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Otowa T.,University of Tokyo | Tanii H.,Mie University | Sugaya N.,Outpatient Clinic for Anxiety Disorders | Yoshida E.,Outpatient Clinic for Anxiety Disorders | And 14 more authors.
Journal of Human Genetics

Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent worry and phobic avoidance. Although a number of association and linkage studies have been conducted, no gene has been identified as a susceptibility locus. We previously conducted a genome-wide association analysis of PD in 200 Japanese patients and the same number of controls, using a 500 K single nucleotide polymorphisms (SNPs) chip. In this study, we report a replication analysis of PD using the DigTag2 assay. The second stage sample consisted of 558 Japanese patients and 566 controls. Thirty-two markers were tested in a replication sample. As a result, no significant association was found after correction for multiple testing. However, the difference was observed at the nominal allele P-value <0.05 for two SNPs (rs6733840 and rs132617). We also conducted haplotype analyses of SNPs in the APOL3 and CLU genes. Our results failed to show any significant association with PD in these genes. Further studies on these variants with a larger sample size may be worth testing to confirm the results. © 2010 The Japan Society of Human Genetics All rights reserved. Source

Otowa T.,University of Tokyo | Tochigi M.,University of Tokyo | Kawamura Y.,University of Tokyo | Sugaya N.,Tokyo Metropolitan Institute of Medical Science | And 11 more authors.
Journal of Human Genetics

Panic disorder (PD) is a severe and chronic psychiatric disorder, with genetic components underlying in its etiology. The PERIOD2 (Per2) gene has been reported to be associated with familial advanced sleep phase syndrome. Considering the high frequency of sleep disturbance in PD, Per2 may be a candidate gene for PD. Therefore, we conducted a two-stage case-control association study in the Japanese population. In the first screening sample of 203 patients and 409 controls, we investigated three single-nucleotide polymorphisms in Per2. We found a potential association in the screening sample (rs2304672, genotype P=0.046, uncorrected), whereas we could not replicate the association in the second sample of 460 patients and 460 controls. Our results suggest that Per2 may not have a major role in the pathogenesis of PD in the Japanese population. © 2011 The Japan Society of Human Genetics All rights reserved. Source

Otowa T.,Virginia Commonwealth University | Otowa T.,University of Tokyo | Shimada T.,University of Tokyo | Kawamura Y.,University of Tokyo | And 14 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

Panic disorder (PD) is a severe and chronic psychiatric disorder with significant genetic components underlying its etiology. The gene regulator of G protein signaling 2 (RGS2) has been reported to be associated with anxiety disorders. To confirm the association of RGS2 with PD, we investigated three single nucleotide polymorphisms (SNPs) of RGS2 (rs10801152, rs4606, and rs1819741) in 677 Japanese PD cases and 460 controls. The SNP rs10801152 was suggestive of an association with PD (allele P=0.045 adjusted using sex and age as confounding factors). The three-SNP haplotype was significantly associated with PD (global permutation P=4×10-4). The haplotypes T-G-C and T-C-T showed significant association and protective effect on PD (T-G-C, permutation P=0.038, OR=0.80, 95%CI=0.68-0.95; T-C-T, permutation P=0.004, OR=0.38, 95%CI=0.21-0.70). These results provide support for an association of RGS2 with PD in a Japanese population. © 2011 Wiley-Liss, Inc. Source

Sugaya N.,Yokohama City University | Yoshida E.,Outpatient Clinic for Anxiety Disorders | Yasuda S.,Outpatient Clinic for Anxiety Disorders | Yasuda S.,Kanagawa Psychiatric Center | And 14 more authors.
BioPsychoSocial Medicine

Several studies have reported an increased tendency towards anger in patients with panic disorder (PD). If this propensity for anger arises from the pathological process of PD, it may be associated with the duration of the illness. The present study therefore examined the relationship between duration of PD and the personality tendency to experience anger in PD patients. Methods: Participants were 413 patients (132 men and 281 women; age=38.7years) with PD. Diagnoses were confirmed using the Mini-International Neuropsychiatric Interview. Illness duration ranged from less than a year to 51years. After participants completed the Revised NEO Personality Inventory, we examined the association between illness duration and the Angry Hostility and Impulsiveness subscale scores. In the analysis, participants were divided into two groups by duration of illness (long group, n = 186 and short group, n=200) using the median value (9years) as a cut-off because of the skewed distribution of the duration. Patients with an illness duration of 9years (n=27) were excluded from the comparison. Results: The duration of illness was significantly correlated with the Angry Hostility score (p=0.002) after controlling for age. Scores were significantly higher in the long group than in the short group (p=0.04). No significant association was observed between Impulsiveness scores and duration of illness. Conclusion: The present study suggests that longer PD duration is related to a stronger tendency to experience anger. © Sugaya et al. Source

Otowa T.,University of Tokyo | Otowa T.,Virginia Commonwealth University | Kawamura Y.,Sakae Seijinkai Hospital | Nishida N.,University of Tokyo | And 31 more authors.
Translational Psychiatry

Panic disorder (PD) is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Due to the lack of power in previous association studies, genes that are truly associated with PD might not be detected. In this study, we conducted a genome-wide association study (GWAS) in two independent data sets using the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. We obtained imputed genotypes for each GWAS and performed a meta-analysis of two GWAS data sets (718 cases and 1717 controls). For follow-up, 12 single-nucleotide polymorphisms (SNPs) were tested in 329 cases and 861 controls. Gene ontology enrichment and candidate gene analyses were conducted using the GWAS or meta-analysis results. We also applied the polygenic score analysis to our two GWAS samples to test the hypothesis of polygenic components contributing to PD. Although genome-wide significant SNPs were not detected in either of the GWAS nor the meta-analysis, suggestive associations were observed in several loci such as BDKRB2 (P=1.3 × 10 -5, odds ratio=1.31). Among previous candidate genes, supportive evidence for association of NPY5R with PD was obtained (gene-wise corrected P=6.4 × 10 -4). Polygenic scores calculated from weakly associated SNPs (P<0.3 and 0.4) in the discovery sample were significantly associated with PD status in the target sample in both directions (sample I to sample II and vice versa) (P<0.05). Our findings suggest that large sets of common variants of small effects collectively account for risk of PD. © 2012 Macmillan Publishers Limited All rights reserved. Source

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