Having a higher number of copies of genes has been shown to raise the risk of a child developing autism, as has early exposure to various pollutants in the mother's environment.
Researchers have now shown that when these two factors are combined, an individual has 10 times the chance of developing the condition, demonstrating the importance of stepping beyond the question of nature versus nurture and looking at the bigger picture.
The analysis by a team led by scientists from Pennsylvania State University is one of the first to examine genetic differences across the whole genome in conjunction with environmental factors surrounding an individual as it develops.
"There are probably hundreds, if not thousands, of genes involved and up until now – with very few exceptions – these have been studied independently of the environmental contributors to autism, which are real," says Penn State researcher Scott B. Selleck.
The question on just how heritable autism is has long been debated, with some early twin studies estimating as much as 90 percent of the condition is the result of genes passed down from parents.
Other researchers suggest the environment shares more of the blame, with the consensus now hovering around 50 percent genetics, 50 percent environment.
This new study shows how complicated the story just might be when it comes to such complex neurological conditions.
"Our team of researchers represents a merger of people with genetic expertise and environmental epidemiologists, allowing us for the first time to answer questions about how genetic and environmental risk factors for autism interact," says Selleck.
Research involved 158 children with autism who were selected through a previous study, and 147 controls who were closely matched in age and demographic.
The team examined a feature called copy-number variations (CNVs); sequences that have been duplicated at least once to form repeats through the genome.
Previous research on individuals with ASD has already shown a higher tendency for their genomes to contain more CNVs than the rest of the population, and that the more of these repeats an individual has, the lower their measures of social and communication skills.
In addition to the subjects' genetic variations, the team analysed their family's residential history, comparing the addresses with data on air quality from the US Environmental Protection Agency (EPA) Air Quality System.
"This allowed us to examine differences between cases of autism and typically developing controls in both their prenatal pollutant exposure and their total load of extra or deleted genetic material," says researcher Irva Hertz-Picciotto from University of California Davis.
Each risk factor on its own – larger numbers of CNV and high amounts of particulate in the air – was found to elevate the risk of autism, in line with previous research.
Once they started to combine the figures, one result in particular stood out.
Ozone, as one of the pollutants examined, hasn't previously been considered a hugely significant risk factor for ASD.
The gas, consisting of three oxygen atoms, is formed from other pollutants such as nitrogen oxides and volatile organic compounds, which react in the presence of sunlight. Those molecules are generally released in vehicle exhaust, industrial processes, and electrical utilities.
The effect of ozone on those with high CVN numbers ramps up the chances of developing the condition, more than either would account for on their own.
Compared with those the bottom quarter of CNV numbers, and the bottom quarter of ozone exposure, there is a ten-fold risk of developing autism for those in the top quarter for both measures.
"This increase in risk is striking, but given what we know about the complexity of diseases like autism, perhaps not surprising," says Selleck.
While the study didn't analyse the cause, the researchers did speculate that ozone could increase the number of reactive oxygen species, such as peroxides, that are known to cause stress to cells and damage DNA.
It's possible that having more variations of genes responsible for certain autism-related functions could open individuals to more oxidation damage.
The researchers acknowledge their sample size was relatively small, and since ozone occurs in conjunction with numerous other pollutants, there could be confounding factors that need to be pulled apart. It also doesn't point at a single cause, instead hinting at one way a number of key genes could be affected by the environment.
Still, given the complexities of the condition, the study does show how variables we've previously dismissed might be working in combination.
"It demonstrates how important it is to consider different types of risk factors for disease together, even those with small individual effects," says Selleck.
This research was published in Autism Research.