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Testing the Whole Haystack
October 24, 2013
An international research consortium led by investigators at Massachusetts General Hospital and the University of Chicago has provided the first direct confirmation that both obsessive-compulsive disorder (OCD) and Tourette syndrome are highly heritable. Their work, which appears in the October issue of PLOS Genetics, also reveals major differences in the genetic makeup of the two conditions that sometimes occur together.
“Both Tourette syndrome and OCD appear to have a genetic architecture of many different genes—perhaps hundreds in each person—acting in concert to cause disease,” said Jeremiah Scharf, HMS assistant professor of neurology at Mass General and 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 Tourette syndrome 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 in the United States. Tourette syndrome is a chronic condition known for causing motor and vocal tics. Usually beginning in childhood, Tourette syndrome is often accompanied by OCD or attention-deficit hyperactivity disorder. Because OCD and Tourette syndrome often develop in close relatives of affected individuals, they have been considered heritable, but identifying specific genes that confer risk has been challenging.
Scharf and several co-authors of the current study published two papers last year in the journal Molecular Psychiatry describing genome-wide association studies (GWAS) of thousands of people affected by OCD or Tourette syndrome. While those studies identified several gene variants that appeared to increase the risk of each individual condition, none of the associations was strong enough to meet the strict standards of genome-wide significance.
The GWAS approach is designed to identify relatively common gene variants. Because OCD and Tourette syndrome 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 comparison of genetic variation across the entire genome, rather than the GWAS method of testing sites on the genome one at a time. GCTA also estimates 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,” said Lea Davis, a research assistant professor of genetic medicine at the University of Chicago and co-corresponding author of the PLOS Genetics paper. “With this approach, we aren’t looking for individual genes. By examining the properties of all genes that could contribute to Tourette syndrome 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 studies: almost 1,500 people with OCD compared with more than 5,500 controls, and nearly 1,500 people with Tourette syndrome compared with more than 5,200 controls. To minimize variations that might result from slight differences in experimental techniques at more than one location, 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 analyzed the resulting data on a chromosome-by-chromosome basis, charting the frequency of the identified variants and the function of variants associated with each condition.
The researchers concluded 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 affected 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,’” Scharf explained. “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 Tourette syndrome and OCD can be discovered using GWAS methods. In fact, the degree of heritability captured by GWAS variants is higher for Tourette syndrome and OCD than for any other complex trait studied to date.”
Nancy Cox, a professor of medicine and human genetics at the University of Chicago and co-senior author of the PLOS Genetics report, added, “Despite confirming 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. Tourette syndrome 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.”
About half the risk for both disorders appears to come from variants already known to influence the expression of genes in the brain. Further investigation of those findings could identify the affected genes and show how changes in their expression contribute to the development of Tourette syndrome and OCD. Additional studies in even larger patient populations, some of which are in the planning stages, could reveal the biologic pathways disrupted in the disorders, potentially leading to new therapeutic approaches.
The study reflects a collaboration between two consortia representing 43 institutions across 12 countries: the Tourette Syndrome Association International Consortium for Genomics and the International OCD Foundation Genetics Collaborative. Scharf is co-chair of the Tourette Syndrome Association International Consortium for Genomics steering committee and a member of the International OCD Foundation Genetics Collaborative steering committee.
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.
Adapted from a Mass General news release.