Replication and meta-analysis of TMEM132D gene variants in panic disorder

Abstract

A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.

Figure 1

Combined meta-analysis for the SNP rs7309727 in the TMEM132D gene. ACG: Aarhus, Copenhagen, Gothenburg; Tartu (Estonia); European Ancestry: all samples except the Japanese sample; European Ancestry primary PD: exclusion of cases with severe and recurrent major depression, bipolar disorder, schizophrenia and substance dependence; IT: Iowa, Toronto (USA, Canada); MPI: Max Planck Institute for Psychiatry, Munich; NIMH: National Institute for Mental Health (USA). *Samples published in Erhardt et al.

Figure 2

Combined meta-analysis of the risk haplotype TA for rs7309727 and rs11060369. ACG: Aarhus, Copenhagen, Gothenburg; Tartu (Estonia); European Ancestry: all samples except the Japanese sample; European Ancestry primary PD: exclusion of cases with severe and recurrent major depression, bipolar disorder, schizophrenia and substance dependence; IT: Iowa, Toronto (USA, Canada); MPI: Max Planck Institute for Psychiatry, Munich; NIMH National Institute for Mental Health (USA). *Samples published in Erhardt et al.