Genetic analysis reveals novel insights into the genetic architecture of obsessive-compulsive disorder, Tourette syndrome
The following is a press release from the University of Chicago:
An international research consortium led by investigators at Massachusetts General Hospital (MGH) and the University of Chicago has answered several questions about the genetic background of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS), providing the first direct confirmation that both are highly heritable and also revealing major differences between the underlying genetic makeup of the disorders. Their report is being published in the October issue of the open-access journal PLOS Genetics.
“Both TS and OCD appear to have a genetic architecture of many different genes – perhaps hundreds in each person – acting in concert to cause disease,” says Jeremiah Scharf, MD, PhD, of the Psychiatric and Neurodevelopmental Genetics Unit in the MGH Departments of Psychiatry and Neurology, senior corresponding author of the report. “By directly comparing and contrasting both disorders, we found that OCD heritability appears to be concentrated in particular chromosomes — particularly chromosome 15 — while TS heritability is spread across many different chromosomes.”
An anxiety disorder characterized by obsessions and compulsions that disrupt the lives of patients, OCD is the fourth most common psychiatric illness. TS is a chronic disorder characterized by motor and vocal tics that usually begins in childhood and is often accompanied by conditions like OCD or attention-deficit hyperactivity disorder. Both conditions have been considered to be heritable, since they are known to often recur in close relatives of affected individuals, but identifying specific genes that confer risk has been challenging.
Two reports published last year in the journal Molecular Psychiatry, with leadership from Scharf and several co-authors of the current study, described genome-wide association studies (GWAS) of thousands of affected individuals and controls. While those studies identified several gene variants that appeared to increase the risk of each disorder, none of the associations were strong enough to meet the strict standards of genome-wide significance. Since the GWAS approach is designed to identify relatively common gene variants and it has been proposed that OCD and TS might be influenced by a number of rare variants, the research team adopted a different method. Called genome-wide complex trait analysis (GCTA), the approach allows simultaneous comparision of genetic variation across the entire genome, rather than the GWAS method of testing sites one at a time, as well as estimating the proportion of disease heritability caused by rare and common variants.
“Trying to find a single causative gene for diseases with a complex genetic background is like looking for the proverbial needle in a haystack,” says Lea Davis, PhD, of the section of Genetic Medicine at the University of Chicago, co-corresponding author of the PLOS Genetics report. “With this approach, we aren’t looking for individual genes. By examining the properties of all genes that could contribute to TS or OCD at once, we’re actually testing the whole haystack and asking where we’re more likely to find the needles.”
Using GCTA, the researchers analyzed the same genetic datasets screened in the Molecular Psychiatry reports – almost 1,500 individuals affected with OCD compared with more than 5,500 controls, and nearly TS 1,500 patients compared with more than 5,200 controls. To minimize variations that might result from slight difference in experimental techniques, all genotyping was done by collaborators at the Broad Institute of Harvard and MIT, who generated the data at the same time using the same equipment. Davis was able to analyze the resulting data on a chromosome-by-chromosome basis, along with the frequency of the identified variants and the function of variants associated with each condition.
The results found that the degree of heritability for both disorders captured by GWAS variants is actually quite close to what previously was predicted based on studies of families impacted by the disorders. “This is a crucial point for genetic researchers, as there has been a lot of controversy in human genetics about what is called ‘missing heritability’,” explains Scharf. “For many diseases, definitive genome-wide significant variants account for only a minute fraction of overall heritability, raising questions about the validity of the approach. Our findings demonstrate that the vast majority of genetic susceptibility to TS and OCD can be discovered using GWAS methods. In fact, the degree of heritability captured by GWAS variants is higher for TS and OCD than for any other complex trait studied to date.”
Nancy Cox, PhD, section chief of Genetic Medicine at the University of Chicago and co-senior author of the PLOS Geneticsreport, adds, “Despite the fact that we confirm there is shared genetic liability between these two disorders, we also show there are notable differences in the types of genetic variants that contribute to risk. TS appears to derive about 20 percent of genetic susceptibility from rare variants, while OCD appears to derive all of its susceptibility from variants that are quite common, which is something that has not been seen before.”
