Using genetics and sharing to study autism

French researcher Thomas Bourgeron is a pioneer in genetic research on autism. The professor was also our guest at the last Neurobiology of Mental Health conference. In this article, he tells us all about his initial findings that link genes to the synapse as well as his appeal to share data.

The Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, defines autism using only two diagnostic criteria: deficits in social interaction and stereotyping. The DSM is the subject of much criticism, with Thomas Bourgeron sounding the alarm: “These diagnostic criteria leave too many other aspects in the dark! Autistic people are all different, which is why we talk about autism spectrum disorders (ASD) – with an ‘s’ on the end!”. Intellectual disability, epilepsy, sleep disturbance and anxiety are all so co-occurrent (among many other characteristics) that the French geneticist calls for them to be taken into account in the phenotyping of autism. The biggest problems for people with autism and their families are linked to comorbidities. “The definitions are used to advance research and diagnosis, but in terms of the individual it’s much more complicated than that!”, explains Bourgeron by way of introduction, reflecting his commitment and desire to articulate the great difficulties involved in ASD research.

The genetic line of inquiry

The first indications that a genetic factor is involved in ASD have a long history. As far back as 1977, studies on the heritability of autism showed that monozygotic twins had an over 80 % chance of developing ASD if one of the twins was affected. Heterozygotic twins, on the other hand, had a 10 % prevalence, “which is higher than the normal prevalence of 1 %, a key argument for a genetic line of inquiry,” explains the geneticist. In addition, there are population studies identif ying recurrences in families with ASD. Research published this year in Jama Psychiatry analyzing two million people across five countries demonstrated a heritability of 80 %, i.e. a very strong genetic contribution.

Nevertheless, acquired types of autism do exist, as can be the case after taking certain types of medication during pregnancy. But autism is very much genetic for the vast majority of people. Professor Bourgeron states that the trajectories of individual lives influence the severity of symptoms: “For instance, a study has shown that some severe cases among children improved with the socio-economic status of the parents.”

Synaptic genes

These studies do not provide any information about the genes involved or the biological pathways. In 2003, Bourgeron and his team identified a genetic mutation that induces a form of autism without any intellectual disability. They subsequently demonstrated that the genes involved coded for synaptic proteins and that harmful gene mutations were observed in the families of ASD individuals. “Neurobiologists very soon took an interest in our results, and the genes coding for proteins of the synaptic architecture such as Shank3, neuroligin and neurexin were identified as playing a role in autism with or without any intellectual disability”, continues Professor Bourgeron. With the advent of genomic techniques, the researchers realized that a subset of people with autism had rare mutations in their synaptic genes. Another subset carried mutations in the genes involved in chromatin remodeling and regulating genes associated with synaptic plasticity. Over 149 genes are currently linked very strongly to autism.

When are common genetic variations present in the general population? There are three million variations on average between two individuals across the entire genome that includes over three billion letters (ATGC). These genetic variations form the genetic background, with some contributing to the emergence of a form of autism. It is the accumulation of these variations in one person that may make the difference and influence the severity of the disorder. “When it comes to autism, you have to take the person’s entire genetic architecture into account since autism is not always monogenic.”

Genetics and social behavior

Professor Bourgeron studies the monogenic and polygenic aspects. After identifying the role of genes in brain function, his lab generated mice with mutated genes so that the scientists could see their effect on the animals’ social behavior. Bourgeron’s lab developed a video analysis algorithm to do this, identifying social behaviors without human intervention. “It works well, and it’s an ethologist approach that shows differences in social behaviors between the mutant mice and control mice”.

Bourgeron then characterized the brain transcriptome (all the RNAs produced by the transcription of the genome) so he could define which regions are involved. All this has been done using total data sharing thanks to several online tools and platforms developed by the professor’s laboratory. Transcriptome, genetic and behavioral data are systematically shared. “We share and advocate the sharing of data, including negative outcomes. That’s what drives research forward, because no one wants to publish negative data even though it is important. We really want to create a sharing community to encourage everyone to do this”.

The Synapsy surprise

It is a community approach, then, that is not unlike Synapsy’s, which aims to bring together different environments. “It’s an excellent approach, like Synapsy’s. I thought that this kind of initiative was going to take off, but in reality, it hasn’t much. Researchers tend to do their research on their own without organizing the sharing of data generated by their work.” For Bourgeron, Synapsy is a “pleasant surprise”, and he is especially pleased with the clinical-basic research combination. He quotes a sentence from Louis Pasteur: “There are no such things as applied sciences, only applications of science”. ●