No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder

Hamilton, Steven P.; Slager, Susan L.; Helleby, Leticia; Heiman, Gary A.; Klein, Donald F.; Hodge, Susan E.; Weissman, Myrna M.; Fyer, Abby J.; Knowles, James A.

doi:10.1038/sj.mp.4000788

Cited by 48 publications

(44 citation statements)

References 40 publications

(43 reference statements)

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“…However, even if this is a true linkage signal, the source of the signal could plausibly be one of the other genes in this map region. A previous investigation suggested genetic association between CCKBR and PD [Kennedy et al, 1999]; however, Hamilton et al [2001] found neither association or linkage of CCKRB to PD, using an short tandem repeat (STR) polymorphism. PD and agoraphobia have often been conceptualized clinically as parts of a severity continuum, with agoraphobia developing at least partly as a response to situational panic attacks, symptomatic of increasing severity of the disorder.…”

Section: Discussionmentioning

confidence: 95%

“…Neither of the initial two genome scan reports [Knowles et al, 1998;Crowe et al, 2001] reported use of a marker at CCKBR, which was the site of our maximum LOD score. However, Hamilton et al [2001] recently reported negative linkage results in the Columbia pedigree series using a different CCKBR marker. Also, our study differed in recruitment strategy from the others in that our focus was not exclusively on PD.…”

Section: Discussionmentioning

confidence: 95%

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Linkage genome scan for loci predisposing to panic disorder or agoraphobia

Bonvicini¹,

Page²,

Woods³

et al. 2001

Am. J. Med. Genet.

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We conducted a 10 cM linkage genome scan in a set of 20 American pedigrees (153 subjects), ascertained through probands with panic disorder (PD). Several anxiety disorders segregate in these families; they were diagnosed on the basis of Schedule for Affective Disorders and Schizophrenia interview. In this article, we describe results for panic disorder and agoraphobia, which are closely related, common, heritable anxiety disorders. This is the first complete linkage genome scan for agoraphobia and the third for PD. A total of 407 markers (389 autosomal, 18 X chromosome) were genotyped. Multipoint LOD score and NPL analysis were completed using GENEHUNTER2. For PD, two genomic regions meet criteria for suggestive linkage. One of these regions is on chromosome 1 (LOD score = 2.04). This region coincides with a region that generated a LOD score of 1.1 in a previous genome scan by Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109]. The other (LOD score = 2.01) is located on chromosome 11p and occurs at marker CCKBR, one of eight candidate genes examined. For agoraphobia, the most promising potential linkage was on chromosome 3 (NPL score = 2.75; P = 0.005). This was accounted for primarily by a single family that by itself generated an NPL score of 10.01 (P = 0.0039) and a LOD score of 2.10. These results provide initial evidence for a genetic locus on chromosome 3 that contributes to risk for agoraphobia. They also support suggestive linkage to two risk loci for panic disorder. Additional potential loci were identified with lesser statistical support; several of these were consistent with previously reported panic disorder linkage results. Overall, the results presented here suggest that PD and agoraphobia are complex traits that share some, but not all, of their susceptibility loci. Published 2001 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

Linkage genome scan for loci predisposing to panic disorder or agoraphobia

Bonvicini¹,

Page²,

Woods³

et al. 2001

Am. J. Med. Genet.

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“…Its heritability is estimated to be between 0.41 and 0.54 [Hettema et al, 2001]. A number of linkage and candidate gene association studies have been published for panic disorder [Hamilton et al, 2001;Sen et al, 2004;Van West and Claes, 2004;Cheng et al, 2006;Zeggini et al, 2007]. While numerous positive candidate gene associations and several linkage loci have been reported, only few of them have been replicated so far [Deckert et al, 1998[Deckert et al, , 1999Hamilton et al, 2002;Hosing et al, 2004;Peters et al, 2004;Domschke et al, 2007].…”

mentioning

confidence: 96%

Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder

Keck

Kern

Erhardt

et al. 2008

American J of Med Genetics Pt B

105

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Accumulating evidence from animal studies suggests that the corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) neuropeptide systems, contribute to anxiety behavior. To investigate whether polymorphisms in the genes regulating these two systems may alter susceptibility to anxiety disorders in humans, we genotyped 71 single nucleotide polymorphisms (SNPs) in CRH, CRHR1, CRHR2, AVP, AVPR1A, AVPR1B in a German sample from Munich with patients suffering from panic disorder and matched healthy controls (n = 186/n = 299). Significant associations were then replicated in a second German sample with 173 patients with panic disorder and 495 controls. In both samples separately and the combined sample, SNPs within CHRH1 and AVPR1B were nominally associated with panic disorder. We then tested two locus multiplicative and interaction effects of polymorphisms of these two genes on panic disorder. Fifteen SNP pairs showed significant multiplicative effects in both samples. The SNP pair with the most significant association in the combined sample (P = 0.00057), which withstood correction for multiple testing, was rs878886 in CRHR1 and rs28632197 in AVPR1B. Both SNPs are of potential functional relevance as rs878886 is located in the 3' untranslated region of the CRHR1 and rs28632197 leads to an arginine to histidine amino acid exchange at position 364 of AVPR1B which is located in the intracellular C-terminal domain of the receptor. These data suggest that polymorphisms in the AVPR1B and the CRHR1 genes alter the susceptibility to panic disorder.

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“…SNPs were detected using fluorescence polarization, a technique that distinguishes the polymorphic base of an SNP by the template-directed incorporation of a dye-labeled dideoxynucleotide onto an oligonucleotide primer that anneals just 5 0 to the polymorphic base (Chen et al, 1999). This homogenous reaction was performed in three stages (Hamilton et al, 2001). Briefly, in the first step, PCR reactions of 5 ml containing 200 nM of the forward and reverse primers ( primers and deoxynucleotides in the PCR products were then degraded by adding a 5 ml solution of 1 U of shrimp alkaline phosphatase (Roche, Indianapolis), 0.5 U of Escherichia coli Exonuclease I (USB, Cleveland), 5mM MgCl 2 , and 50mM Tris-HCl (pH 8.5).…”

Section: Dna Analysismentioning

confidence: 99%

Evidence for Genetic Linkage Between a Polymorphism in the Adenosine 2A Receptor and Panic Disorder

Hamilton

Slager

León

et al. 2003

Neuropsychopharmacol

138

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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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No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder

Cited by 48 publications

References 40 publications

Linkage genome scan for loci predisposing to panic disorder or agoraphobia

Linkage genome scan for loci predisposing to panic disorder or agoraphobia

Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder

Evidence for Genetic Linkage Between a Polymorphism in the Adenosine 2A Receptor and Panic Disorder

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