In terms of the potential impact of the risk-associated variants, about half the risk for both disorders appears to be accounted for by variants already known to influence the expression of genes in the brain. Further investigation of those findings could lead to identification of the affected genes and how the expression changes contribute to the development of TS and OCD. Additional studies in even larger patient populations, some of which are in the planning stages, could identify the biologic pathways disrupted in the disorder, potentially leading to new therapeutic approaches.
The study is a collaboration between two consortia — the Tourette Syndrome Association International Consortium for Genomics (TSAICG) and the International OCD Foundation Genetics Collaborative (IOCDFGC) — representing 43 institutions across 12 countries. Scharf, an assistant professor of Neurology at Harvard Medical School, is co-chair of the TSAICG steering committee and a member of the IOCDFGC steering committee. Cox is a professor of Medicine and Human Genetics, and Davis a research associate (assistant professor) at the University of Chicago. Additional co-authors include Carol Mathews, MD, University of California at San Francisco; James Knowles, MD, University of Southern California, and Evelyn Stewart, MD, University of British Columbia.
Support for the study includes National Institutes of Health grants U01 NS40024, R01 MH101820, and K23 MH085057; and grants from the Tourette Syndrome Association and the David Judah Fund.
The University of Chicago Medicine and Biological Sciences is one of the nation’s leading academic medical institutions. It comprises the Pritzker School of Medicine, a top 10 medical school in the nation; the University of Chicago Biomedical Sciences Division; and the University of Chicago Medical Center, which recently opened the Center for Care and Discovery, a $700 million specialty medical facility. Twelve Nobel Prize winners in physiology or medicine have been affiliated with the University of Chicago Medicine.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.
Image credit: Dreamstime
The following is a press release from the University of Nottingham:
Professor Stephen Jackson, in the University’s School of Psychology, said: “This new study is very important as it indicates that motor and vocal tics in children may be controlled by brain changes that alter the excitability of brain cells ahead of voluntary movements. You can think of this as a bit like turning the volume down on an over-loud motor system. This is important as it suggests a mechanism that might lead to an effective non-pharmacological therapy for Tourette Syndrome.”
The neurological condition TS affects around one child in every 100 and usually starts during early childhood. Scientists believe that the tics that affect children with TS are caused by faulty wiring in the brain that leads to hyper excitability in the brain regions controlling motor function.
In adolescence, there is a period of ‘pruning back’ in which redundant brain connections are removed and other structural and functional brain changes occur.
During this time, around one-third of children with TS will find that their tics disappear and another third are able to more effectively control their tics. Unfortunately, the remaining third of individuals will see little or no change in their tics and are likely to remain troubled by their TS symptoms into adulthood.
This clinical observation suggests that there are mechanisms in the brain that are involved in controlling tics and undergo development or re-organisation during the teenage years.
Amelia Draper added: “The research is based on the general hypothesis that an area in the brain called the striatum is overactive as a result of alterations in the early development of the brain. As a result, the signals that are relayed to the brain’s cortex region lead to hyper-excitability and cause tics to occur.
“We have looked at how that hyperactivity and the resultant tics might be controlled by finding a way to ‘turn down the volume’ on that ‘cortical excitability’. This is potentially extremely important as the parents of children with tics are desperate to find a safe and effective therapy that is an alternative to drug treatments.”
In the current study the team used a method called Transcranial Magnetic Stimulation (TMS) in which a magnetic field is passed over the brain to produce a weak electrical current which stimulates motor function to induce a twitch response.
By delivering TMS at different points in time as participants were about to undertake a hand movement, the researchers were able to measure alterations in brain excitability ahead of the movement and chart the differences between each person.
The study showed that subjects with TS, unlike those of a similar age without the condition, were least able to modulate the hyperactivity in the brain.
Professor Jackson said: “If there is a relationship between this cortical excitability or hyperactivity and tics then this is really important as it means that there may be something that we might be able to do to help children with TS to better control these unwanted movements.”
