By Isabelle Wilson-
Scientists have made a major breakthrough in understanding the genetic roots of obsessive-compulsive disorder (OCD) and chronic tic disorders, including Tourette disorder, identifying 36 genes that substantially increase the risk of developing one or both conditions.
The findings represent a dramatic expansion of what researchers previously knew about the biology of these highly heritable neurological and psychiatric disorders.
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Until now, only four genes had been considered to have sufficiently strong evidence of being linked to OCD and chronic tic disorders. The new research therefore increases the catalogue of high-confidence risk genes ninefold, offering scientists a far more detailed picture of how these conditions may emerge in the developing brain.
Published in Nature Neuroscience, the study brought together an unusually large team of geneticists and neuroscientists led by researchers at Rutgers University in New Jersey.
The scientists analysed newly generated and previously sequenced exome data — the portion of DNA responsible for producing proteins and accounting for roughly one per cent of the human genome — from nearly 4,000 people diagnosed with OCD, chronic tic disorders or both.
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The dataset included more than 2,400 parent-child trios and over 1,500 individuals studied without their parents. Researchers said the sample was nearly twice the size of previous datasets used to investigate the genetic basis of these conditions.
That scale is important because OCD and chronic tic disorders are both strongly influenced by genetics, yet their underlying biological mechanisms have remained poorly understood.
The new findings provide researchers with a much broader set of genetic clues and begin to connect those clues to specific parts of the developing brain.
“This research dramatically expands the catalog of shared risk genes,” said Gary Heiman, a genetic epidemiologist at Rutgers University and one of the study’s senior co-authors.
The findings, he said, also reveal biological links with conditions such as autism and schizophrenia, and identify brain circuits involved in impulse control, movement and habit formation.
The study is particularly significant because OCD and chronic tic disorders frequently occur together. Researchers have found that around half of people with chronic tic disorders also experience obsessive-compulsive behaviours, while as many as 30 per cent of people with OCD have a history of tics.
Rather than treating the conditions as completely separate disorders, the genetic findings strengthen the case for overlapping biological mechanisms.
In order to investigate those mechanisms, the researchers went beyond identifying genes. They compared their genetic findings with brain maps from humans, rhesus macaques and mice, allowing them to construct a detailed neurological picture of where and when risk-associated genes become active.
The analysis pointed strongly towards dysfunction in the cortico-striato-thalamo-cortical circuit, a large network connecting several critical regions of the brain.
This circuit is involved in functions including cognition, impulse control, movement, decision-making and the formation of habits — all areas that can be disrupted in OCD and chronic tic disorders.
The researchers found increased activity of risk-associated genes in several components of this circuit during both prenatal and postnatal stages of brain development. These included the cortex, striatum and thalamus.
The cortex forms the outer layer of the brain and plays a central role in thinking, learning, reasoning and memory. Deep within the brain, the striatum is involved in decision-making, motivation and movement, while the thalamus acts as a major relay centre, helping process and transmit signals between different areas of the brain.
The findings suggest that genetic vulnerability to OCD and chronic tic disorders may not simply arise from a single faulty biological mechanism.
Instead, numerous genes appear to influence interconnected brain systems across critical periods of development, potentially altering how neural circuits responsible for controlling thoughts, impulses, movements and habits are formed and regulated.
The researchers also found substantial postnatal expression of risk-associated genes in the cerebellum, the region of the brain traditionally associated with coordinating movement, timing and balance.
Another important finding involved telencephalic projecting excitatory neurons, a specialised class of brain cells responsible for transmitting signals between different regions of the brain.
Their involvement provides another potential biological link between genetic risk and the abnormal signalling patterns associated with OCD and chronic tic disorders.
The research could ultimately change how scientists think about these conditions. OCD and Tourette disorder are often recognised primarily through their symptoms — repetitive thoughts and compulsive behaviours in OCD, and involuntary movements or sounds in tic disorders.
The new study instead highlights a complex biological architecture involving genes, brain cells, neural circuits and developmental timing.
Perhaps the most striking aspect of the research is the scale of the advance in genetic knowledge. From only four previously established high-confidence genes, researchers have now identified 36 genes with substantial links to OCD and chronic tic disorders.
However, the available evidence does not support saying that the study has never been rivalled. Its unusually large sample, detailed genetic analysis and integration of genetic data with brain maps make it a major and highly significant contribution, but the supplied research does not establish that it is the largest, most comprehensive or most important study ever conducted in this field.
The study is considered to represent a substantial expansion of the known genetic landscape of OCD and chronic tic disorders.
By nearly doubling the size of previous sample sets and combining genetic information with evidence about brain regions, developmental stages and specific cell types, researchers have moved closer to explaining how inherited risk may translate into the symptoms experienced by millions of people.
The findings also raise new questions. If dozens of genes contribute to overlapping disorders, researchers will need to determine how those genes interact with one another, how they influence developing neural circuitsm, and why the same underlying biological vulnerabilities can produce different combinations of obsessive-compulsive behaviours and tics.
The study does not offer a single genetic cause of OCD or Tourette disorder. Instead, it points towards a far more complicated picture: a network of genetic vulnerabilities acting across developing brain cells and interconnected neural circuits.
That emerging picture could prove crucial to future research into diagnosis and treatment. Understanding which genes are involved, where they are active, and at what stage of brain development they exert their effects, may eventually help scientists identify new biological targets for therapies.
The research offers a powerful shift towards biology — revealing how the intricate genetic and neural machinery of the developing brain may help shape vulnerability to OCD, chronic tic disorders and Tourette disorder.
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