A new study suggests that variants in hundreds of genes, working in combination, contribute to the development of Tourette’s syndrome (TS), a neurodevelopmental disorder characterized by chronic involuntary motor and vocal tics.
The findings, published in the American Journal of Psychiatry, show that the condition may be part of a continuous spectrum of tic disorders, ranging from mild, sometimes transient tics to severe cases that can include psychiatric symptoms. In fact, individuals with more severe symptoms were found to have a greater number of TS-associated variants.
The study was led by researchers at Massachusetts General Hospital (MGH), the University of California at Los Angeles (UCLA), the University of Florida and Purdue University.
“This study confirms that, for most patients, the underlying genetic basis of Tourette’s syndrome is polygenic — that is, many genes working together to cause a disease,” said Jeremiah Scharf, M.D., Ph.D., of the Psychiatric & Neurodevelopmental Genetics Unit in the MGH Departments of Neurology and Psychiatry and the MGH Center for Genomic Medicine.
“This means that most people who have TS do not carry a single inactive gene but instead inherit hundreds of small DNA changes from both parents that combine to cause TS. This finding has multiple important implications, both scientifically as well as for patient advocacy and understanding of their symptoms.”
While it is well known that most of the risk for TS is inherited, the few risk-associated gene variants that have been identified account for only a small percentage of cases.
Many common gene variants working together have been linked to a higher risk for the disorder. This suggests that large-scale, genome-wide association studies (GWAS) could clarify which potential risk genes do and which do not actually contribute the development of TS.
To achieve the largest possible data set, the research team combined results from 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. That added up to a total of 4,819 individuals with TS and almost 9,500 unaffected control volunteers.
A second analysis from the Iceland-based deCode genetics study compared more than 700 TS patients to more than 450 with other tic disorders and more than 6,000 controls.
The results identified multiple gene variants associated with increased TS risk, and individuals inheriting more risk variants had more severe symptoms. However, the presence of TS-associated variants was not restricted to those with tic disorders.
“Every one of the variants that contribute to developing TS is present in a significant proportion of the general population, which means that most people with TS do not have ‘broken’ or ‘mutated’ genes,” said Scharf.
“The movements and thoughts that individuals with TS have are the same ones that all of us have, but just to a greater degree. As doctors and researchers, we know that there is nothing that separates those with TS from other children and adults, and now we’ve shown this is actually true on a genetic level.”
The findings raise 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 will resolve as the child matures, something that is not currently possible. Future research working with even larger groups of participants should improve this potential predictive ability.
Scharf notes that the brain regions most likely to be affected by the risk-associated variants are part of a circuit involved in motor learning, planning and selection of appropriate movements or actions, areas previously suggested to contribute to TS and other tic disorders.
“Studies of other polygenic disorders — both brain and non-brain based — have shown that even if a single gene variant plays only a small role in causing a disorder, every gene may be a candidate for understanding disease mechanisms and finding new treatments.”
“We hope that by continuing to find new TS genes, we will be able to find new treatments that are more effective without causing the significant side effects associated with existing therapies,” said Scharf.
Source: Massachusetts General Hospital