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Chromosome 9q may be linked to panic disorder.

NEW YORK -- Recent data provide strong evidence that chromosome 9 may be linked to panic disorder, Dr. Joel Gelernter said at an industry-supported symposium held during the annual meeting of the American Psychiatric Association.

The results may be relevant not only to panic disorder, but also to anxiety in general, since the study included patients with other forms of anxiety.

The conclusion from this and other genome-wide linkage studies is that there are probably both shared and specific genetic loci that influence the risk for anxiety disorders, said Dr. Gelernter, professor of psychiatry at Yale University, New Haven.

"There are probably genes that increase the risk for any diagnosis related to anxiety or a range of anxiety diagnoses, but there are also probably specific risk loci that just increase risk for panic disorder, or simple phobia, or social phobia," he said.

Major anxiety disorders such as panic disorder, social phobia, simple phobia, and agoraphobia are all genetically influenced and moderately heritable. Heritabilities range from about 40% to 60%, but the inheritance patterns are complex and don't follow a classic Mendelian dominance/recessive pattern.

The phenotypes are difficult to define, although recently there has been a huge increase in mapping of Mendelian as well as complex traits using two methods: gene linkage, which can examine the entire genome, and genetic association, which starts with a candidate gene or a set of genes.

"The genetic linkages point to the chromosomal locations of genes that influence risk of the illness," Dr. Gelernter said. "The next step is identifying the actual genes. This can be a long and involved process, but once the actual genes are identified, it will be possible to learn more about the pathophysiologic processes that lead to the disorders."

Four studies to date have used genome-wide linkage to examine panic disorder, with the link to chromosome 9q being the most statistically significant relationship, Dr. Gelernter said.

In a study conducted in Iceland, linkage analysis of 25 extended families--each of which had multiple individuals with panic disorder--resulted in a logarithm of the odds (LOD) score of 4.18 at D9S271, on chromosome 9q31. The usual criterion for genome-wide significance is LOD 3.3 or 2.6, depending on the study design, with an LOD score between 3 and 3.6 usually regarded as very promising, he said.

The LOD score was only 2 in a broader anxiety disorder sample of 62 Icelandic families with diagnoses including panic disorder, agoraphobia, simple phobia, social phobia, generalized anxiety disorder, and somatoform pain, which was highly comorbid with anxiety in the sample (Am. J. Hum. Genet. 72[5]:1221-30, 2003).

Dr. Gelernter and his colleagues at Yale collected data from a set of 20 American pedigrees; these data support the same region for social phobia and habitual smoking. They also found potential linkages at chromosome 1 for panic disorder alone, chromosome 3 for agoraphobia, chromosome 11 for panic disorder and habitual smoking, and chromosome 16 for both social phobia and simple phobia.

A significant linkage was found at chromosome 14 for simple phobia, and possible linkages for social phobia, panic disorder, and agoraphobia. Dr. Gelernter said there were other points of agreement between data sets with lesser signals as well.

Finally, researchers from Columbia University have mapped a potential subtype of panic disorder called "panic syndrome" to chromosome 13q. Panic syndrome is defined as panic disorder plus a number of medical conditions, most notably bladder and renal disorders, but also thyroid problems, migraines, and mitral valve prolapse.

A genome scan performed on 587 subjects found significant linkage to chromosome 13q and chromosome 22, with maximum heterogeneity LOD (HLOD) scores of 3.57 and 4.11, respectively. Multipoint analysis did not support the observation on chromosome 22 (Proc. Natl. Acad. Sci. U S A 100[5]:2550-55, 2003).

"An HLOD score of greater than 3 is taken as evidence of a quite solid linkage," Dr. Gelernter said at the symposium, sponsored by Forest Pharmaceuticals Inc. "These are very promising results."

BY PATRICE G.W. NORTON

Contributing Writer
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Title Annotation:Adult Psychiatry
Author:Norton, Patrice G.W.
Publication:Clinical Psychiatry News
Geographic Code:1USA
Date:Aug 1, 2004
Words:671
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