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On the trail of anxious mice
Mouse data provide targets for genome screens in human anxiety disorders
  
By
Edward R. Winstead



Featured article.

The sights and sounds of unfamiliar environments can trigger panic in mice with anxious dispositions, causing them to freeze in place. Naturally nervous mice are not explorers and may seem wary of open spaces. The characterization of anxious behavior in several inbred mouse strains has allowed researchers to map locations in the mouse genome likely to contain genes underlying their nervous temperament.


Detail from the The Last Judgement by Michelangelo Buonarroti (1475-1564)

In an example of the value of comparative genomics, a team from Massachusetts General Hospital in Boston used mouse data to determine targets for genome scans in humans. Jordan W. Smoller, of the Department of Psychiatry, and colleagues screened the genomes of individuals in a large family with a history of anxiety disorders. The researchers found evidence for panic or anxiety hotspots on three human chromosomes, according to a paper in the American Journal of Medical Genetics.

Rather than screening the entire human genome, the researchers targeted 11 chromosome regions. The regions were selected because of their sequence similarity to segments on mouse chromosomes that have been linked to anxiety-related traits. In addition, all of human chromosomes 1q, 8 and 14 were screened because they include regions that are homologous to regions implicated in temperament on mouse chromosomes 1, 12 and 15.

"We examined…mapping studies of mouse emotionality and fear behavior that were available in the published literature as of November, 1997, when we began our analysis," the researchers write in their paper. Emotionality is what researchers call inhibited or restrained behavior in response to novelty and open spaces. This may be analogous to behavior seen in panic disorder and agoraphobia.

Mouse Chromosomal Regions Containing Anxiety QTLs and Homologous Human Chromosomal Regions Selected for the Targeted Genome Scan
Mouse chromosome Region Human chromosome Region
Chromosome 1 56-106cM Chromosome 1a 181-278 cM
    Chromosome 2 102-152 cm
    Chromosome 2 233-261 cm
    Chromosome 18 85-109 cm
Chromosome 10 4-24 cm Chromosome 6 99-190 cm
    Chromosome 10 70-171 cm
  74 cm Chromosome 12 61-135 cm
Chromosome 12 41-61cM Chromosome 14a 76-134 cm
Chromosome 15 25-47 cm Chromosome 8a 104-154 cm
    Chromosome 12 48-56 cm
    Chromosome 22 4-55 cm

aIn addition to these regions, the entirety of chromosomes 1q, 8 and 14 were included in the analysis

Smoller's team tracked the inheritance of DNA markers among affected and unaffected family members to determine the possible locations of genes of interest. The genome scans included a total of 99 markers on 9 human chromosomes.

The linkage analysis was conducted for panic disorder/agoraphobia and a new classification called "diathesis-type," or D-type. Individuals with the D-type classification had evidence of early-onset anxiety disorder, often with multiple anxiety problems including panic disorder. The new classification was created for the purposes of the analysis.

The researchers found statistical evidence of possible linkage to a region of chromosome 10 for anxiety-proneness (D-type) and to a region on chromosome 12 for panic disorder/agoraphobia. They also detected modest evidence of linkage to a region of chromosome 1 for D-type.

"Although none of these results reached genomewide levels of statistical significance, they warrant further evaluation in other family collections," the researchers write. And though the data are merely suggestive, they add, "this study illustrates the potential advantages of using mouse gene-mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder."

The family included 99 individuals in 6 generations. Members of the research team interviewed 77 members of generations IV, V and VI to determine what type, if any, of anxiety disorder each individual had. Diagnoses were made by a 'best-estimate procedure': two of the study's senior investigators reviewed each interview and narrative summary to establish consensus diagnoses.

As a final check prior to the analysis, two of the study's psychiatrists re-reviewed the diagnoses of participants who had been rated as affected for panic disorder/agoraphobia or D-type. They also reviewed cases in which participants were under age 20 at the time of the interview or where there had been disagreement among the psychiatrists during the original diagnoses.

DNA was available for 75 family members. The diagnoses and D-type ratings were made without knowledge of an individual's DNA. The researchers hypothesized that genome scans of individuals with D-type ratings would prove useful because of evidence that the 'inhibited' temperament associated with severe anxiety proneness runs in families.

This temperament is a risk factor for the new classification of D-type, several studies suggest. The offspring of parents with panic disorder/agoraphobia are more likely to be inhibited in unfamiliar situations than are offspring of other parents. And parents of inhibited children have higher rates of childhood-onset anxiety disorders and chronic persistent anxiety beginning in childhood.

In the last half-century, animal models of anxiety have been studied extensively, and investigators have reported anxious behavior common to rodents and humans. For example, the researchers write, "biological and behavioral responses that accompany panic attacks resemble those seen in animal models of conditioned fear, and agoraphobia is often conceptualized as a conditioned fear response to contexts associated with aversive panic attacks."

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Smoller, J.W. et al. Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am J Med Genet 105, 195-206 (published online April 11, 2001).
 

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