G30 locus in panic disorder. Molecular Psychiatry (2005) 10, 428â429. doi:10.1038/sj.mp.4001598. Published online 12 October 2004. SIRâRecently, Hamilton ...
Scientific Correspondence
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Investigation of the DAOA/ G30 locus in panic disorder Molecular Psychiatry (2005) 10, 428–429. doi:10.1038/sj.mp.4001598 Published online 12 October 2004 SIR—Recently, Hamilton et al1 performed a genomewide scan in 60 multiplex pedigrees with a ‘panic disorder syndrome’ and found the most convincing linkage evidence on 13q32–q33. This chromosomal region has received strong attention in the study of schizophrenia and bipolar affective disorder (BPAD), since genetic variants within or near to the overlapping genes D-amino-acid oxidase activator (DAOA) and G30 located on 13q33 were associated with both schizophrenia and BPAD.2–4 In this study, we hypothesized that the DAOA/G30 locus might also confer risk for the development of panic disorder (PD). Several lines of evidence support this hypothesis: firstly, DAOA/G30 is located within the linkage peak for panic disorder syndrome observed by Hamilton et al.1 Secondly, results of several clinical and epidemiological studies suggest a shared etiologic background between PD and schizophrenia, for example, Bayle et al,5 as well as between PD and BPAD, for example, MacKinnon et al.6 Thirdly, recent findings suggest the involvement of DAOA in the glutamatergic signaling pathway,2 a pathway that has been implicated in anxiogenesis. We analyzed SNPs at the DAOA/G30 locus in a sample consisting of 152 patients with PD and 208 controls of German descent. Patients were diagnosed according to DSM-IIIR and DSM-IV on the basis of structured clinical interviews (SADS-LA7 and CIDI8) and/or a review of medical records. The control individuals were anonymous blood donors, who had been recruited independently from the controls used in our previous association study of schizophrenia and BPAD.4 We focused on SNPs rs2391191 (M15), rs3918342 (M23), and rs421292 (M24), as these had shown the strongest association in our previous work.4 Additionally, we typed two flanking SNPs, rs778293 (M22) and rs3916972 (M25), covering this chromosomal region. Genotyping was carried out Molecular Psychiatry
using the MassARRAY system (Sequenom, San Diego, USA) according to the genotyping method described by Ding and Cantor,9 with minor modifications (see Supplementary table). We performed both singlemarker and haplotype analyses with the program COCAPHASE 2.40.10 Of the five variants at the DAOA/G30 locus typed, three SNPs (rs778293, rs3918342, and rs1421292) proved to be in significant LD with PD (Table 1), with the strongest evidence being observed for rs1421292 (P ¼ 0.031, OR 1.39). At the genotypic level, significant association was found between PD patients and rs1421292 under a dominant model (P ¼ 0.024, OR 2.12, Table 1). Given that a Bonferroni correction to adjust for multiple testing of loci would be overly conservative, and given the high levels of LD of these closely related markers, we used a permutation procedure instead. Our best P-value in the allelewise analysis was 0.031. In our simulation, a P-value of 0.031 or smaller would be seen by chance alone in 1129 times out of 10 000 replicates, yielding an empirical P-value of 0.113. In a subsequent step, we performed haplotype analysis (data not shown) comprising SNPs rs778293, rs3918342, and rs1421292, which were associated with disease in the single-locus analysis. The three-marker haplotype T–T–A was significantly less frequent in patients with PD (40 vs 48% in controls, P ¼ 0.030), and the haplotype C–C–T was more frequent in PD patients (42 vs 35% in controls, P ¼ 0.072). Although far from being significant (P-values 40.1), it is interesting to note that the allelic and haplotypic associations seem to be stronger in PD than in schizophrenia and BPAD. For example, the same alleles of rs3918342 and rs1421292 previously shown to be associated with schizophrenia and BPAD4 were even more frequent in patients with PD (rs3918342 allele C: 53% in schizophrenia and BPAD,4 57% in PD; rs1421292 allele T: 56 and 55% in schizophrenia and BPAD,4 respectively, 60% in PD). Despite the fact that the observed single-marker associations do not withstand a stringent and robust adjustment for multiple testing at a nominal level of significance, our results suggest that variability at the DAOA/G30 locus may be involved in the etiology of PD. Since we have previously observed the same alleles and haplotypes to be associated with disease in our study on BPAD and schizophrenia, we believe that our findings are of potential interest for the psychiatric genetic community and may give a new perspective on conventional diagnostic categories. J Schumacher1, R Abou Jamra1, T Becker2, N Klopp3,4, P Franke5, C Jacob6, P Sand6, J Fritze7, S Ohlraun5,8, TG Schulze5,8, M Rietschel5,8, T Illig3,4, P Propping1, S Cichon9, J Deckert10 and MM No¨then9 1 Institute of Human Genetics, University of Bonn, Germany; 2Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Germany; 3Genome Analysis Center (GAC), GSF-National Research Center for
