Collaborative investigation reveals genetic spectrum of tic disorders, with more risk variants leading to more severe symptoms

A meta-analysis of several studies on the genetic background of Tourette syndrome (TS) – a neurodevelopmental disorder characterized by chronic involuntary motor and vocal tics – reveals that variants in hundreds of genes, working in combination, contribute to the development of and suggests that Tourette’s disease is part of a continuous spectrum of tics, ranging from mild, sometimes transient tics to severe cases that may include psychiatric symptoms.

The report by an international team – led by researchers from Massachusetts General Hospital (MGH), University of California, Los Angeles (UCLA), University of Florida and Purdue University – also describes the discovery. that individuals with more TS-associated variants are more severely affected, raising the possibility of predicting whether children with mild tics will develop full TS in the future.

“This study confirms that, for most patients, the underlying genetic basis of Tourette syndrome is polygenic, meaning that many genes work together to cause disease,” says Jeremiah Scharf, MD, PhD, from the Psychiatric and Neurodevelopmental Genetics Unit of the MGH Departments of Neurology and Psychiatry and the MGH Center for Genomic Medicine, co-lead author and corresponding author of the report in the American Journal of Psychiatry. “This means that most people with TS do not carry a single inactive gene, but rather inherit hundreds of small DNA changes from both parents that combine to cause TS. This finding has multiple important implications, including both scientifically and for patients’ advocacy and understanding of their symptoms.”

Although it is well known that most of the risk of TS is hereditary, the few risk-associated genetic variants that have been identified represent only a small percentage of cases. Many common gene variants acting in an aggregated manner have been associated with an increased risk of disease, suggesting that large-scale and genome-wide association studies (GWAS) could clarify potential risk genes that contribute and those that do not actually contribute to the development of ST.

To obtain the largest data set possible, the researchers combined the results of the only published GWAS study with new data from three international genetics consortia – the Tourette Association of America International Consortium for Genetics, the Gilles de la Tourette GWAS Replication Initiative and the Tourette International Collaborative Genetics Study – for a total of 4,819 people with TS and nearly 9,500 unaffected control volunteers. A secondary analysis of data from the deCode Icelandic Genetic Study compared more than 700 people with TS to more than 450 with other tic disorders and more than 6,000 controls.

The results of this analysis identified several gene variants – only one of which met genome-wide significance – associated with an increased risk of TS. Using an aggregated polygenic risk score based on identified risk variants to analyze each individual in the study – with and without TS, as well as individuals with less severe tics – confirmed that those who inherited more risk variants had more severe symptoms. However, the presence of TS-associated variants was not limited to individuals with tics.

“Each of the variants that contribute to the development of TS are present in a significant proportion of the general population, which means that most people with TS do not have ‘broken’ or ‘mutated’ genes,” says Scharf. “The movements and thoughts of people with TS are the same as all of us, but to a greater degree. As doctors and researchers, we know that there is nothing that separates people with TS from other children and adults, and now we’ve shown that’s actually true at the genetic level.”

The development of a polygenic risk score for TS raises the future possibility of predicting whether the symptoms of children who develop tics, which typically worsen in early adolescence, will continue to be severe or resolve as they age. the child grows, which is currently not possible. . Future studies with even larger groups of participants should improve this potential predictive ability.

“This study is an example of the great impact of collaborative research in order to finally be able to understand the cause of a complex disease,” says Peristera Paschou, PhD, associate professor in the Department of Biological Sciences at Purdue University and one of the senior co-authors. “As a next step, we are now extending the analysis to an even larger sample of nearly 12,000 TS patients, once again made possible through widespread international collaboration. We hope this will yield even higher potency to further clarify the genetics of TS. “

Co-lead author Jae Hoon Sul, PhD, of the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, says, “We need larger sample sizes to identify the specific genes that cause TS, and there is an ongoing collaborative effort across the US, Canada and Europe to increase numbers to the tens of thousands of individuals with TS, which will certainly improve our chance of finding more related genes at TS. Only by all of us working together can we achieve this important goal.

Scharf, an assistant professor of neurology at Harvard Medical School, notes that the brain regions most likely to be affected by risk-associated variants in the polygenic risk score are part of a circuit involved in motor learning, planning and selecting appropriate movements. or actions, areas previously suggested to contribute to TS and other tics. “Studies of other polygenic disorders – both brain and non-brain – have shown that even if a single gene variant plays only a small role in causing a disorder, each gene may be a candidate for understanding mechanisms of disease and finding new treatments.We hope that by continuing to find new TS genes, we will be able to find new and more effective treatments without causing the significant side effects associated with existing therapies.

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