Loose-Fitting Genes

In the last few weeks, there has been a flurry of research on autism, a nervous system disorder that impairs social interaction in children and adults. First, the Center for Disease Control (CDC) released new data from their Autism and Developmental Disability Monitoring Network showing that the incidence of autism has increased 25% since 2006 and has doubled since 2002. Boys now have a 1 in 54 chance of being diagnosed as autistic. For girls, it is 1 in 252.

As with previous reported increases in autism, there is controvery over whether the change is real or illusory, and if it is real, what is causing it. Historically, scientists have assumed that autism is genetically determined and most current research makes that assumption. However, the genetic makeup of the human population changes very slowly on a time scale of centuries. A doubling in ten years is almost an epidemic, and is more consistent with an environmental explanation. The roughly 100,000 new chemicals have been added to our environment since World War II would seem to be the most likely suspects. They may combine and interact to influence the nervous system in an almost infinite number of ways.

However, many researchers have suggested a third possibility—that the apparent increase in autism is due to an increase in diagnosis that does not reflect a real change in the presence of the disease. Two reasons are typically given for this measurement error explanation:

• More children are being tested, due to increased public awareness of autism and greater availability of treatment. The more people you test, the more autism you find.
• Scientists have gradually relaxed their criteria for labeling someone autistic. In this regard, the new edition of the Diagnostic and Statistical Manual (DSM-5) of the American Psychiatric Association has tightened those criteria making it almost certain that fewer people will qualify as autistic in the future. It is not clear what role criticism of alleged errors in diagnosis played in the decision to set the bar for autism higher, but I suspect it had some effect.

One possible reason for the popularity of the measurement error explanation is that it allows researchers to maintain their belief in the genetic theory of autism. There is strong resistance by both corporations and government to any claim that illness is environmentally caused. The greatest resistance comes from the most likely suspects—the fossil fuel, chemical (especially agricultural chemical), and pharmaceutical industries. One result of this is an unwillingness to fund research on environmental causes of illness.

A parallel situation exists in cancer research.  It is also difficult to obtain funding to study environmental causes of cancer.  However, cancer research is more complex, since different types of cancer clearly have different causal paths.  An additional complication is that there is a longstanding tradition of blaming the victim for his or her cancer.

Secondly, a recent twin study by Joachim Hallmayer and colleagues at Stanford University has directly challenged traditional theories of autism. It was once common to hear researchers claim, on the basis of fairly weak evidence, that autism was 90% genetic and 10% environmental. The Stanford study is the largest study yet done, involving 192 pairs of twins. All the participants were tested for autism by the research team using a common set of criteria.

Basically, twin studies compare the common incidence of a condition among pairs of identical twins, who share all their genes, fraternal twins, who share half their genes, and unrelated individuals. The researchers used a complex mathematical model, but to simplify their results, they found that:

• Identical twins are more likely to both be autistic than fraternal twins, which supports the genetic theory.
• Fraternal twins are much more likely to both be autistic than would be predicted by comparing them to two people randomly chosen from the general population, suggesting that there is something in their common environments that plays a role.

The researchers best estimate based on their data is that autism is 62% environmentally caused and 38% genetically caused.

Thirdly, three studies simultaneously published in the journal Nature report that prenatal mutations of three specific genes are associated with autism. These defective genes occurred more frequently among older parents, and were four times more likely to originate with the father than the mother. This research was made possible by improvements in the ability to scan genes for mutations. This technology may lead to the identification of other defective genes that predict autism.

The article about this study referred to a blog post by Dr. Thomas Insel, Director of the National Institute of Mental Health, which funded one of the studies. Dr. Insel has a lot of power to determine what types of research get funded. He said that in light of the figures reported by the CDC, people often ask:

Why is anyone looking for genetic causes when there is such a rapid increase in prevalence? Shouldn't every research dollar be invested in finding the environmental culprit rather than searching for rare gene variants?

Yes, that's what I was wondering too. He gives a two part answer:

• Some autism is caused only by genes.
• Autism may be caused by a complex interaction between genetic and environmental causes. This is not only plausible but extremely likely. For example, a genetic weakness may not cause autism by itself, but exposure to a particular environment may cause a mutation of that gene and trigger the disease. However, it is also possible that environmental conditions may be direct causes of autism without any mediation by genes. This is the case with other diseases. Dr. Insel's theory allows for the possibility of direct genetic causation of autism but not direct environmental causation.  

Dr. Stephan Sanders of Yale, the lead researcher in one of the Nature studies, offers a third reason for doing genetic research. Because there are only 20,000 genes but “millions” (sic) of environmental toxins, looking for genetic “culprits” may be a faster way of identifying genetic-environmental interactions than searching for an environmental “villain.”

Dr. Sanders also assumes that autism can be caused by a genetic-environmental interaction but not by directly the environment. His research strategy reminds me of the story about the drunk who searches under a street lamp for his lost keys, not because he dropped them there, but because the light is better. It also seems disingenuous to suggest that all substances in the environment are equally likely to be responsible.  An epidemiologist might start by looking at geographical variation in the incidence of autism.

It may be time for researchers to take a fresh look at the causes of autism.

Note: The Pittsburgh Post Gazette publishes only abridged versions of some of their articles on their website. Some of the details of the Nature studies come from the newspaper article.