Genetics of panic disorder

Genetics of panic disorder Studies assessing the diagnosis of panic disorder by the direct interview of family members, a method commonly employed in the 1980s, showed that the risk of developing the disorder is higher in the first-degree probands. This has been estimated to be 17% for first-degree relatives compared to 2% for the control population. In addition, relatives of probands had a higher prevalence of generalized anxiety disorder and major depression. This was confirmed in another study of anxiety disorders in female relatives and showed a morbidity risk for all anxiety disorders to be 32% among firstdegree relatives of agoraphobic patients with panic attacks and 33% in those with panic disorder. The risk was found to be even greater in the offspring when both had anxiety disorders. Overall, family studies have shown that first-degree relatives of probands with panic disorder have a three- to 21- fold higher risk of developing panic disorder than first-degree relatives of healthy probands. The relationships between panic disorder and other types of anxiety disorder have also been the subject of study. Thus some investigators have reported that relatives of those with agoraphobia have a higher risk for the disorder than relatives of patients with panic disorder, leading to the suggestion that agoraphobia should be considered a more severe form of panic disorder which has an independent genetic transmission. Other studies, however, have found that the diagnosis of separation anxiety and agoraphobia in probands increased the risk of both panic disorder and agoraphobia in the relatives of the patients. Such observations support the hypothesis that panic disorder and agoraphobia are two phenotypic expressions of the same condition due to a different degree of genetic penetrance. The analysis of the relationship between panic disorder and major depression has produced conflicting results. The possible link between these disorders has been provided by the frequent occurrence of major depression in patients with panic disorder and agoraphobia, bothconditions responding to antidepressant treatments. Whereas most of the genetic analyses available suggest that there is an independent genetic basis for these conditions, it is noteworthy that relatives of patients with both panic disorder and agoraphobia are more likely to develop depression, phobias and alcoholism when compared with relatives of probands with panic disorder alone. There does not appear to be an association between generalized anxiety disorder and panic disorder, suggesting that they are separate entities. Generalized anxiety disorder appears to be more prevalent (approximately 20%) in relatives of probands with the disorder than in those of relatives with panic disorder (5%) or agoraphobia (4%). Twin studies have demonstrated only a moderate concordance in monozygotic versus dizygotic pairs. Using the hypersensitivity to carbon dioxide as a challenge test, it has been shown that there is a significantly higher concordance rate in monozygotic (56%) than in dizygotic (13%) twins. In recent years, emphasis has tended to switch from family and twin studies to molecular genetics. Linkage analysis in families with a psychiatric disorder has often proven to be a fruitful method to determine the degree of inheritance of a disorder. The method of parametric linkage estimates the likelihood of the distribution of genetic markers of an illness by a predetermined model and expressed as the logarithm of the odds score (the so-called lod score). For simple Mendelian inheritance of a disease, a lod score of 3.0 or greater, obtained by scanning the genome for markers of the disease, is considered to be a statistically significant linkage. However, most psychiatric disorders do not follow classical Mendelian genetics so such an approach is of limited value. For this reason, other linkage methods have been developed. For example, the allelic-sharing method is based on detecting the frequency of the inheritance of the same genetic marker from each parent. The presence of a gene that causes the disorder is revealed when the allele that is shared between the siblings is greater than 50%. To date, all the linkage studies in panic disorder have been inconclusive. Neither has the search for candidate genes for neurotransmitters (for example, GABA, tyrosine hydroxylase, serotonin receptors, dopamine receptors, adrenoceptors, opioid receptors) proven to be any more fruitful. However, there is some preliminary evidence for an association between the cholecytokinin (CCK) promoter gene and panic disorder which, if replicated, would support the hypothesis that the CCK-B receptor is hypersensitive in panic disorder.