Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Abstract

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson's Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.Comparability of PGC2 studies PGC2 compiled the largest collection of global PTSD GWAS to date, with subjects recruited from both clinically deeply characterized, small patient groups and large cohorts with self-reported PTSD symptoms. We did not restrict the type of trauma subjects were exposed to, and trauma included both civilian and/or military events, often with pre-existing exposure to childhood trauma. To evaluate the comparability of these phenotypically heterogeneous studies we first estimated genetic correlations with LDSC, 15 a method that leverages GWAS summary results, the only data type available to PGC-PTSD for several of the larger military and non-US cohorts. We found significant genetic correlations (r g ) between studies using a cross-validation approach including all PGC2 EUA subjects (10 runs with studies randomly placed into 2 groups; mean r g = 0.56, mean SE = 0.23, mean p = 0.029, Supplementary Table 8).Next, additional analyses on the UK Biobank cohort (UKBB) were performed. This cohort comprises a very large proportion of the data, with almost as many EUA cases as the rest of the EUA PGC2 combined (referred to as PGC1.5). PTSD screening in UKBB was based on self-reported symptoms from a mental health survey. 16 We found a considerable genetic correlation between the UKBB and PGC1.5 EUA subjects (r g = 0.73, SE = 0.21, p = 0.0005; Supplementary Table 9). Further, sensitivity analyses in the UKBB using 3 alternative inclusion criteria for PTSD cases and controls showed stable correlations with PGC1.5 (P1 -P3; r g = 0.72 -0.79; Supplementary Table 10). Subsequent analyses were based on the UKBB phenotype including the largest number of subjects (P1; N = 126,188). Sex-stratified genetic correlations support the findings of a significant genetic signal...

The genetics of the mood disorder spectrum: genome-wide association analyses of over 185,000 cases and 439,000 controls

“…LDSC separates genome-wide inflation into components 4 due to polygenicity and confounding (25). Inflation not due to polygenicity was 5 quantified as (intercept-1)/(mean observed chi-square-1) (26). Genetic correlations 6 were calculated in LDSC between each analysis and 414 traits curated from 7 published GWAS.…”

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

“…We compared our top SNP associations from the PTSD case-control and PCL-total results against the largest available PTSD external dataset, PGC-PTSD 2.0 (Nievergelt et al, 2018). For our case-control phenotype, we used the lead SNPs in MVP, and for our continuous PTSD symptom scores (PCL) we considered independent GWS variants (r 2 <0.1).…”

“…Although most Americans (50-85%) experience traumatic events over a lifetime, most do not develop PTSD -lifetime PTSD prevalence is approximately 7% (Kessler and Wang, 2008), suggesting differential resilience to stress and vulnerability to the disorder (Atwoli et al, 2015). There is a substantial heritable basis for PTSD risk (Stein et al, 2002;Wolf et al, 2018), and evidence from genome-wide association studies (GWAS) shows that PTSD, like other mental disorders , is highly polygenic (Benjet et al, 2016;Daskalakis et al, 2018;Duncan et al, 2018;Nievergelt et al, 2018;Xie et al, 2013).…”

“…Other approaches to surmounting phenotypic heterogeneity include the accrual of ever larger sample sizes, which has proven effective for other mental disorders such as schizophrenia and major depression . The largest PTSD GWAS study to date, conducted by the PTSD Working Group of the Psychiatric Genomics Consortium (PGC-PTSD) included approximately 30,000 cases (Nievergelt et al, 2018), still moderately-powered by contemporary GWAS standards, assimilating information from over 60 separate heterogeneous sources. The use of biobanks with relatively large numbers of PTSD cases offers the opportunity to provide unprecedented sample size, ascertain granularity of symptoms and associated comorbid conditions and, importantly, uniformity of phenotypic and genotypic platforms .…”

“…Heritability of each of these phenotypes as well as observed (phenotypic) and genetic (rg) correlations were examined with the aim of determining coherence among them; rg with other behavioral and health-related traits were also examined. Results for the phenotype with greatest estimated heritability in MVP were replicated in an external dataset using polygenic risk scores (PRSs) (Wray et al, 2014) from MVP-PTSD as predictors of PTSD case-control status in PGC-PTSD Freeze 2.0 (Nievergelt et al, 2018). Postmortem brain expression analysis (Girgenti and Duman, 2018) was subsequently used to validate key GWAS observations.…”