Friday, August 24, 2012

Parental Age, Autism and Schizophrenia

I first heard about some interesting news a couple days ago on Twitter. An acquaintance of mine, @UAJamie posted a link to a New York Times article reporting on some very recent research into possible causes of disorders like autism and schizophrenia. In the past year or so, there have been studies suggesting that the age of the parents may play a role in the risk of autism, but no clear connection has been made, let alone any reason that such should be the case.

In "Father's Age Linked to Risk of Autism and Schizophrenia", we learn about a new study finding that the older the father (but not the mother) is, the greater the risk of autism and schizophrenia. The reason? The older the father is at the time the child is conceived, the greater the number of genetic mutations. A very interesting finding, but it raises some questions. Unfortunately, the full article published in Nature, Rate of de novo mutations and the importance of father's age to disease risk, is behind a pay wall, so I have to rely on the abstract and news reports. With that in mind, let's dig in.

The researchers examined 78 parent-child trios in which neither parent had signs of mental disorders, but the children had a diagnosis of either autism or schizophrenia. The controls were a group of 1,859 other Icelanders, though the demographics of this group are not clear, other than that the controls had no autism or schizophrenia diagnoses.

My biggest concern about the study is that it rests on correlation. This raises the question of whether the number of genetic mutations found are causally connected to mental disorders like autism and schizophrenia, or if it is merely a coincidence. The abstract isn't a whole lot of help, here, as no mention is made regarding the difference in mutation rates or risk of mental disorders between the study group and the controls. No graphs are available without paying for the article, so we have to look to news reports. The Times article reports that when the father's age is removed as a factor, the risk of autism or schizophrenia is no different between the study and control groups. To me, what connection these mutations really have, if any, is kind of a big question, which this study does not seem to be designed to answer.

The researchers have seen that the older the father, the greater the number of mutations. We have also seen increases in the number of diagnoses of autism, and overall, people are waiting longer to have a family, which means increased parental age at first birth. For example, in the U.S., the age of first-time mothers has been increasing for some time:

Graph from CDC.
The Netherlands has also seen increasing ages of first-time parents:

Graph from Statistics Netherlands.
It is difficult to conclude from this study whether these observations are connected or, like the Pastafarian connection between global temperatures and number of pirates, are merely coincidental. From what I can see, the apparent connection between the father's age, the number of mutations and the risk of autism or schizophrenia is mostly speculation on the part of media reporting the story. At least, that seems to be the case from what's available in the abstract and what's actually written in places like the Times or The Wall Street Journal. It's certainly plausible, but I would like to see the study replicated with a greater focus on determining whether there is a causal connection.

Many of the media reports seem to be focusing predominantly on the connection between these mutations and autism, but what about schizophrenia? We know that autism diagnoses have been increasing in recent years, though we have few data points to determine the actual rate of change from year to year, not to mention a lot of confounding factors, like changing diagnostic criteria, gradually increasing awareness, expanded screening and support and resources becoming more available (though nowhere near ideal, yet). The two disorders share a lot of history, such as autistic children in 1906 being labeled as schizophrenic or having dementia. There have also been various social stigmas attached to each. Yet while autism has overcome some of those stigmas, it doesn't seem like schizophrenia has achieved the same level of social awareness and acceptance (the cultural nuances are much more complex and something for a whole other post).

If the correlation with father's age and risk of mental disorders is true, and that it accounts for some of the increase in autism, then we should expect to see an increase in the number of schizophrenia diagnoses. But while we have some evidence that autism diagnoses have gone up, there isn't really any good research on how the incidence of schizophrenia has changed over time. Making matters worse is that historical data on schizophrenia is not particularly reliable, particularly the further back one looks. For example, black men have historically been over-diagnosed with the disorder, reflecting cultural and racial biases.

But let's assume for the moment that schizophrenia rates have remained relatively stable. That alone may not be sufficient evidence to cast a shadow on this study's results showing some possible connection between the father's age and risk of schizophrenia. The reason for this is that the disorder is not typically diagnosed until a person is in their 20s. Since it is only in the last several decades that parents have been waiting until they are older, on average, to have children, we might not have had enough time pass, yet, to register any changes in incidence.

The study is intriguing, adds weight to the genetic aetiology of disorders like autism and schizophrenia and raises a number questions for further investigation. The down side of this news was summed up nicely by ethicist Art Caplan:
The discovery of the role paternal age plays is frustrating because there are too many factors leading to decisions to delay having children. Women get the frequent message in the media that they can have children whenever they want— that technology makes parenting possible at any age. Young men and women find too little support from government or business for child-rearing.

The study is heartbreaking because it does not bode well for finding a cure for those already impacting by autism, schizophrenia and other age-related genetic disorders. The impact of genetic mutations is huge and it is systemic. These genes are going to interact with the environment is complex ways that are not likely to be easily reversed by a drug or any other quick fix.
It will be interesting to see where these results lead from here, and what developments will come for autism, schizophrenia and myriad other mental disorders.

Edited to Add: A microbiologist friend of mine pondered that perhaps autism and schizophrenia share some proteins that are either over- or under-expressed, but being expressed at different ages. The genes encoding these proteins may not always be expressed in every generation, either, as two copies (one from the mother, one from the father) may be required. It's an interesting thought. Anyone know of some research along these lines?

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