Abstract
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.
Highlights
Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent worry and phobic avoidance
The results of genotyped single-nucleotide polymorphism (SNP) showing P-value o10 À 4 in the genome-wide association study (GWAS) I and II are provided in Supplementary Tables S1 and S2, respectively
We performed a new GWAS and a meta-analysis of our two GWAS data sets followed by a replication study in Japanese (1047 PD cases and 2578 controls in total)
Summary
Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent worry and phobic avoidance. Lifetime prevalence of PD is 1–3%, and twice as many women as men suffer from the disorder.[1] The disorder frequently takes a chronic course, with many remissions and relapses. A large number of genetic studies of PD including linkage and association analyses have been conducted.[6,7,8] Suggestive evidence for linkage in several regions and association of candidate genes such as monoamine- and neuropeptide-related genes has been reported. These studies have failed to find conclusive susceptibility genes for PD
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