A genome-wide association study of emotion dysregulation: Evidence for interleukin 2 receptor alpha

Abstract

Emotion dysregulation has been implicated as a risk factor for many psychiatric conditions. Therefore, examining genetic risk associated with emotion dysregulation could help inform cross-disorder risk more generally. A genome-wide association study (GWAS) of emotion dysregulation using single nucleotide polymorphism (SNP) array technology was conducted in a highly traumatized, minority, urban sample (N = 2600, males = 774). Post-hoc analyses examined associations between SNPs identified in the GWAS and current depression, posttraumatic stress disorder (PTSD), and history of suicide attempt. Methylation quantitative trait loci were identified and gene set enrichment analyses were used to broadly determine biological processes involved with these SNPs. Among males, SNP rs6602398, located within the interleukin receptor 2A gene, IL2RA, was significantly associated with emotion dysregulation (p = 1.1 × 10^-8). Logistic regression analyses revealed this SNP was significantly associated with depression (Exp(B) = 2.67, p < 0.001) and PTSD (Exp(B) = 2.07, p < 0.01). This SNP was associated with differential DNA methylation (p < 0.05) suggesting it may be functionally active. Finally, through gene set enrichment analyses, ten psychiatric disease pathways (adjusted p < 0.01) and the calcium signaling pathway (adjusted p = 0.008) were significantly associated with emotion dysregulation. We found initial evidence for an association between emotion dysregulation and genetic risk loci that have already been implicated in medical disorders that have high comorbidity with psychiatric disorders. Our results provide further evidence that emotion dysregulation can be understood as a potential psychiatric cross-disorder risk factor, and that sex differences across these phenotypes may be critical. Continued research into genetic and biological risk associated with emotion dysregulation is needed.

Keywords: Emotion dysregulation; Genetics; Genome-wide association study; Transdiagnostic risk; Traumatized population.

Figure 1

Representation of analytic approach and relative sample sizes for each analysis conducted. GSEA = Gene Set Enrichment Analysis; KEGG = Kyoto Encyclopedia of Genes and Genomes.

Figure 2

rs6602398, on chromosome 10, is associated with emotion dysregulation in males. a) Manhattan plot for emotion dysregulation in the sample (African American males only, N=774) shows genome-wide associated SNP rs6602398 (β (SE)=14.9 (2.6); p=1.1×10⁻⁸). b) Regional plot of chromosome 10 showing a peak of associated SNPs associated with emotion dysregulation in IL2RA (significant SNP rs6602398 is shown by a diamond) in males. Plot generated with LocusZoom (Prium et al., 2010).

Figure 2

rs6602398, on chromosome 10, is associated with emotion dysregulation in males. a) Manhattan plot for emotion dysregulation in the sample (African American males only, N=774) shows genome-wide associated SNP rs6602398 (β (SE)=14.9 (2.6); p=1.1×10⁻⁸). b) Regional plot of chromosome 10 showing a peak of associated SNPs associated with emotion dysregulation in IL2RA (significant SNP rs6602398 is shown by a diamond) in males. Plot generated with LocusZoom (Prium et al., 2010).