Defending Aggregate Genetic Effects in Psychiatric Disorders

This post is in response to Duncan Double's commentary on Ken Kendler's paper "The dappled nature of causes of psychiatric illness: replacing the organic–functional/hardware–software dichotomy with empirically based pluralism".

I disagree with much of Double's characterization and interpretation of Kendler's paper and I find the responses wholly inadequate. Unpacking and addressing each and every point will take a long time, so for the purposes of illustration of the inadequacies of Double's comments, I'll consider his response to the discussion of aggregate genetic effects.

To demonstrate what aggregate genetic effects are, let's look at what Kendler writes about schizophrenia: "Adoption and twin studies show consistent and strong evidence for aggregate genetic effects in schizophrenia with the best estimates of heritability being quite high (~80%).34 To date, only a very small proportion of this risk has been indexed by known molecular variants. However, recent analysis of GWAS data for schizophrenia suggests that much of this aggregate genetic effect can indeed be explained by common genetic variants of very small effect size.23,35"

How does Double respond to this?

1) Double writes: "This genetic case is often overstated. The real situation is that genes set the boundaries of the possible; environments define the actual"

That is just another way of saying that outcomes are determined by gene-environment interactions. There is nothing controversial about gene-environment interactions; it is accepted dogma in current genetics. This is genetics 101. Kendler doesn't deny gene-environment interactions. He supports them. He writes:

"Genetic factors can moderate the impact of stressful events on risk for MD while key features of the social environment can alter the impact of genetic effects on alcohol intake. But this complication only strengthens my argument."

Exactly. To acknowledge gene-environment interactions is to acknowledge a causal role for BOTH genes and environments.

2) Double: "There has been over half a century of false positive gene discovery claims in psychiatry".

Double is referring to single gene explanations and discoveries of single genes of large effects which have not borne out; there is no evidence of single genes of large effect sizes for schizophrenia or other major psychiatric disorders. The evidence instead suggests multiple genes of very small individual effect sizes but a large aggregate effect. The high genetic heritability of schizophrenia has been pretty consistently reported in literature. If Double dispute this, can he cite even one good study which demonstrates that schizophrenia does not have a high genetic heritability?

3) Double: "In fact, the complexity of the genetics of common disorders, such as schizophrenia, makes accurate prediction unlikely"

Prediction is an entirely separate question from causation. The fact that complexity of genetics makes prediction unlikely doesn't negate or refute the finding that there are large aggregate genetic effects.

4) Double: "if there is any genetic influence in mental disorders, it does not seem specific"

Influence doesn't have to be specific in order to be causal. Obesity is a causal risk factor for diabetes, but it is not a specific risk factor for diabetes. Tobacco smoking is a risk factor for lung cancer, but it is not specific. Even psychosocial causal risk factors are extremely non-specific in psychiatry.

None of these arguments actually do anything to refute the causal role played by aggregate genetic effects in psychiatric disorders.

Technically I don't even have to look at other causal risk factors. As long as we can show that aggregate genetic factors have a causal role in major mental disorders, Duncan Double's claim that psychiatric disorders have no biological causes falls apart.

Comments

Anonymous said…
Again, and for the last time.
The does not exist such that may be called a psychiatric disorder. The non useful individual is a psychologically ill person. There is not a criteria of truth even except such that rests upon social convention. This is severely limited by culture/environment. The basis of experience is sensation which in its higher form turns into emotion, and which in an ordered society will condense into language. There is no higher truth at all but all a process of evolution. Combat is a process which is used primarily by nature to determine the enduring truth. In lower forms combat is merely physical and in humans of lower order it is both physical and verbal. In the most evolved forms it is psychic/spiritual/mystical/religious.
You want to endure at all costs. Ponder in your solitude what I have said and I am not the
most competent user of the English language. So there please excuse me.
Steve said…
As to your point about genetic variant claims of schizophrenia, it is not accurate to say that that failure to find such genetic variants applies only to single gene studies. None of the significant genetic variants in previous genome wide associations studies have been found significant in a subsequent, independent GWAS.