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Few people probably think about the fact that autism can present in many different ways. Among researchers, however, these differences are of great interest, as far from all of them have been mapped and described. But now a new British–Danish study has uncovered part of this variation. The researchers have discovered that the development of autism can take different directions depending on the age at diagnosis. And that difference is also visible in the genes. The study, which is partly supported by the Lundbeck Foundation, has just been published in the journal Nature.

The two Danish professors Anders Børglum and Jakob Grove from iPSYCH at the Department of Biomedicine, Aarhus University, are co-authors of the article.

“Of all the psychiatric diagnoses we work with, autism is probably the one with the greatest variation. This applies to genetics, symptoms, and developmental course, and this is what we wanted to explore with this study. It is part of a larger effort aimed at describing these differences more precisely so we can develop more targeted services and better support and treatment,” says Anders Børglum.

“For us as researchers, it is also important that we understand all the variations, because the more of them there are, the larger the dataset we need for our research to have statistical weight,” says Jakob Grove.

The University of Cambridge led the study, which, in addition to Aarhus University, also involved the University of Bristol.

Surprising results

In the study, the researchers for the first time took as their starting point the age at diagnosis and, through a series of comprehensive genetic analyses, examined whether different ages of diagnosis also reflect genetic variation.

The researchers reviewed several thousand genomes and looked for genetic variants—small differences in the DNA sequence. In combination with environmental and other factors, hundreds to thousands of these small variants can increase the likelihood of certain traits or conditions. Therefore, researchers sum the effects of the variants and calculate a polygenic score as a measure of a person’s overall genetic likelihood of developing a particular trait, a disease, or—as in this case—a neurodevelopmental disorder.

Previous research has identified genetic variants that can increase the likelihood of autism, as well as variants that can simultaneously increase the risk of other psychiatric diagnoses.

By comparing genetic data with data on autism trajectories and age at diagnosis, the researchers found two different genetic profiles with genetic variants that may influence an early versus a later diagnosis, each with its own developmental pattern.

In one trajectory, a child with an early diagnosis—before age six—will likely have had communication and behavioral difficulties from early childhood, and these difficulties will either continue unchanged or diminish with age.

In the other trajectory, individuals diagnosed later—during later childhood, adolescence, or adulthood—likely did not have nearly as visible or challenging problems in childhood, but will encounter social and behavioral difficulties during adolescence.

The two genetic profiles share variants that increase the likelihood of autism, as well as variants associated with mental disorders such as depression, ADHD, and PTSD. But those with a late diagnosis have, on average, more genetic variants linked to mental disorders—and that is a crucial difference.

Although the researchers expected to find differences related to age at diagnosis, they were still surprised by the results.

“It was fairly obvious that there would be differences between the two groups, but they were more pronounced than I had expected,” says Anders Børglum.

And one difference in particular was surprising, says Jakob Grove:

“That a later diagnosis appears to be linked to a particular genetic vulnerability to some of the conditions we see as comorbidities of autism—such as depression and PTSD—was unexpected. It suggests an innate vulnerability, and that is an important point—something people working in this field need to be especially aware of.”

Jakob Grove emphasizes, however, that genetic analyses operate with statistical averages and probable associations, not causal relationships. Therefore, it is important to interpret the results with caution.

“This is not a judgement. It is not the case that a person will necessarily develop these comorbid conditions—it is still a matter of probabilities, and there are many cases where the course develops positively, and no additional conditions arise.”

The study shows that 11 percent of the variation in age at diagnosis can be explained by genetics. Thus, many other factors are at play—for example, conditions during pregnancy and birth, living environment, upbringing, and parental education.

For the analyses, the researchers used data from four birth cohorts, and in total, data from 400,000 Danes, Irish, English, Finns, Americans, and Australians were included in the various analyses in the study.

For the analyses, the researchers used data from four birth cohorts, and in total, data from 400,000 Danes, Irish, English, Finns, Americans, and Australians were included in the various analyses in the study.

The Danish researchers contributed, among other things, analyses and genetic data on a total of 130,000 Danes with and without psychiatric diagnoses from iPSYCH, which is a national research project. Here, researchers in psychiatry, genetics, and register-based research work to identify the causes behind psychiatric diagnoses such as autism, schizophrenia, and depression.

A different experience of the world 

Denmark, at least 65,000 people currently have a diagnosis of “autism spectrum disorders” (ASD), also simply referred to as “autism.” They typically experience the world differently from most others and have, to varying degrees, difficulties with communication, behavior, and social interaction.

The spectrum ranges widely—from people with severe disabilities who require daily support, to people who are independent and view their autism as a natural variation and an equally valid way of being in the world.

Because the number of people receiving a diagnosis has risen sharply over a number of years, both in Denmark and internationally, the neurodevelopmental condition has attracted increasing attention—also within scientific circles.

The researchers from Aarhus are likewise focused on exploring autism further. They are already examining the connection between autism and depression and schizophrenia, and they aim to learn more about the background for the increased vulnerability to mental disorders among those with a late diagnosis. They also plan to delve deeper into additional differences, including those related to sex. Far more boys than girls receive the diagnosis, and girls and women typically receive a diagnosis later.

“As is always the case with research, it really begins with a study where we find some answers but where new questions also arise. We want to dig much deeper into these relationships, so this study is a springboard for moving forward,” says Jakob Grove.