An international study led by researchers at the University of Cambridge department of psychiatry has discovered that autism diagnosed during early childhood has a different genetic and developmental profile to that of autism diagnosed from late childhood onwards.

The study analyzed behavioral data across childhood and adolescence from the U.K. and Australia, and genetic data from over 45,000 autistic individuals across several large cohorts in Europe and the U.S. The results identified different genetic profiles related to two trajectories that autistic children tend to follow. One linked to early diagnosis and communication difficulties in infancy. The other linked to later diagnosis, increased social and behavioral difficulties in adolescence, and higher rates of conditions like ADHD, depression, and PTSD.

The team says the findings challenge the long-held assumption that autism is a single condition with a unified underlying cause. Reporting on their study in Nature (“Polygenic and developmental profiles of autism differ by age at diagnosis”) lead author Xinhe Zhang, PhD, and colleagues concluded that their findings, “… have important implications for how we conceptualize autism and provide a model to explain some of the diversity found in autism.”

Ever since its earliest descriptions in the 1940s, autism has been thought of as a condition that emerges in early childhood, the authors wrote. However, they point outed, a greater proportion of autistic individuals are now being diagnosed from mid-childhood onward, than in early childhood. “It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles.”

Using longitudinal data from four independent birth cohorts, the investigators demonstrated that two different socioemotional and behavioral trajectories are associated with age at autism diagnosis. The results suggested that children diagnosed as autistic earlier in life (typically before six years old) were more likely to show behavioral difficulties from early childhood, such as problems with social interaction.

However, those diagnosed with autism later on in life (in late childhood or beyond) were more likely to experience social and behavioural difficulties during adolescence. They also had an increased likelihood of mental health conditions such as depression.

When the team then linked the genetic data to age at autism diagnosis, the team found that the underlying genetic profiles differed between those diagnosed with autism earlier and later in life, with only a modest overlap. They found that commonly heritable polygenic factors could explain 11% of the variation in age at autism diagnosis. “In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance,” they noted.

The scientists looked at polygenic factors: sets of thousands of genetic variants that can collectively shape particular traits. The results suggested that the average genetic profile of later-diagnosed autism is closer to that of ADHD, as well as to mental health conditions like depression and PTSD, than it is to autism diagnosed in early childhood.

The study authors point out that a lack of support in early childhood will also play a role in increased risk of mental health issues in the later-diagnosed group, for example by being more vulnerable to bullying pre-diagnosis.

Nevertheless, they say that the stronger genetic overlap between later-diagnosed autism and certain psychiatric disorders suggests there may be some genetic factors that partly increase the risk of mental health conditions among those diagnosed with autism later in life.

“We found that, on average, individuals diagnosed with autism earlier and later in life follow different developmental pathways, and surprisingly have different underlying genetic profiles,” said Zhang. “Our findings suggest that the timing of autism diagnosis reflects more than just differences in access to healthcare or awareness, important as these are. However, it is important to note that these are average differences on a gradient, so earlier and later diagnosed autism are not valid diagnostic terms.”

In their paper the investigators noted that their results demonstrate that the polygenic architecture of autism can be broken down into two “modestly genetically correlated” autism polygenic factors. “One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioral difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions.”

“The term ‘autism’ likely describes multiple conditions,” said senior study author Varun Warrier, PhD. “For the first time, we have found that earlier and later diagnosed autism have different underlying biological and developmental profiles. An important next step will be to understand the complex interaction between genetics and social factors that lead to poorer mental health outcomes among later-diagnosed autistic individuals.”

This study has implications for how autism is conceptualized, studied, and supported, the research team notes. The findings suggest that genetic and developmental variation contributes to when and how autistic traits manifest, and why some individuals are diagnosed only later in life.

“Some of the genetic influences predispose people to show autism traits from a very young age that may be more easily identified, leading to an earlier diagnosis,” added Warrier. “For others, genetic influences may alter which autism features emerge and when. Some of these children may have features that are not picked up by parents or caregivers until they cause significant distress in late childhood or adolescence … Understanding how the features of autism emerge not just in early childhood but later in childhood and adolescence could help us recognize, diagnose, and support autistic people of all ages.”

In their paper the team concluded, “These findings provide further support for the hypothesis that the umbrella term ‘autism’ describes multiple phenomena with differing etiologies, developmental trajectories and correlations with mental-health conditions. These findings have implications for how we conceptualize neurodevelopment more broadly, and for understanding diagnosis, sex and gender differences, and co-occurring health profiles in autism.”