The imprinted brain theory originated in the idea that autism spectrum disorders (ASDs) could be seen as the mentalistic mirror images of psychotic spectrum disorders (PSDs) such as schizophrenia.* Many findings relating to either ASD or PSD fit the predictions of the theory, but few studies address both at once. This is frustrating because the applicability of the theory to both types of disorder is its most important distinguishing feature by comparison to rivals like the extreme male brain theory for example, which only applies to autism.
Nevertheless, a recent review article in Neurobiology of Disease looked at common risk factors for both autism and schizophrenia and drew attention to one in particular that seems only explicable in terms of the genetic mechanism proposed by the imprinted brain theory: paternal age.
A mature woman’s egg cells are formed before she is born and have gone through only 20-odd cell divisions, all but the last before her birth. Men by contrast produce sperm every day of their adult lifetimes in a 14-stage process taking approximately 72 days to complete. A man aged 30 produces sperm that are the result of almost 400 cell divisions, and one of 50 sperm cells that have gone through more than twice that number. Each time a cell divides, its DNA is copied in its entirety, and the more times DNA is copied, the more likely are errors and misprints to appear in the genetic code.
This in itself could well explain why older fathers are more likely to have autistic or schizophrenic children than younger ones but why maternal age has no such effect. The implication is that autism and psychotic illnesses such as schizophrenia may be sister disorders related to faulty copying of DNA—something much more likely in the sperm of an older father than in the egg of a mother of any age.
Indeed, this is the central claim of the imprinted brain theory: specifically that the errors are likely to be epigenetic—that is, ones that affect gene expression, and not simply inheritance. The classic one suggested by the theory is so-called genomic imprinting: the expression of one parent’s copy of a particular gene rather than the other’s. Another copying error that can have similar effects is copy number variation, where one parent’s copy of a gene is either deleted or duplicated.
However, the imprinted brain theory also makes unique and counter-intuitive predictions about the difference between autism and schizophrenia in this respect. According to the theory, ASD results from an imbalance in gene expression in favor of the father’s genes and PSDs such as schizophrenia one in favor of those of the mother. Errors in copying DNA in a man’s sperm could cut either way: enhancing the effect of his genes relative to the mother’s—for example by duplicating a paternally-expressed gene—or contrariwise: for example by enabling the expression of a normally paternally-silenced but maternally-expressed gene.
Already there is considerable evidence that such epigenetic effects explain a great deal about both ASD and PSD, much of it noted in these posts, and the same fundamental principle explains many of the other risk factors in schizophrenia and autism that the review mentions. Maternal starvation is one where an environmental insult mimics the resource-limiting effects of maternal genes by contrast to paternal gene expression—specifically the key growth factor gene, IGF2, which is paternally expressed but maternally silenced. Down-regulation of this gene in the children of mothers who experience starvation during pregnancy explains why those children have a greatly increased risk of schizophrenia.
But good theories not only make counter-intuitive and testable predictions, they also sometimes reveal a startlingly new perspective on existing findings. In respect of nutrition during pregnancy, the imprinted brain theory predicts that the exact opposite situation—better than average nutrition for the mother during gestation—ought to correlate with increased risk of autism because it mimics resource-demanding paternal genes, such as IGF2 and just like IGF2, promotes fetal growth.
Indeed, as I point out in The Imprinted Brain, this factor alone could explain the exponential rise in mild ASD in modern, affluent societies, where maternal nutrition is demonstrably better than it has ever been in the past. And as I pointed out in the second of these posts, this could certainly explain both why Asperger was to discover the syndrome named after him following two decades of unprecedented increases in birth weights in pre-world war 2 Vienna and why autism’s other discovered, Kanner, originally portrayed autism as an upper class disorder.
Another set of risk factors for both autism and schizophrenia discussed by the review are those associated with pregnancy and birth complications. Some of these, such as oxygen-starvation during delivery, are known to affect the brain directly. In that particular case it does so disproportionately where schizophrenia is concerned, and others could conceivably do the same for autism. But some of the factors mentioned, such as gestational diabetes—which doubles the risk of autism—have already been identified as a consequence of genetic conflict between paternal and maternal genes over resource-allocation to the foetus. Indeed, paternal genes are directly implicated in gestational diabetes, thanks to the fact that higher blood-sugar levels in the mother favour growth of the foetus to the benefit of the father’s genes invested in it, but at a risk to the mother. And clearly, if this is the case, then the finding that gestational diabetes is a risk factor for autism is exactly what the theory would lead you to expect.
Infection is another risk factor discussed in the review and one that I have dealt with in a previous post. And as I argued there, recent findings—and in particular a model explicitly derived from the imprinted brains theory’s diametric schema of mental illness—explain most of the findings touched on in this excellent and timely review.