Further research by the team has involved the use of a similar type of brain stimulation called transcranial direct current stimulation (TDCS) to study the brains of children with TS. Early results suggest that TDS can be applied to decrease neuronal excitability and this may be effective in suppressing tics for extended periods. In addition, if another form of TDCS is applied, one that increases neuronal excitability, it may act to improve learning and memory function, particularly in the context of behavioural therapies. Following use of these treatments lasting effects can be applied to the brain.
Effective and longer lasting
If proven to be effective, the technology could be adapted into a TENS machine-style device that would offer a cheap, portable and individualised therapy for children with TS.
Professor Jackson added: “For the one-third of people who aren’t going to get better this could offer them a much needed assistance with controlling their tics, while relying less on other conventional pharmaceutical therapies which can have associated side effects such as weight gain or tiredness.
“It can be applied at home while the child is watching TV or eating their cornflakes so it would reduce the amount of school they would miss and potentially we can use the TDCS to both control the tics and make that control more effective and longer lasting.”
As part of her work Amelia Draper is also using MRI scanning technology to examine the potential relationship between cortical excitability and a brain chemical that appears to be strongly linked to neuronal excitability in TS.
Rod Shaw, Chief Executive of the James Tudor Foundation, said: “We’re glad to see that the funding we have given to this project is producing some interesting and potentially useful results.”
Professor Jackson’s research is a key project within the University’s appeal, Impact: The Nottingham Campaign, which is delivering the University’s vision to change lives, tackle global issues and shape the future. Find out more about our research and how you can support us at http://tiny.cc/UoNImpact
Image credit: Dreamstime. Child in photo does not have TS and is used for illustration purposes only.
Psychiatric News Alert posts:
The Centers for Disease and Control and Prevention (CDC) reports that there has been a 42% increase in attention-deficit/hyperactivity disorder (ADHD) diagnoses in children aged 4 to 17 from 2003 to 2011. Data were published in the Journal of the American Academy of Child and Adolescent Psychiatry. The study included 2011 data from a randomized, cross-sectional national survey of more than 95,000 U.S. households known as the National Survey of Children’s Health. Information was gathered on the prevalence of parent-reported ADHD diagnoses, current ADHD diagnosis, and current medication prescriptions to treat the condition. Information was compared with data from previous surveys conducted in 2003 and 2007.
Read more of this Psychiatric News Alert.
Dr. Ken Pope pointed mail list members to this news release by from the Rochester Institute of Technology:
A novel approach to treating children diagnosed with autism spectrum disorder could help them navigate their world by teaching them to turn their symptoms into strengths.
In the article “Symptoms as Solutions: Hypnosis and Biofeedback for Autonomic Regulation in Autism Spectrum Disorders,” published in the winter edition of the American Journal of Clinical Hypnosis, Dr. Laurence Sugarman, a pediatrician and researcher at Rochester Institute of Technology, details a treatment method that teaches affected children how to control their psychophysiology and behavior using computerized biofeedback and clinical hypnosis.
The article coincides with the publication of the second edition of Sugarman’s textbook, Therapeutic Hypnosis with Children and Adolescents, Crown House Publishing, 2013, written with William Wester.
Sugarman’s model is tied to learning to self-regulate the autonomic nervous system—including the fight or flight mechanism—that, for many people with autism, is an engine idling on high.
“Teaching kids with autism spectrum disorder skills in turning down their fight or flight response and turning up the opposite may fundamentally allow them to be more socially engaging, decrease some of the need for cognitive rigidity and repetitive behaviors and, more importantly, allow them to feel better,” says Sugarman, director of RIT’s Center for Applied Psychophysiology and Self-regulation in the Institute for Health Sciences and Technology.
His treatment model underlies three ongoing projects at the center involving different age groups: teaching coping skills to RIT students with anxiety or autism; developing a computer-based role-playing game using autonomous biofeedback for teenagers; and creating a new service and research program for family members with autism for AutismUp (formerly Upstate New York Families for Effective Autism Treatment). The latter, called the Parent Effectiveness Program, began this fall and will repeat in the spring. The study trains parents of young children diagnosed with autism and measures results of their training on the behaviors of their affected children.
