A Subgroup Analysis of Genome-wide Association Study for Panic Disorder

Abstract

Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. To date, few genetic and environmental factors were found to be involved in PD and pathogenesis of PD is remained to be elucidated. Single nucleotide polymorphisms (SNPs) in TMEM132D and COMT, are only a few genetic factors of PD that were replicated in several studies in European population, but not in Japanese population. We previously performed a genome-wide association study (GWAS), however, there seemed to be polymorphisms which did not reach genome-wide significance threshold due to their low allele frequencies and odds ratios, although they were truly associated with PD. We then performed pathway analyses to overcome the limitations of a conventional single-marker analysis. The pathway analyses identified the associations of immune pathways with PD. Based on the results of pathway analyses, we especially focused on and investigated HLA-B and HLA-DRB1. As a result, a frequency of HLA-DRB1*13:02 was significantly higher in PD patients than in control (P=2.62×10⁻⁵, odds ratio=1.70). We further examined sub-group analyses of GWAS, taking effects of HLA alleles into account. The SNP genotype data were subdivided into two datasets: those of HLA-DRB1*13:02-positive subjects (cases: N=103; controls: N=198) and those of HLA-DRB1*13:02-negative subjects (cases: N=438; controls: N=1,341). As a result, one SNP in MCPH1 showed a genome-wide significant association with PD and several SNPs in TMEM132D showed suggestive associations with PD in subjects without HLA-DRB1*13:02.