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No genetic linkage or association between a functional promoter polymorphism in the monoamine oxidase-A gene and panic disorder

Molecular Psychiatry volume 5, pages 465–466 (2000)Cite this article

SIR – Panic disorder is a common psychiatric condition defined by recurrent panic attacks and anticipatory anxiety, with a lifetime prevalence of 1–3%.1 Accumulating evidence predicts a familial component to this disorder, with a 2.6- to 20-fold relative risk in the first-degree relatives of probands,2 while twin studies show that about 40% of the liability towards panic disorder consists of heritable factors.3 The two tandemly linked monoamine oxidases (MAOA and MAOB) on the X chromosome are attractive candidate genes for panic disorder because inhibitors of these enzymes (MAOIs) are powerful antipanic agents. Biological studies of MAO activity in patients with panic disorder are equivocal, showing higher,4 lower,5 or no difference.6 In one recent case-control study, variation in a functional promoter polymorphism in the gene for MAOA7 was observed to be associated with panic disorder in females in two patient populations.8 Given this observation and the possible importance of MAO function in panic disorder, we have utilized a family-based design to look for linkage or association between panic disorder and this MAOA polymorphism.

In the current study, 620 individuals in 70 multiplex families, and 81 triads consisting of proband (62 female and 19 male), mother, and father were genotyped. Ascertainment and diagnostic protocols were as previously described.9, 10 PCR amplification of the MAOA variable number tandem repeat was performed as described,7 with the addition of 1 M anhydrous betaine. PCR products were separated by electrophoresis on a 4% polyacrylamide gel on an ABI Prism 377 DNA Sequencer, and were analyzed using GENESCAN software. Genotypes were scored by PCR product size and numbered as in Deckert et al8 (3, 330 bp; 3a, 345 bp; 4, 360 bp; 5, 390 bp). These alleles, reflecting repeat number, correspond to numbers 1 to 4, respectively, in Sabol et al.7 Alleles in the ‘triad’ families were analyzed with the haplotype-based haplotype relative risk (HHRR) method,11, 12 the transmission disequilibrium test (TDT) statistic,12 and the contingency table χ2 tests. Monte-Carlo simulations were performed with the CLUMP program to assess the significance of the derived χ2 test statistics for the large contingency tables with low numbers of rare alleles.13 Pedigrees were analyzed for linkage using both dominant and recessive genetic models of inheritance and a penetrance of 50%, assuming both genetic heterogeneity and homogeneity, under three diagnostic models (narrow, intermediate, and broad) using the FASTLINK package with the X-linked option for X-linked markers.14 There are 339, 385, and 431 affecteds in our pedigrees under the narrow, intermediate, and broad models, repectively. The triad probands all met criteria for definitely or probably affected (broad model).

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Acknowledgements

The authors would like to acknowledge the invaluable contribution made by the families who participated in this study, Dr Joseph Terwilliger for discussions about the HHRR, and an anonymous reviewer for helpful suggestions. This study was supported by grants: NIMH; MH28274 (MMW), MH37592 (AJF), MH30906 (DFK), and MH48858 (SEH).

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Authors and Affiliations

  1. Department of Psychiatry, College of Physicians and Surgeons at Columbia University and the New York State Psychiatric Institute,

    S P Hamilton, S L Slager, G A Heiman, D F Klein, S E Hodge, M M Weissman, A J Fyer & J A Knowles

  2. Department of Genetics and Development, Columbia University,

    F Haghighi

  3. The Columbia Genome Center and College of Physicians and Surgeons at Columbia University,

    J A Knowles

  4. Division of Biostatics, Columbia University,

    S E Hodge

  5. Mailman School of Public Health, Columbia University,

    M M Weissman

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  1. S P Hamilton
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  2. S L Slager
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  7. M M Weissman
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  9. J A Knowles
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Correspondence to J A Knowles.

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Hamilton, S., Slager, S., Heiman, G. et al. No genetic linkage or association between a functional promoter polymorphism in the monoamine oxidase-A gene and panic disorder. Mol Psychiatry 5, 465–466 (2000). https://doi.org/10.1038/sj.mp.4000772

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