Sugarman developed his method in response to the rise in autism spectrum disorders he has witnessed in his 30 years working with children in primary care and, then, in developmental behavioral pediatrics at the Easter Seals Diagnostic and Treatment Center in Rochester. Instead of trying to change the symptoms associated with autism, his approach recognizes the symptoms as an effort to self-regulate inner turmoil.
The treatment integrates autonomic biofeedback and clinical hypnosis into his therapy. Sensors attached to his patients measure respiration, perspiration, heart rate and variation, and blood flow/circulation. Children with autism learn to correlate the signals and visual representations displayed on the computer screen (the “Dynamic Feedback Signal Set”) with their emotions. During therapy sessions, the children practice changing their feedback response and learn to manipulate their own internal wiring. Sugarman uses clinical hypnosis to generalize and internalize feedback techniques—discerning situations and controlling their responses—into their daily lives.
Sugarman is a proponent of clinical hypnosis. He is the past-president of the American Board of Medical Hypnosis, the credentialing body for competency in clinical hypnosis for physicians in the United States. He also has a long association with the American Society of Clinical Hypnosis as an approved consultant, fellow in clinical hypnosis, past vice president and past co-director of education for the society.
“Hypnosis is a 250-year-old Western study of how social influence and internal physiology can be changed,” he says. “Mindfulness is a slice of this.”
Sugarman teaches pediatric hypnosis workshops around the world. This fall, he presented at the Regional Center for Child and Adolescent Psychiatry in Oslo, Norway, and the Milton Erickson Geselleschaft in Heidelberg, Germany. In Heidelberg, Sugarman also presented his treatment model and research using biofeedback and hypnosis with children with autism receiving “very affirmative responses.”
“We think we can make a big difference for young people with autism spectrum disorder,” Sugarman says. “The need is there.”
I hadn’t really thought about writing a Tips post for surviving the holiday season. Then I saw a column in the Toronto Star that offered tips that generally will not work for our kids, so I decided maybe I should post something after all. But before I do, let me point out what triggered this response:
“Tantrums are about power struggles and attention,” said Natalia McPhedran, an Ottawa-based children’s coach and author of Life With Kids — Empowering Our Children To Be Ready For The Real World, due out this month.
“If we use techniques at home that avoid the power struggles at home, I think that you’re halfway there by the time you get to the mall because they know: ‘OK, Mom means business.’”
McPhedran — a mother of two — outlines expectations prior to a shopping trip. That includes specifying the purpose of the visit to ensure youngsters don’t get sidetracked.
While her advice sounds good, it won’t work when a meltdown has nothing or little to do a power struggle or seeking attention. Our kids’ meltdowns have many causes or pathways – most of which have nothing to do with a power struggle or seeking attention. Our kids may be over-stimulated or having a problem coping with the intense noise or visual stimulation in a store – or the smell of someone’s perfume. They may have compulsions triggered by what they experience in the mall or store environment, and suddenly stop while they are supposed to be walking with you because they “have to” count all the shirts in a store display. Then, too, the child’s endurance for shopping will be nowheres close to your endurance. You are motivated to get the shopping done and have something you are interested in looking for or at. The child generally couldn’t care less about shopping for a tablet cover for Uncle Don, although some kids will respond if you try to engage them by saying, “There are going to be a bunch of choices and I’ll want you to help me decide what you think Uncle Don would like best.”
And forget about preventing your children from getting “sidetracked” while shopping in a mall. I always considered myself lucky if I didn’t get sidetracked while shopping. Imagine a child with ADHD!
So let’s consider what you can do to minimize problems as you get ready for the holidays. Happily for me right now, I discovered I already wrote a Tips post on this subject a few years ago that’s still valid. You can read it here.
And if you have any of your holiday tips that you’d like to share with other parents, feel free to use the Comments section below to share them.