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Dr. Bob is Robert Hsiung, MD,
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Posted by Michael Bell on February 13, 2007, at 23:54:32
To our knowledge, this is the first genome-wide scan linkage study of social phobia. The strongest evidence for linkage to social phobia was on chromosome 16. A Zlr score of 3.41 was observed for chromosome 16 near marker D16S415 (p=0.0003), in the context of lod scores higher than 2 under several models (with the most notable parametric model results based on the assumption of recessive inheritance). The most obvious candidate gene mapped in this broad region is SLC6A2 ("solute carrier family 6 member 2"), the norepinephrine transporter protein locus (protein product, NET1), which maps close to D16S3136.
The norepinephrine transporter plays the physiological role of reuptake of norepinephrine and dopamine into presynaptic neurons, terminating neurotransmission. It is a target for some medications that are effective for the treatment of social anxiety disorder, including venlafaxine (38) and, possibly, paroxetine (39). Adrenergic tone clearly plays a role in the experience of some of the physiological concomitants of anxiety, and blockade of norepinephrine can be involved in relief of some symptoms of anxiety. Furthermore, there is preliminary evidence that dopamine metabolism may be abnormal in social phobia (40). These observations make SLC6A2 (which succeeded "SLC6A5" as the locus symbol for this gene) a clear candidate gene for anxiety disorders in general (41) and social phobia in particular.
We are aware of two previous linkage studies of social phobia (20, 21). Those reports considered markers at a total of six candidate loci in a group of subjects somewhat smaller than the present study group, without evidence of linkage; SLC6A2 was not among the candidate genes evaluated.
We may consider all of the linkage results presented herein in the context of results for other anxiety disorders, sometimes comorbid with social phobia and with each other, obtained in the larger group of subjects from which the present study group was drawn. Chromosome 16 markers generated Hlod scores in the range of 1.1–1.4 and Zlr scores as high as 2.51 for the simple phobia phenotype (24) but no lod, Hlod, or nonparametric linkage scores of interest (NPL scores, in this case) for panic disorder or agoraphobia (23).
The region of interest for social phobia on chromosome 9 does not overlap with regions of interest for simple phobia, panic disorder, or agoraphobia. Hlod scores for this region were high consistently across all parametric models (Figure 2). The region of interest for social phobia on chromosome 14 (Hlod score=2.82 under the dominant/narrow model, Zlr score=2.52 under a broad model) (Figure 1 and Figure 2) overlaps with a region of significant linkage for simple phobia we reported earlier (lod score as high as 3.70 under a simple parametric model) (24). This same region also generated NPL scores higher than 2 for both panic disorder and agoraphobia (23). The region of interest for social phobia on chromosome 18 (Zlr score=2.41 under a model with a narrow diagnosis definition) does not find any corresponding positive linkage values for panic disorder or agoraphobia, but we previously (24) reported a Zlr score of 1.84 for simple phobia (model with narrow diagnosis definition) about 10 cM distant.
The regions of greatest interest for panic disorder (chromosomes 1 and 11) and agoraphobia (chromosome 3) (23) were not identified as areas of interest for social phobia. Thus, the results, considered together, suggest that a chromosome 16 locus may be important in determining social phobia risk, is less likely to be important for simple phobia risk, and does not contribute to panic disorder or agoraphobia. Conversely, the loci that were most likely to be important for the risk for panic disorder and agoraphobia do not appear to be important for social phobia. Finally, a chromosome 14 locus that is significantly linked to simple phobia may be of lesser importance for social phobia, panic disorder, and agoraphobia. Of all of the possible linkages identified in parts of this group of subjects, the putative chromosome 14 locus is most likely to play a role in susceptibility to a range of anxiety-related phenotypes. These observations are consistent with a hypothesis suggested by patterns of comorbidity among the anxiety disorders and presented by us (23) and earlier by Kendler et al. (42) in a broader context, that there may be risk loci that increase risk for several anxiety disorders and other risk loci that are more specific to certain anxiety disorders. Without the existence of such shared risk loci, it is difficult to explain the elevated rates of co-segregating social and simple phobia in pedigrees recruited not for these disorders but for high rates of panic disorder.
It is possible that social phobia as observed in this set of families selected for panic disorder may represent a genetic subtype that is different from social phobia as observed in the general population or in families selected specifically for aggregation of social phobia. If this is the case, the findings may not generalize to a differently ascertained study group. This strategy may also have decreased genetic heterogeneity for social phobia in our particular group, and such a decrease would be expected to be advantageous for gene mapping for those specific loci enriched in the group.
Power analysis suggested that this study group had adequate power to detect linkage when the phenotype studied was inherited in a simple Mendelian fashion, which was clearly a liberal assumption. Not surprisingly, our data support complex inheritance for this common disorder. The size of the group was only small to moderate for mapping a complex trait, but the power is made greater than that for a disorder with later onset (such as panic disorder) by the relatively greater informativeness of younger subjects due to a more favorable age-corrected liability curve for social phobia. Also, an extended-pedigree design, such as we employed, provides greater power for a given group size than many other designs used to study the genetics of complex traits, such as affected sibling pair designs.
A confluence of strong "suggestive" results under different analytic models, taken together with the presence in the genomic region of a favored candidate gene (SLC6A2, which encodes NET1) (41), supports the possibility of a social phobia risk locus on chromosome 16. These results require confirmation in additional groups of subjects. Ideally, this would occur in subjects collected through social phobia probands. A future study could also be enhanced by consideration of quantitative or presumptive intermediate phenotypes, such as heart rate, plasma norepinephrine level or other catecholamine index (such as 3-methoxy-4-hydroxyphenylglycol), or imaging measures that offer an opportunity to use specific ligands to directly image the norepinephrine transporter.
Posted by Declan on February 14, 2007, at 1:02:37
In reply to interesting gene link study results re: soc phobia, posted by Michael Bell on February 13, 2007, at 23:54:32
D-cycloserine?
Placebo? Great stuff?
What do you feel about it now?
Posted by munificentexegete on February 14, 2007, at 4:25:16
In reply to Re: interesting gene link study results re: soc ph » Michael Bell, posted by Declan on February 14, 2007, at 1:02:37
> D-cycloserine?
>
> Placebo? Great stuff?
>
> What do you feel about it now?
lol, good question.
Posted by SFY on February 14, 2007, at 11:14:33
In reply to interesting gene link study results re: soc phobia, posted by Michael Bell on February 13, 2007, at 23:54:32
Posted by Phillipa on February 14, 2007, at 11:51:23
In reply to Re: interesting gene link study results re: soc ph, posted by munificentexegete on February 14, 2007, at 4:25:16
Can you explain in simple language. Thanks Phillipa
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