Interrupting Napoleon on the genetics of mental illness

Today’s Nature has got an interesting letter on psychiatric genetics suggesting an interesting approach to studying the genetics of mental illness.

It’s from neuroscientists John McGrath and Jean-Paul Selten and comments on an earlier Nature article which we discussed previously.

Napoleon Bonaparte advised: “Never interrupt your enemy when he is making a mistake.” Those of us who assess the contribution of non-heritable risk factors to neuropsychiatric illness would like to politely interrupt this battle to remind opponents that environmental risk factors have now overtaken genetic factors with respect to both effect size and the proportion of the population that is affected.

For schizophrenia, for example, factors relating to urban birth, cannabis use and migrant status are well replicated and have relatively large effects ‚Äî in contrast to the scant evidence that remains after decades of genetics research. Although the ‘heritability index’ for schizophrenia is large (about 85%), this metric encompasses the neglected contribution of gene‚Äìenvironment interactions, as well as the high-profile genetic component. This key point is largely forgotten in the heat of the battle.

It has been convincingly argued (A. Caspi and T. E. Moffitt Nature Rev. Neurosci. 7, 583‚Äì590; 2006) that the power to detect genuine genetic-susceptibility loci would be substantially increased if we could stratify samples according to environmental risk factors. Let’s have more funding to help fine-map the wide range of non-heritable risk factors associated with disabling disorders such as schizophrenia and depression, and discover how they act. These clues are too valuable to overlook.

It’s an interesting point and is relevant to the fact that heritability must be one of the most misinterpreted statistics in genetics.

If a study reports that schizophrenia has a heritability of 85%, many people interpret it to mean that 85% of the risk of developing schizophrenia comes from genetics and this is something to do with the condition itself.

In fact, what it shows is that 85% of the risk of schizophrenia in the samples taken so far is estimated to come from genetics, but crucially this estimate is dependent on the environment in quite subtle ways.

The letter above mentions gene-environment interactions: where exactly the same genes can produce different heritability depending on the environment.

Imagine that everyone lived in a virtually identical environment and we all had almost exactly the same life experiences. The only possible difference in the prevalence of mental disorder would have to come from genetics, because the environment is virtually the same for everyone. In this case, heritability would be close to 100%.

Alternatively, if the environment was widely different for everyone, much more of the difference would come from experience and so the heritability estimate would be less.

In other words, the estimate of heritability depends partly on the variability in the environment experienced by the people being studied.

I was told by a genetics researcher that studies on the genetics of intelligence in school children tend to show that IQ is more heritable in the UK than the US, because in the UK we have a National Curriculum – a specified education programme that every child follows.

This means that UK children have a more similar learning environment, whereas in the US the curriculum is decided state-by-state meaning there’s much more variability in experience. Hence, IQ is less heritable in US school children.

I’ve not found the the studies on IQ in school children, so I’m not sure how it stands at the moment, but it serves as a good illustration of how heritability estimates can be environment dependent.

Actually, this week’s Nature has two other letters on the same topic, and additional feature articles on autism and neural synchrony, as well as a couple brain-relevant book reviews.

Link to contents of this week’s Nature.
pdf of Nature Reviews Genetics paper on twin studies and heritability.

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