Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder

Steven P. Hamilton, Susan L Slager, Ada Baisre De Leon, Gary A. Heiman, Donald F. Klein, Susan E. Hodge, Myrna M. Weissman, Abby J. Fyer, James A. Knowles

Research output: Contribution to journalArticle

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Abstract

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 (θ = 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 = 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.

Original languageEnglish (US)
Pages (from-to)558-565
Number of pages8
JournalNeuropsychopharmacology
Volume29
Issue number3
DOIs
StatePublished - Mar 2004

Fingerprint

Genetic Linkage
Purinergic P1 Receptors
Panic Disorder
Single Nucleotide Polymorphism
Agoraphobia
Linkage Disequilibrium
Pedigree
Haplotypes
Genes
Chromosomes, Human, Pair 22
Genetic Models
DNA Sequence Analysis
Adenosine
Exons
Anxiety
Pharmacology
Phenotype

Keywords

  • Adenosine receptor
  • ADORA2A
  • Association
  • Genetic
  • Linkage
  • Panic disorder
  • SNP

ASJC Scopus subject areas

  • Pharmacology

Cite this

Hamilton, S. P., Slager, S. L., De Leon, A. B., Heiman, G. A., Klein, D. F., Hodge, S. E., ... Knowles, J. A. (2004). Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. Neuropsychopharmacology, 29(3), 558-565. https://doi.org/10.1038/sj.npp.1300311

Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. / Hamilton, Steven P.; Slager, Susan L; De Leon, Ada Baisre; Heiman, Gary A.; Klein, Donald F.; Hodge, Susan E.; Weissman, Myrna M.; Fyer, Abby J.; Knowles, James A.

In: Neuropsychopharmacology, Vol. 29, No. 3, 03.2004, p. 558-565.

Research output: Contribution to journalArticle

Hamilton, SP, Slager, SL, De Leon, AB, Heiman, GA, Klein, DF, Hodge, SE, Weissman, MM, Fyer, AJ & Knowles, JA 2004, 'Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder', Neuropsychopharmacology, vol. 29, no. 3, pp. 558-565. https://doi.org/10.1038/sj.npp.1300311
Hamilton, Steven P. ; Slager, Susan L ; De Leon, Ada Baisre ; Heiman, Gary A. ; Klein, Donald F. ; Hodge, Susan E. ; Weissman, Myrna M. ; Fyer, Abby J. ; Knowles, James A. / Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. In: Neuropsychopharmacology. 2004 ; Vol. 29, No. 3. pp. 558-565.
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