Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Abstract

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Extended data Figure 1:. Comparison of the genetic architecture of PTSD in the three main data sources.

Quantification of polygenicity and polygenic overlap in the three main data subsets based on (1) symptom scores in clinical studies and cohorts assessed on a variety of instruments in Freeze 2.5 (yellow; 26,080 cases and 192,966 controls), (2) PCL (for DSM-IV) based symptom scores in the MVP (red; 32,372 cases and 154,317 controls), and (3) ICD9/10 codes in EHR studies (blue; 78,684 cases and 738,463 controls) indicate a similar genetic architecture. The circles on the top half of the plot depict univariate MiXeR estimates of the total polygenicity for each data subset. Numbers within circles indicate polygenicity values, expressed as the number of variants (in thousands, with SE in parenthesis) necessary to explain 90% of SNP based heritability (h²_SNP). h²_SNP estimates are written in the boxes at the bottom of the circles. The Euler diagrams on the bottom half of the plot depict bivariate MiXeR estimates of the polygenic overlap between data subsets. Values in the overlapping part of the Euler diagrams denote shared polygenicity and values on the non-overlapping parts note dataset-specific polygenicity. Genetic correlations (r_g) between dataset pairs are noted in the boxes below the Euler diagrams. Arrowed lines are drawn between univariate and bivariate results to indicate which dataset pairs are being evaluated. Abbreviations: Neff, effective sample size.

Extended data Figure 2:. Manhattan plot of the PTSD GWAS meta-analysis in individuals of European ancestry (EA).

Results of the EA GWAS meta-analysis (137,136 PTSD cases, 1,085,746 controls) identifying 81 genome-wide significant PTSD loci. The y axis refers to the −log10 p-value from a meta-analysis using a sample size weighted fixed-effects model. Circle colors alternate between chromosomes: even chromosomes are colored blue and odd chromosomes are colored black. The horizontal red bar indicates genome-wide significant associations (p < 5×10⁻⁸).

Extended Data Figure 3:. Significant PTSD gene-sets.

MAGMA gene-set analysis using the Molecular Signatures database (MSigDB) identifies 11 significant gene-sets. The dotted line indicates significance adjusted for the number of comparisons (p < 0.05/15,483 gene-sets). Bars depict -log₁₀ p-values. Corresponding gene-set names are indicated to the left of bars. Terms are clustered and colored according to their Gene Ontology term category (biological processes, yellow; molecular function, blue; cellular component, red).

Extended Data Figure 4:. MAGMA tissue enrichment analysis.

MAGMA gene-property analysis in 53 specific tissue types from GTEx v8 shows enrichment of PTSD-related genes in 13 brain tissue types and in the pituitary. Bars depict -log₁₀ p-values. Corresponding tissue names are indicated below bars. The dotted horizontal line indicates statistical significance adjusted for the number of comparisons (p < 0.05/53). Significant tissues are colored red.

Extended Data Figure 5:. MAGMA cell-type enrichment analysis in midbrain.

MAGMA gene-property analysis of 25 midbrain cell types (GSE76381) indicate enrichment of GABAergic neurons, GABAergic neuroblasts, and mediolateral neuroblasts. Vertical bars depict -log₁₀ p-values. Significant cell types are colored blue and grey if not. The dotted horizontal line indicates statistical significance adjusted for the number of comparisons (p < 0.05/25). The asterisk (*) indicates that GABAergic neurons remained significant in stepwise conditional analysis of the other significant cell types. Abbreviations: Gaba - GABAergic neurons; NbGaba - neuroblast gabaergic; NbML1–5, mediolateral neuroblasts; DA0–2 - dopaminergicneurons; Sert, serotonergic; RN, red nucleus; Rgl 1–3, radial glia-like cells; NbM, medial neuroblast; OPC, oligodendrocyte precursor cells. ProgFPL - progenitor lateral floorplate; OMTN - oculomotor and trochlear nucleus; Endo, endothelial cells; ProgM, progenitor midline;NProg, neuronal progenitor; ProgBP, progenitorbasal plate; Mgl, microglia; ProgFPM, progenitor medial floorplate; Peric – pericytes.

Extended Data Figure 6:. PTSD genes in SynGO.

Sunburst plots show enrichment of PTSD-related genes in SynGO cellular components. The synapse is at the center ring, pre- and post-synaptic locations are at the first rings, and child terms are in subsequent outer rings. a, enrichment test results for all 415 genes mapped to PTSD GWAS loci by FUMA from one of three gene-mapping strategies (positional, expression quantitative trait loci, and chromatin interaction mapping). b, enrichment test results for 43 genes prioritized into Tier 1 using a gene prioritization strategy. Plots are colored by -log10 Q-value (see color code in the bar at left) from enrichment of PTSD genes relative to a brain expressed background set.

