove rthe places with the misinformation that might be misconstrued. You are challenged on the etical groiuds. If you continue , you will be analysed here regarding how your functionla steps affect your thinking and how far that is from your gene ( not genieus) Ok?

    Because these clinicians are all over the places themselves, at times, some of your willingness to come forward is thought provoking.

    I suspect fraud to extort assets from the genetic lines, when you propagate such uncheacked generalities. This is not scientific what you wrote here.

  4. #4 ala
    July 11, 2008

    There is childhood schi. /You seem to be baby of clinical science that does not even know that. If you dispute that childhood digneses are wrong that give the fast input to the APOA to correct thta in the next edition of the DSM/

    You need good clinical, full exposure intership.

    Stop misinformation and biases.

    Genes all right; aren’t they flexible though? How many functional cycles does it take to modify or form a gine.
    ( how mfast did you become phylogeneticaly/)

    You genues need to get that straight yourself before you start preaching others.

    The clinicians are not to make the bogy blob of science
    that confuses general public.

    The genetic disease a lot of times is the prejudice in your mind alone. Schi is deemed not genetic by the John Hapkins comprehensive reseach.
    Are you genetically affected by any chance? If that continues, I am promissing the functional analyses of what you are doing here. (Cause is realy transparent but I am withelding the comment on it)

    Go to school under the good and woilling clinician guidlines ( hard to get), instead of going all ove rthe places with the misinformation that might be misconstrued. You are challenged on the etical groiuds. If you continue , you will be analysed here regarding how your functionla steps affect your thinking and how far that is from your gene ( not genieus) Ok?

    Because these clinicians are all over the places themselves, at times, some of your willingness to come forward is thought provoking.

    I suspect fraud to extort assets from the genetic lines, when you propagate such uncheacked generalities. This is not scientific what you wrote here.

  5. #5 ala
    July 11, 2008

    There is childhood schi. /You seem to be baby of clinical science that does not even know that. If you dispute that childhood digneses are wrong that give the fast input to the APOA to correct thta in the next edition of the DSM/

    You need good clinical, full exposure intership.

    Stop misinformation and biases.

    Genes all right; aren’t they flexible though? How many functional cycles does it take to modify or form a gine.
    ( how mfast did you become phylogeneticaly/)

    You genues need to get that straight yourself before you start preaching others.

    The clinicians are not to make the bogy blob of science
    that confuses general public.

    The genetic disease a lot of times is the prejudice in your mind alone. Schi is deemed not genetic by the John Hapkins comprehensive reseach.
    Are you genetically affected by any chance? If that continues, I am promissing the functional analyses of what you are doing here. (Cause is realy transparent but I am withelding the comment on it)

    Go to school under the good and woilling clinician guidlines ( hard to get), instead of going all ove rthe places with the misinformation that might be misconstrued. You are challenged on the etical groiuds. If you continue , you will be analysed here regarding how your functionla steps affect your thinking and how far that is from your gene ( not genieus) Ok?

    Because these clinicians are all over the places themselves, at times, some of your willingness to come forward is thought provoking.

    I suspect fraud to extort assets from the genetic lines, when you propagate such uncheacked generalities. This is not scientific what you wrote here.

  6. #6 Donna B.
    July 12, 2008

    I’m not a scientist or clinician, just an interested layman (oops.. layperson) who has been reading scientific journals for 25 years, with an emphasis on the brain.

    So, here’s my “analysis” and “diagnosis of the author of the three previous comments: excessive alcohol content in the presence of a keyboard.

    Now… back to the subject of the post, sort of. Could it be possible that a number of mental illnesses are caused by early brain trauma? Just an idea.

  7. #7 semyjohn
    July 17, 2008

    Discoveries in genetics and neuroscience can be expected to lead to better models that provide improved representation of the complexity of the brain and behaviour and the development of both. There are likely to be profound implications for clinical practice. The complex genetics of risk should reinvigorate research on the epidemiology and classification of mental disorders and explain the complex patterns of disease transmission within families. Knowledge of the timing of the expression of risk genes during brain development and of their function should not only contribute to an understanding of gene action and the pathophysiology of disease but should also help to direct the search for modifiable environmental risk factors that convert risk into illness.
    SEMYJOHN
    Addiction Recovery Missouri