Altered Gene Increases Men's Risk For Obsessive-Compulsive Disorder

April 29, 1997

First Isolation of a susceptibility gene for the psychiatric illness

Possessing an altered form of a gene involved in the communication between the brain's nerve cells may put certain men at greater risk of developing obsessive-compulsive disorder (OCD), report scientists from The Rockefeller University and four other institutions in the April 29 Proceedings of the National Academy of Sciences. The discovery, the first susceptibility gene isolated for OCD, offers a possible target for developing treatments for the disorder, which affects 1 to 3 percent of the U.S. population.

"Inheritance of OCD is not simple and most likely involves a number of susceptibility genes and environmental influences. We believe we have found one susceptibility gene, which when it occurs in a particular form contributes to a man's risk of developing OCD. The association was not significant in women, and it is possible that either our sample did not have the power to detect it or a different gene is involved in their development of OCD," explains first author Maria Karayiorgou, M.D., assistant professor and head of the Laboratory of Human Neurogenetics at Rockefeller. Karayiorgou conducted the study with colleagues from Columbia University, Cornell University and the National Institutes of Health (NIH).

The gene carries the instructions to make an enzyme, catechol-O- methyltransferase (COMT), thought to end the action of two chemicals that transmit signals between nerve cells. These two neurotransmitters, dopamine and norepinephrine, are involved in many brain activities, including its control of emotions, particularly rewards and anxiety.

Normally, the chemicals pass from one nerve to the other at the junction, called a synapse, then recycle and finally break down into smaller substances. In men with OCD, the researchers found, alterations in the comt gene cause a decrease in the production of the COMT enzyme. Consequently, the scientists suggest, the amounts of two neurotransmitters in the synapses increase, possibly because they may not be recycled efficiently, resulting in a biochemical imbalance that contributes to OCD.

Because of their illness, OCD patients engage in uncontrolled repetitive rituals including hand washing, cleaning, checking or counting, which provide only temporary relief. The patients also have recurrent, unwanted thoughts such as anxiety about contamination or being hurt. Many may have tics or other uncontrolled movements.

Often chronic and relapsing, OCD typically begins in early childhood or adolescence. OCD-related social and economic costs in the United States tally $8.4 billion, nearly 6 percent of the country's yearly total mental health care costs, according to the National Institute of Mental Health (NIMH), part of the U.S. federal government's NIH.

"Very little is known about the disease process of OCD, but several studies suggest a genetic component to the disease," says senior author Joseph A. Gogos, M.D., Ph.D. "However, unlike the rare, simple Mendelian genetic disorders, in which one or two copies of a single gene can cause such illnesses as Huntington's chorea, cystic fibrosis or some forms of early onset Alzheimer's disease, complex psychiatric disorders like OCD are likely to be associated with common variations in the functions of several genes." Gogos is a guest investigator at Rockefeller and a postdoctoral fellow at the Center for Neurobiology and Behavior at the Columbia University's College of Physcians and Surgeons.

In Karayiorgou's previous research, she and her colleagues found that patients with small deletions in a region called q11 of chromosome 22 have a number of psychiatric illnesses, including schizophrenia and OCD. Recently, other researchers described a high frequency of obsessive compulsive symptoms in children with this deletion. Frequently, these deletions include the comt gene, suggesting it as a candidate susceptibility gene for OCD.

In the new study, the investigators found one form of the comt gene occurs more frequently in men with OCD. Normally, genes occur in different forms called alleles. One allele of the comt gene features the change of a single nucleic acid, of which DNA is built. This modification results in an altered protein structure for the COMT enzyme--a switch of one amino acid, from valine to methionine.

"We found that men who only have the altered comt gene have a significantly increased risk for OCD. This form of the gene yields a COMT enzyme that is three to four times less active than its counterparts made by the other comt gene alleles. Because of the enzyme's low activity, we think dopamine or norepinephrine are not broken down at the synapse as fast as they should be or in as much of a quantity as needed, which could contribute to OCD," says Karayiorgou.

Because each person inherits two copies of the comt gene, one from each parent, three different gene combinations, called genotypes, are possible: two copies of the normal allele that yield a high activity enzyme (H/H), two copies of the altered allele with low activity (L/L) or one copy of each kind (H/L). In combination with analyses of other comt gene alleles, the scientists concluded that the L allele's ability to increase a man's risk for OCD is recessive--a man would need two copies of the altered, low activity gene to have a significant risk for OCD.

Men with the L/L genotypes have a strong risk factor for OCD, but men of H/L and H/H genotypes did not differ significantly from each other in their risk factors. Specifically, a L/L man has an approximate OCD risk of 8.4 times more than an H/H man and more than five times greater than a H/L man, the team found.

But just having two copies of the L comt gene allele is not enough to develop OCD, the scientists note. "About 15 to 25 percent of the population has two copies of L allele, yet only 1 to 3 percent develop OCD. Clearly, more than just one gene as well as environmental influences are involved," says Gogos.

Moreover, the relationship between gender and OCD is not fully understood, note the scientists, but may be explained by the relationship between OCD's onset and severity and the hormones from the sex glands, the testes and ovaries. For example, some women develop OCD or have their illness worsen when they become pregnant, a condition that markedly increases levels of these hormones. Other studies have shown that COMT enzyme activity is under hormonal control.

To conduct the study, the investigators examined the DNA of genes from the blood cells of 42 men and 31 women diagnosed and treated for OCD at the NIMH Adult OCD Outpatient Clinic and by private physicians. For comparison, the team also reviewed samples from 75 men and 73 women without OCD. None of the participants were related.

In ongoing studies, Karayiorgou and Gogos have developed a mouse that lacks a comt gene to investigate the relationship between the absence of the COMT enzyme, the turnover of neurotransmitters in the brain and the animal's behavior. They also plan to examine the transmission of the comt gene alleles in families of OCD patients. Families interested in participating in the OCD studies should call (212) 327-8335.

The Rockefeller University, the DeWitt Wallace Research Fund and the National Center for Human Genome Research at NIH, supported the study. Karayiorgou and Gogos's coauthors include Jurg Ott, Ph.D., and Brandi L. Galke, B.S., at Rockefeller, Margaret Altemus, M.D., at Cornell University Medical College, David Goldman, M.D., at the National Institute of Alcohol Abuse and Alcoholism at NIH, and Dennis Murphy, M.D., of NIMH.

Rockefeller began in 1901 as the Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981. Recently, the university created five centers to foster collaborations among scientists to pursue investigations of Alzheimer's disease, of biochemistry and structural biology, of human genetics, of sensory neurosciences and of the links between physics and biology.
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Rockefeller University

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