Unbiased pyrosequencing detected an astrovirus after conventional methods failed to identify the causative agent.
Substantial evidence supports that there is a genetic component to panic disorder (PD). Until recently, attempts at localizing genes for PD by using standard phenotypic data have not proven successful. Previous work suggests that a potential subtype of PD called the panic syndrome exists, and it is characterized by a number of medical conditions, most notably bladder͞renal disorders. In the current study, a genome scan with 384 microsatellite markers was performed on 587 individuals in 60 multiplex pedigrees segregating PD and bladder͞kidney conditions. Using both single-locus and multipoint analytic methods, we found significant linkage on chromosome 22 (maximum heterogeneity logarithm of odds score ؍ 4.11 at D22S445) and on chromosome 13q (heterogeneity logarithm of odds score ؍ 3.57 at D13S793) under a dominantgenetic model and a broad phenotypic definition. Multipoint analyses did not support the observation on chromosome 22. The chromosome 13 findings were corroborated by multipoint findings, and extend our previous findings from 19 of the 60 families. Several other regions showed elevated scores by using when one analytic method was used, but not the other. These results suggest that there are genes on chromosome 13q, and possibly on chromosome 22 as well, that influence the susceptibility toward a pleiotropic syndrome that includes PD, bladder problems, severe headaches, mitral valve prolapse, and thyroid conditions. A mong human psychiatric disorders, panic disorder (PD) is unusual for its combination of physiological and psychological symptoms. Whereas somatoform disorders are characterized by the former, and mood͞psychotic disorders by the latter, it is only in PD that bodily sensations and emotional reactions are so critically intertwined. A formal diagnosis of PD requires having recurrent panic attacks, which are brief episodes of intense fear that are accompanied by a number of physical symptoms, including palpitations, sweating, sensations of shortness of breath or smothering, the feeling of choking, chest pain, paresthesias, and nausea, among others. These attacks must be accompanied by anticipatory anxiety, the fear that one will have additional attacks. The worldwide lifetime prevalence of PD is Ϸ1-3% (1), and numerous family studies suggest a relative risk of Ϸ8 for PD in first-degree relatives of PD probands when compared with the relatives of controls (2). Twin studies provide evidence for a heritability estimate as high as 0.48 (3). The past several years have seen efforts to identify the genetic factors contributing to PD. Three genome scans, a focused genome screen, and a number of candidate-gene studies of PD have been completed by us and others. Our first-stage genome scan of 23 pedigrees revealed six markers that gave logarithm of odds (LOD) scores of Ͼ1.0, but none with scores of Ͼ2.0 (4). Also, using 23 families, Crowe et al. (5) reported, in a second genome scan, a maximum LOD score of 2.23 on chromosome 7p15. This location was just 10 centimorgans (cM) from the location of our ...
Data from clinical and behavioral pharmacological studies have implicated adenosine in anxiety behaviors, while genetic studies have suggested that adenosine receptors may be associated with panic disorder. We have undertaken an analysis of several DNA sequence variations in the adenosine 2A receptor (ADORA2A) in a large sample of panic disorder pedigrees. Individuals from 70 panic disorder pedigrees, and 83 child-parent 'trios', were genotyped at five single-nucleotide polymorphisms (SNPs) in and near the ADORA2A gene and were analyzed for genetic linkage and association. Linkage analysis revealed elevated LOD scores for a silent substitution (1083C/T, SNP-4) in the second coding exon. This SNP has been previously reported to be associated with panic disorder. We observed a maximal heterogeneity LOD score of 2.98 (y ¼ 0) under a recessive genetic model and narrow diagnostic model. Other SNPs showed no evidence for linkage. Association tests were not significant for any of the five ADORA2A SNPs. When SNP haplotypes were assessed in the triads with TRANSMIT, one 3-marker haplotype (SNPs 1, 4, 5) was nominally significantly associated with panic disorder (p ¼ 0.029). Pairwise estimations of linkage disequilibrium between the SNPs showed strong patterns of linkage disequilibrium across the ADORA2A locus. Analyses carried out by broadening the panic disorder phenotype to include agoraphobia continued to support linkage to ADORA2A. Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder.
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