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.

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

“…Risk genotypes were associated with higher TMEM132D mRNA expression in human postmortem frontal cortex, results further supported by a mouse model in which high anxiety-related behavior was associated with a Tmem132d SNP and correlated with expression of Tmem132d mRNA in the anterior cingulate cortex (Erhardt et al, 2011). In a subsequent meta-analysis of eight independent case-control samples, genome-wide significant associations of rs7309727 and the haplotype of rs7309727-rs11060369 were reported when the analysis was restricted to European ancestry cases with primary PD (Erhardt et al, 2012). The function of this gene is not fully understood, but it has been suggested that it has a role in threat processing (Haaker et al, 2014).…”

Specific and common genes implicated across major mental disorders: A review of meta-analysis studies

“…The function of TMEM132D still remains to be confirmed but there is some suggestion of its involvement in neuronal sprouting and brain connectivity (Erhardt et al, 2012). Significant effects at p < .05 were also identified for the 5-HTTLPR genetic variant in OCD as listed in Supplementary Table 1.…”

“…Strong gene effects (p < .001) were also identified for 2 variants of the TMEM132D gene: the rs7309727 T allele and the rs11060369 A allele in predicting PD in mixed/Caucasians (Erhardt et al, 2012). The function of TMEM132D still remains to be confirmed but there is some suggestion of its involvement in neuronal sprouting and brain connectivity (Erhardt et al, 2012).…”

Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways

“…13,14 A recent genome-wide copy number variation study also found an excess of common duplications in a region on 16p11.2. 15 Genome-wide association (GWA) studies of PD [11][12][13][14][15][16][17][18][19][20][21] have not yet established risk loci, though 1 genetic 12,14,22,23 and functional 12,22 data have recently implicated variation in TMEM132D.…”