Extended Data Figure 7:. Genetic correlations and polygenic overlap between PTSD and other psychiatric disorders.

a, Genetic correlations (r_g) between PTSD and other psychiatric disorders are indicated by circles that are drawn along the x axis. Red dots indicate SNP based heritability (h²_SNP) z-score > 6 in the psychiatric disorder GWAS and colored grey to indicate z-score < 6 (r_g estimates may be unreliable). The first author and publication year of source summary data is noted in parenthesis following the disorder name. b, Quantification of the polygenic overlap between PTSD and other psychiatric disorders. Euler diagrams depict Bivariate MiXeR analysis of PTSD (blue circles) and bipolar disorder (BIP), major depression (MDD), and schizophrenia (SCZ) (red circles). Values in the overlapping part of the Euler diagrams denote shared polygenicity (expressed as the number of influential variants, in thousands, with SE in parenthesis), and values in the non-overlapping part indicate dataset-specific variation. r_g between dataset pairs are noted in the boxes below the Euler plots. Abbreviations: ADHD, attention deficit hyperactive disorder; alc. dep, alcohol dependence; BIP, bipolar disorder; MDD, major depression; OCD, obsessive compulsive disorder; SCZ, schizophrenia.

Figure 1 |. Data sources and analyses in PTSD Freeze 3.

a, Data sources of genome-wide association studies (GWAS) included in PGC-PTSD Freeze 3. Collections of contributing studies are pictured as bubble plots where each circle represents a contributing study. Circle areas are proportional to sample size and colors indicate the ancestry classification of participants (blue, EA; red, AA; purple, LAT). Arrowed lines indicate data sources being pooled together to perform GWAS meta-analyses stratified by ancestry. b, Methods applied for genetic characterization of PTSD, gene prioritization analyses, and translational applications. Abbreviations: EA, European ancestry, AA, African ancestry, LAT, Native American (Latin American) ancestry; EHR, electronic health record

Figure 2 |. GWAS meta-analyses in European and multi-ancestry individuals identify a total of 95 PTSD risk loci.

Overlaid Manhattan plots of European ancestry (EA; 137,136 cases and 1,085,746 controls) and multi-ancestry meta-analyses (150,760 cases and 1,130,173 controls), showing 81 genome-wide significant (GWS) loci for the EA (full circles) and 85 GWS loci for the multi-ancestry (hollow circles) analyses. Circle colors alternate between chromosomes, with even chromosomes colored blue and odd chromosomes colored black. The y-axis refers to −log₁₀ P-values from two-sided z-tests for meta-analysis effect estimates. The horizontal red bar indicates the threshold for GWS associations (P < 5 × 10⁻⁸).

Figure 3 |. Manhattan plots of PTSD associations in multi-omic analyses.

a,b, Gene expression data from 13 brain tissue types and the pituitary were used to conduct transcriptome-wide association study (TWAS) identifying 9 loci with differential expression between PTSD cases and controls (a) and expression quantitative trait locus summary based Mendelian randomization (eQTL SMR) identifying 4 loci where gene expression has putative causal effects on PTSD (b). c, Blood protein quantitative trait locus (pQTL) SMR identify 16 blood proteins whose abundance has a putative causal effect on PTSD. The y-axis refers to −log₁₀ P-values from two-sided z-tests for TWAS, two-sided Chi-square tests for eQTL SMR, and two-sided Chi-square tests for pQTL SMR. The horizontal red bars indicate gene-wide significance (P < 0.05/14,935 for TWAS, P < 0.05/9,903 for eQTL SMR, and P < 0.05/1,209 for pQTL SMR). Significant findings are labeled.

Figure 4 |. Gene prioritization in PTSD loci.

Summary of evidence categories of prioritized genes (Tier 1 or 2) for the top 20% of PTSD loci (as ranked by leading SNP P-value). Locus number, prioritized genes within locus, gene locations (in terms of cytogenic band), and gene tier ranks (Tier 1, orange; Tier 2, blue) are indicated on the left. Categories of evidence are grouped and colored according to the domain they belong to. CADD scores, pLI scores and fine-mapping PIPs are written within their respective squares. The total weighted scores taken across all 9 evidence categories are shown on the rightmost squares. Abbreviations: eQTL, expression QTL; CI, chromatin interaction; CADD, combined annotation dependent depletion; RDB, regulome DB; pLI, predicted loss of impact; PIP, posterior importance probability; TWAS, transcriptome-wide association study; SMR, summary Mendelian randomization; pQTL, protein QTL.

Figure 5 |. Polygenic risk score analysis for PTSD across different data sets and ancestries.

PGC-PTSD Freeze 2 and Freeze 3 European ancestry (EA) based genetic risk score (PRS) predictions into independent samples of different ancestries. The y-axis represents PTSD risk relative to the lowest quintile of PRS with 95% confidence intervals. For EA, predictions based on Freeze 3 training data (10,334 cases and 55,504 controls; blue circles) demonstrate a significant performance increase compared to predictions based on the previous Freeze 2 training GWAS (yellow circles). Based on Freeze 3 EA training data, EA individuals in the highest quintile of PRS have 2.40 (95% CI = [2.26,2.56]) fold the risk of PTSD relative to individuals in the lowest quintile PRS (blue circles). Lower prediction accuracies are found for individuals of African (AA; 10,151 cases and 22,420 controls; red circles) and Native American (LAT; 5,346 cases and 10,821 controls; purple circles) ancestries, indicating poor PRS transferability across ancestries.