Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q

Abstract

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 ...

Replication of a genome-wide association study of panic disorder in a Japanese population

“…15 In association analyses, candidate genes including HTR 1A, 16 2A, 17,18 CCK, 19 ADORA2A, 20 MAOA 21 and COMT 22,23 have been investigated. Most of the association studies were, however, of small sample size (No200) and the results were controversial.…”

Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype

“…[3][4][5] Several genome-wide linkage studies have tried to identify genomic regions harboring quantitative trait loci (QTLs) that influence the vulnerability for anxiety disorders. All these studies [6][7][8][9][10][11][12][13][14][15] ascertained the pedigrees through probands with panic disorder, except for one study 16 that included pedigrees with at least one member having an anxiety disorder or somatoform pain. Panic disorder is the most frequently analyzed phenotype.…”

“…[6][7][8]13,14 Two studies focused on panic disorder with comorbid medical conditions, that is renal/ bladder conditions, thyroid irregularities, mitral valve prolapse and severe headaches. 11,15 Simple phobia and social phobia have each been investigated once. 9,10 Other anxiety phenotypes 12,14,16 have been based on findings from genetic epidemiological studies indicating a common genetic background for anxiety disorders, 4,17 Thorgeirsson et al 16 considered anxiety disorder or somatoform pain as indicators of affection status.…”

Association of the Val158Met Catechol O-Methyltransferase Genetic Polymorphism with Panic Disorder

“…Family and twin studies suggest a genetic component in the etiopathogenesis of PD with an estimated heritability of up to 46% (Hettema et al, 2001). In genomewide scans, several possible regions for panic disorder have been identified (Crowe et al, 1987;Gelernter et al, 2001;Hamilton et al, 2003;Knowles et al, 1998;Thorgeirsson et al, 2003), among them one locus on chromosome 11 in the region of the cholecystokinin-B receptor (CCKBR) gene (Gelernter et al, 2001). PD is considered a complex psychiatric disorder as there has been no simple Mendelian pattern of inheritance found in segregation studies (Vieland et al, 1996).…”