Genes play a large role in human disease, but getting beyond the mere claim that our health is influenced by genetics is fiendishly difficult. The path between genetic causes and disease effects can be torturous. The effect of any one gene on your health depends on both your environment and your other genes. As if that weren't difficult enough, mutations in different genes can lead to the same disease. The result can be deeply frustrating to both patients and researchers who were hoping for more rapid progress from the powerful DNA analysis technologies that have emerged recently. Nothing illustrates these frustrations better than our efforts to understand what causes autism.
With the new genetic tools developed in the wake of the Human Genome Project, researchers have engaged in an intense hunt for genes that, when mutated, enhance the risk for autism. The latest results, published by an international consortium in this month's issue of The American Journal of Human Genetics, come from a study of more than 2,400 autism-affected families, along with an equal number of healthy control subjects. The researchers were looking for a particular type of mutation called copy-number variation (CNV), where an individual has extra or fewer copies of a particular gene, due to the duplication or deletion of segments of DNA. By comparing the genomes of family members, they identified new CNV mutations in the autistic children that weren't present in the parents. Previous studies suggested that newly arising CNV mutations are important in autism, and sure enough, in this study autism-affected individuals were three times more likely to carry a CNV mutation than the healthy controls.
That there is a substantial genetic contribution to autism is well-established, but it has been difficult to pin down just how large it is.
That sounds like an exciting result until you realize that, even among the autistic subjects, these CNVs were rare: Only 4.7 percent of autistic subjects carried one (compared to one to two percent of control subjects that had a CNV). Further complicating the story was the fact that in different individuals, different genes were affected by the CNV mutations. From these results, the scientists argue that the genetic risk for autism will "collectively encompass hundreds of genes." While this study makes a valuable contribution to autism research, there is a long way to go.
How strong is the genetic basis for autism, anyway? Could it be that researchers are searching for genetic causes that don't exist? Actually, no. That there is a substantial genetic contribution to autism is well-established, but it has been difficult to pin down just how large it is. Previous studies have estimated the heritability of autism to be as high as 90 percent, or as low as 38 percent. A large study published this week in the Journal of the American Medical Association by researchers at the Karolinska Instutet in Sweden have come up with the most precise estimate yet for the heritability of autism: 54 percent. The scientists looked at autism diagnoses in a population of more than two million Swedish children born between 1982 and 2006. By looking at rates of autism diagnosis among relatives—specifically identical twins, fraternal twins, full siblings, half siblings, and cousins—the researchers determined that, at least among Swedish families, "genetic and nongenetic influences on the risk for [autism spectrum disorders] and autistic disorder were similarly important." Strikingly, they found that shared family environmental influences "have only a negligible effect on [autism spectrum disorder] etiology”; only non-shared, individual-specific environmental influences were significant. Just what those influences are remains unknown.
THOSE ENVIRONMENTAL INFLUENCES don't include vaccines. The work by U.K. physician Andrew Wakefield suggesting a link between vaccines and an autism-like disorder has been discredited, and was likely fraudulent. Subsequent studies that included large populations have thoroughlydebunked the idea that vaccines cause autism. What about other potential sources of toxicants? So far, researchers don't have much to go on. A review of studies of toxic exposures and autism published earlier this year showed that in general, the evidence for a connection between any specific toxin and autism is weak. "Because of the limitations of many of the reviewed studies," the authors wrote, "additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings." Again the tangled relationship between genes and environment could be at play here—certain genetic mutations could render some children more susceptible to toxic exposures that are harmless for everyone else. We just don't know. But more research is coming. The National Institutes of Health has just issued a new call for proposals to "identify environmental contributors to risk and expression of autism spectrum disorders."
Regardless of what the genetic and environmental causes are, they all must somehow impact the developing brain. But researchers are also struggling to understand what autism means for the brain: How are the brains of autistic children different from those of normally developing children? To answer that question, you need access to brain tissue from autistic children, which is understandably (and fortunately) difficult to come by. A study published in March in The New England Journal of Medicine looked at postmortem brain tissue from 11 autistic children and 11 healthy children ranging from two to 15 years old. The researchers examined the detailed cellular architecture of the neocortex, a particularly critical region implicated in autism. While they acknowledged that the study was very small and only exploratory, the team reported "patches of disorganization" in the neocortex, together with indications of mis-expressed genes and improper cell types. These results suggest that brain development in at least some autistic children goes awry very early, most likely before birth.
Autism is a clear example of why solving human disease can be so difficult. There are strong motivations to tackle this disease: It affects children, strong patient advocacy groups are searching for answers, the National Institutes of Health has offered funding, and the problem is intellectually challenging, lying at the intersection of our genes and some of our most characteristically human traits. But the causes of autism are complex, and despite our best efforts we will be struggling to understand it for a long time to come.