Genetic Association Analysis of 300 Genes Identifies a Risk Haplotype in SLC18A2 for Post-traumatic Stress Disorder in Two Independent Samples

Abstract

The genetic architecture of post-traumatic stress disorder (PTSD) remains poorly understood with the vast majority of genetic association studies reporting on single candidate genes. We conducted a large genetic study in trauma-exposed European-American women (N ¼ 2538; 845 PTSD cases, 1693 controls) by testing 3742 SNPs across more than 300 genes and conducting polygenic analyses using results from the Psychiatric Genome-Wide Association Studies Consortium (PGC). We tested the association between each SNP and two measures of PTSD, a severity score and diagnosis. We found a significant association between PTSD (diagnosis) and SNPs (top SNP: rs363276, odds ratio (OR) ¼ 1.4, p ¼ 2.1E-05) in SLC18A2 (vesicular monoamine transporter 2). A haplotype analysis of 9 SNPs in SLC18A2, including rs363276, identified a risk haplotype (CGGCGGAAG, p ¼ 0.0046), and the same risk haplotype was associated with PTSD in an independent cohort of trauma-exposed African-Americans (p ¼ 0.049; N ¼ 748, men and women). SLC18A2 is involved in transporting monoamines to synaptic vesicles and has been implicated in a number of neuropsychiatric disorders including major depression. Eight genes previously associated with PTSD had SNPs with nominally significant associations (po0.05). The polygenic analyses suggested that there are SNPs in common between PTSD severity and bipolar disorder. Our data are consistent with a genetic architecture for PTSD that is highly polygenic, influenced by numerous SNPs with weak effects, and may overlap with mood disorders. Genome-wide studies with very large samples sizes are needed to detect these types of effects.

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“…We used the standard polygenic scoring approach (Purcell et al, 2009) with results from the PGC for MDD, BP, and SCZ (Cross-Disorder Group of the Psychiatric Genomics Consortium and Genetic Risk Outcome of Psychosis Consortium, 2013) and found that PTSD diagnosis was predicted by risk scores derived from BPD, but not from MDD or SCZ. Our results for BPD reached significance at p-value thresholds >0.3 from the original GWAS, similar to the PTSD candidate gene study (Solovieff et al, 2014). Pleiotropic effects across a range of psychiatric disorders have recently been reported (Cross-Disorder Group and Genetic Risk Outcome, 2013) and provide exciting new insights into the genetic architecture of PTSD and other psychopathologies.…”

“…On the other hand, the large MRS GWAS was able to replicate a recent finding from a candidate gene study including 300 genes (Solovieff et al, 2014) that demonstrated for the first time the existence of common SNPs between PTSD severity and bipolar disorder based on cross-disorder polygenic risk score analyses. We used the standard polygenic scoring approach (Purcell et al, 2009) with results from the PGC for MDD, BP, and SCZ (Cross-Disorder Group of the Psychiatric Genomics Consortium and Genetic Risk Outcome of Psychosis Consortium, 2013) and found that PTSD diagnosis was predicted by risk scores derived from BPD, but not from MDD or SCZ.…”

“…We also compiled a list of genes that have been reported in the literature to be significantly associated with PTSD, either showing a main effect for the genetic marker, and/or a significant GxE interaction (Amstadter et al, 2009(Amstadter et al, , 2011Binder et al, 2008;Boscarino et al, 2011;Cao et al, 2013;Comings et al, 1996;Dragan and Oniszczenko, 2009;Gillespie et al, 2013;Goenjian et al, 2012;Grabe et al, 2009;Guffanti et al, 2013;Hauer et al, 2011;Kolassa et al, 2010;Logue et al, 2013a,b;Lyons et al, 2013;Mellman et al, 2009;Nelson et al, 2009;Ressler et al, 2011;Segman et al, 2002;Solovieff et al, 2014;Voisey et al, 2010;Wilker et al, 2013;Xie et al, 2013). Since most studies were performed in subjects of either European or African descent, we used these specific ancestry groups for comparison with MRS. We found that most of the 25 candidate genes showed nominally significant associations in MRS for at least one of the SNPs tested.…”

“…Comparing the number of PTSD cases and overall study sizes between MRS and other studies indicated that we were adequately powered to detect many of the reported effects at least for the EA studies. A similar, well-powered study recently failed to replicate findings for 20 PTSD candidate genes after appropriate adjusting for multiple testing (Solovieff et al, 2014). This lack of replication may be due to a relatively large heterogeneity between PTSD studies, which are complicated by the requirement of exposure to a traumatic event, leading to potential differences in type, timing of, and time since trauma, and the observed GxE interactions.…”

“…Most research has focused on: (1) the hypothalamic-pituitary-adrenal (HPA) axis, (2) the ascending brainstem locus coeruleus noradrenergic system, and (3) the limbic amygdalar frontal pathway mediating fear processing. Among the over 25 PTSD candidate genes currently reported (Amstadter et al, 2009(Amstadter et al, , 2011Binder et al, 2008;Boscarino et al, 2011;Cao et al, 2013;Comings et al, 1996;Dragan and Oniszczenko, 2009;Gillespie et al, 2013;Goenjian et al, 2012;Grabe et al, 2009;Guffanti et al, 2013;Hauer et al, 2011;Kolassa et al, 2010;Logue et al, 2013a,b;Lyons et al, 2013;Mellman et al, 2009;Nelson et al, 2009;Ressler et al, 2011;Segman et al, 2002;Solovieff et al, 2014;Voisey et al, 2010;Wilker et al, 2013;Xie et al, 2013), promising findings include associations of PTSD symptoms with the serotonin transporter gene (SERT, SLC6A4) (Xie et al, 2009), which is linked to depression and anxiety disorders, as well as differential acquisition of conditioned fear and increased amygdala excitability in humans. In addition, FKBP5, a co-chaperone of the glucocorticoid receptor involved in the HPA axis, has a significant interaction with severity of child abuse in the prediction of adult PTSD symptoms, indicating a gene by environment (GxE) interaction (Binder et al, 2008).…”