[总论]强制症,图雷特综合症的遗传结构(原文及背景常识)

[总论]强制症,图雷特综合症的遗传结构(原文及背景常识) Insights into the genetic architecture of OCD, Tourette syndrome 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 Genetics report, 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. What Is Obsessive Compulsive Disorder (OCD)? What Causes Obsessive Compulsive Behavior? Obsessive-compulsive disorder, also known as OCD, is an anxiety disorder which is characterized with compulsive actions, such as hoarding, counting, checking and cleaning, and obsessive thoughts. Obsessive-compulsive disorder is often chronic and is a potentially disabling condition - the sufferer may be caught in a seemingly unbreakable circle of senseless and distressing behaviors and repetitive thoughts. An obsession is an unpleasant, unwelcome thought, urge or image that keeps entering the person's mind, eventually causing severe anxiety. Many of us imagine an obsession as something desirable and pleasant - but for a person with OCD, the obsession is disturbing, unpleasant and frightening. A compulsion is a repetitive behavior carried out by the person with the obsessive thought as a means of preventing that obsession from occurring, or relieving the anxiety it cuases. For example: A person may shower every time they touch another person, go to the toilet, or go outside, because they are scared of catching a disease - the obsession is catching the disease while the compulsion is to have a shower. According to Medilexicon's medical dictionary, Obsessive-Compulsive Disorder is "a type of anxiety disorder the essential features of which include recurrent obsessions, persistent intrusive ideas, thoughts, impulses or images, or compulsions (repetitive, purposeful, and intentional behaviors performed to decrease anxiety in response to an obsession) sufficiently severe to cause marked distress, be time-consuming, or significantly interfere with the person's normal routine, occupational functioning, or usual social activities or relationships with others." According to the World Health Organization, OCD affects 2% to 3% of people worldwide. It is a major cause of illness-related disability. A symptom is something only the patient can feel, such as a headache, while a sign can be detected by others as well, for example a skin rash. Not all people with OCD are affected in the same way, although most share common patterns of thoughts and behaviors, which typically follow these four main steps: , Obsession - the patient's thoughts are dominated by a constant obsessive concern or fear, such as dirt, a burglar breaking into the house, running somebody over while driving, etc. , Anxiety - the obsessive thoughts trigger a sensation of extreme anxiety and anguish. , Compulsion - a pattern of compulsive behaviors are adopted to relieve the distress and anxiety, this may involve washing one's hands (possibly many times or for a long time), locking the house in a set pattern before leaving, positioning things around the house in a orderly or symmetrical away, etc. , Temporary relief - the compulsive behaviors help relieve some of the symptoms of anxiety. However, the obsession soon returns, and with it extreme anxiety, and the cycle repeats itself again and again and again. Obsessive thoughts For people with OCD, the obsessions are persistent, unwelcome, and repeated images, ideas, impulses or thoughts that appear uncontrollably and do not seem to make any sense. They interfere with other thoughts or when the patient is trying to do other things. We all get those unpleasant or unwelcome thoughts now-and-again, perhaps a worry about being made redundant or fired, or one may wonder whether a partner is being unfaithful. However, if you are able to put these types of concerns into context and can carry on with your day-to-day life, or if they are not worries of little substance and do not boomerang back and forth all day long, you do not have the symptoms of OCD. On the other hand, if the thought is persistent, unwanted, you don't like it, and it dominates your mind so much that it interrupts other thoughts, you could have an OCD-type obsession. Below are the most common obsessions that afflict people with OCD: , Deliberately harming others - fearing that one might deliberately hurt somebody else. Even though the idea of attacking somebody may seem abhorrent, the obsession is there and the thought (fear) keeps coming back. , Accidentally harming yourself or others - such as leaving the stove on, setting the house on fire, leaving something on the stairs and somebody trips over it. , Contamination - fearing becoming infected, or ill because of some substance. , Order and symmetry - there may be a powerful and uncontrollable urge to have everything looking orderly and/or symmetrical. The sufferer may go into the kitchen regularly to check whether all the food and drink cans are pointing in the same direction. , Religious or morality fear - the sufferer may worry that one day he/she may do something that offends his/her religious or moral beliefs. People with OCD worry more about morality problemsthan the rest of the population, experts from the University of Melbourne, Australia, and the Hospital De Mar, Barcelona, Spain, reported in Archives of General Psychiatry (November 2012 issue). , Sexual images or thoughts - the person may have unwanted persistent sexual thoughts or images that disturb or frighten them. Compulsive behavior These are repetitive behaviors that people are driven to perform in order to prevent or reduce the anxiety related to their obsessions. However, the compulsive behavior is excessive and is not realistically linked to the obsessive thought at all. Compulsions usually have themes, just like obsessions do, and may include: , Checking , Orderliness , Seeking reassurances incessantly , Cleaning and washing , Doing the same thing again and again An OCD person's compulsion may be: , A strong urge to confess , Arranging ornaments, cans, clothes, etc. in a certain way, either symmetrically or so they all point in the same direction , Checking all the doors in the house repeatedly to make sure none are unlocked , Checking that all appliances in the kitchen are turned off , Counting numbers in certain patterns , Hand washing, often so intensely and frequently that the skin becomes raw. Some people may wash their hands more than 50 times per day , Hoarding - however, according to an article in Archives of General Psychiatry, hoarding is not related to OCD , Repeating words silently Signs of compulsive behaviors generally come on gradually. They may also vary in intensity throughout the patient's life, becoming more severe during periods of stress. Children with OCD tend to repeat an action several times in their attempt to neutralize the obsessive thought.