rs2391191 corresponds to M15, rs778293 corresponds to M22, rs3918342 corresponds to M23, rs1421292 corresponds to M24, and rs3916972 corresponds to M25. Second allele is the rare allele. c Odds ratios are calculated using the more frequent alleles in affected individuals compared to controls. d The best model out of a dominant and a recessive model is shown. The P-value for the better model was corrected by a factor of 2.1 is the rare allele, 2 is the frequent allele. e Genotype frequencies were in Hardy–Weinberg equilibrium for cases and controls. These P-values are Bonferroni-corrected by 2, since we tested a dominant and a recessive model. f Odds ratios are given for the best-fitting model. The underlined genotypes are compared to the remaining genotypes in controls. g Empirical P-value after adjustment for multiple testing through permutation: 0.113. b
a
(1.13, (1.84, (1.84, (2.12, (1.19, 1.000 0.068 0.054 0.024 1.000 0.316 0.304 0.154 0.320 0.438 0.176 0.209 0.295 0.122 0.132 rs2391191 rs778293 rs3918342 rs1421292 rs3916972
24887 16550 12486 48399 —
G/A T/C T/C T/A T/C
0.58 0.62 0.51 0.52 0.64
(G) (T) (T) (T) (T)
0.57 0.55 0.43 0.60 0.65
(G) (T) (T) (T) (T)
0.703 0.049 0.047 0.031g 0.652
(1.06, (1.35, (1.35, (1.39, (1.08,
0.78–1.45) 1.00–1.83) 1.00–1.83) 1.03–1.89) 0.78–1.48)
0.159 0.126 0.242 0.228 0.153
0.512 0.507 0.507 0.510 0.421
0.329 0.367 0.251 0.262 0.426
0.507 0.486 0.550 0.558 0.431
2–2 1–2 1–1 2–2 1–2 1–1
PD (n ¼ 152) Controls (n ¼ 208) P-values (odds ratio, 95% CI)c
Allelewise analysis
PD (n ¼ 152) Controls (n ¼ 208) Inter-SNP Polymorphismb distances (bp) SNPa
Table 1
Statistical evaluation of allele and genotype frequencies for SNPs at the DAOA/G30 locus
Best modeld
P-valuese (odds ratio, 95% CI)f
0.63–2.01) 1.04–3.26) 1.07–3.17) 1.17–3.83) 0.64–2.21)
Scientific Correspondence
Environment and Health, Neuherberg, Germany; 4Institute of Epidemiology, GSF-National Research Center for Environment and Health, Neuherberg, Germany; 5Department of Psychiatry, University of Bonn, Germany; 6 Department of Psychiatry, University of Wu¨rzburg, Germany; 7Department of Psychiatry, University of Frankfurt, Germany; 8Central Institute of Mental Health, Division Genetic Epidemiology in Psychiatry, Mannheim, Germany; 9 Life & Brain Center, University of Bonn, Germany; 10 Department of Psychiatry, University of Mu¨nster, Germany
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Correspondence should be addressed to: Dr J Schumacher, MD, Institute of Human Genetics, University of Bonn, Wilhelmstr. 31, D-53111 Bonn, Germany. E-mail: johannes.schumacher@ uni-bonn.de
1 Hamilton SP et al. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc Natl Acad Sci USA 2003; 100: 2550–2555. 2 Chumakov I et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 2002; 99: 13675–13680. 3 Hattori E et al. Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series. Am J Hum Genet 2003; 72: 1131–1140. 4 Schumacher J et al. Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. Mol Psychiatry 2004; 9: 203–207. 5 Bayle FJ et al. Clinical features of panic attacks in schizophrenia. Eur Psychiatry 2001; 16: 349–353. 6 MacKinnon DF et al. Association of rapid mood switching with panic disorder and familial panic risk in familial bipolar disorder. Am J Psychiatry 2003; 160: 1696–1698. 7 Mannuzza S et al. Schedule for affective disorders and schizophrenia—lifetime version modified for the study of anxiety disorders (SADS-LA): rationale and conceptual development. J Psychiatr Res 1986; 20: 317–325. 8 Robins LN et al. The composite international diagnostic interview. Arch Gen Psychiat 1988; 45: 1069–1077. 9 Ding C, Cantor CR. Direct molecular haplotyping of long-range genomic DNA with M1-PCR. Proc Natl Acad Sci USA 2003; 13: 7449–7455. 10 Dudbridge F. Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121. Supplementary Information accompanies the paper on Molecular Psychiatry website (http://www.nature.com/mp).
Evidence for linkage to chromosome 13q32 in an independent sample of schizophrenia families Molecular Psychiatry (2005) 10, 429–431. doi:10.1038/sj.mp.4001639 Published online 1 March 2005 SIR — Schizophrenia is a severe psychiatric disorder that affects 1% of the population worldwide. One Molecular Psychiatry
