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

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.

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders.

Posttraumatic 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 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, 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.

Rare copy number variation in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.

Sex and sensitive period differences in potential effects of maltreatment on axial versus radial diffusivity in the corpus callosum.

Corpus callosum (CC) abnormalities have been observed in several psychiatric disorders. Maltreatment has also been associated with marked differences in CC anatomy and microstructure, though rarely controlled for in psychiatric neuroimaging studies. The aim of this study was to identify type and timing of maltreatment associated with alterations in CC microstructure and to ascertain if they differ by sex. T1 and diffusion-weighted MRIs were obtained from 345 (135 M/210 F) healthy 18-25-year-olds. The Maltreatment and Abuse Chronology of Exposure scale provided retrospective data on exposure to ten types of maltreatment across each year of childhood. AI predictive analytics were used to identify the most significant type and time risk factors. The most striking maltreatment-associated alterations in males were in axial diffusivity and were most specifically associated with exposure to emotional abuse or neglect during segment-specific sensitive periods. In contrast, maltreatment was associated with marked alteration in radial diffusivity and fractional anisotropy in females and was most specifically associated with early physical neglect during one common sensitive period involving all segments except the splenium. Overall sex differences, controlling for maltreatment, brain size, and sociodemographic factors were limited to the genu with greater fractional anisotropy in males and radial diffusivity in females. These findings suggest that maltreatment may target myelinization in females and axonal development in males and that these sex differences need to be taken into account in studies seeking to delineate the contribution of CC abnormalities and interhemispheric communication to psychiatric disorders.

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information.

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Genomic influences on self-reported childhood maltreatment.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h2snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h2snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10-8, FOXP1; rs10262462, p = 3.24 × 10-8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h2snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r2 = 0.0025; p = 1.8 × 10-15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (rg = 0.70, p = 4.65 × 10-40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Susceptibility or Resilience to Maltreatment Can Be Explained by Specific Differences in Brain Network Architecture.

BACKGROUND: Childhood maltreatment is a major risk factor for psychopathology. However, some maltreated individuals appear remarkably resilient to the psychiatric effects while manifesting the same array of brain abnormalities as maltreated individuals with psychopathology. Hence, a critical aim is to identify compensatory brain alterations that enable resilient individuals to maintain mental well-being despite alterations in stress-susceptible regions. METHODS: Network models were constructed from diffusion tensor imaging and tractography in physically healthy unmedicated 18- to 25-year-old participants (N = 342, n = 192 maltreated) to develop network-based explanatory models. RESULTS: First, we determined that susceptible and resilient individuals had the same alterations in global fiber stream network architecture using two different definitions of resilience: 1) no lifetime history of Axis I or II disorders, and 2) no clinically significant symptoms of anxiety, depression, anger-hostility, or somatization. Second, we confirmed an a priori hypothesis that right amygdala nodal efficiency was lower in asymptomatic resilient than in susceptible participants or control subjects. Third, we identified eight other nodes with reduced nodal efficiency in resilient individuals and showed that nodal efficiency moderated the relationship between maltreatment and psychopathology. Fourth, we found that models based on global network architecture and nodal efficiency could delineate group membership (control, susceptible, resilient) with 75%, 82%, and 80% cross-validated accuracy. CONCLUSIONS: Together these findings suggest that sparse fiber networks with increased small-worldness following maltreatment render individuals vulnerable to psychopathology if abnormalities occur in specific nodes, but that decreased ability of certain nodes to propagate information throughout the network mitigates the effects and leads to resilience.

Differential effects of childhood neglect and abuse during sensitive exposure periods on male and female hippocampus.

The hippocampus is a highly stress susceptible structure and hippocampal abnormalities have been reported in a host of psychiatric disorders including major depression and post-traumatic stress disorder (PTSD). The hippocampus appears to be particularly susceptible to early life stress with a graded reduction in volume based on number of types (multiplicity) or severity of maltreatment. We assessed whether the most important predictors of adult hippocampal volume were multiplicity, severity or duration of exposure or timing of maltreatment during developmental sensitive periods. 3T MRIs were collected on 336 unmedicated, right-handed subjects (132M/204F, 18-25 years). Exposure to broad categories of abuse and neglect during each year of childhood were assessed using the Maltreatment and Abuse Chronology of Exposure scale and evaluated using artificial intelligence and predictive analytics. Male hippocampal volume was predicted by neglect, but not abuse, up through 7 years of age. Female hippocampal volume was predicted by abuse, but not neglect, at 10, 11, 15 and 16 years. Exposure at peak age had greater predictive importance than multiplicity, severity or duration. There were also marked gender differences in subfields and portions (head, body or tail) affected by exposure. History and symptoms of major depression, PTSD or anxiety disorders were not predictive of hippocampal volume once maltreatment was accounted for. Neglect appears to foster inadequate hippocampal development in males while abuse appears to produce a stress-related deficit in females. Studies assessing hippocampal volume in psychiatric disorders need to control for the gender-specific effects of abuse and neglect.

Childhood maltreatment is associated with alteration in global network fiber-tract architecture independent of history of depression and anxiety.

Childhood maltreatment is a major risk factor for psychopathology. It is also associated with alterations in the network architecture of the brain, which we hypothesized may play a significant role in the development of psychopathology. In this study, we analyzed the global network architecture of physically healthy unmedicated 18-25 year old subjects (n=262) using diffusion tensor imaging (DTI) MRI and tractography. Anatomical networks were constructed from fiber streams interconnecting 90 cortical or subcortical regions for subjects with no-to-low (n=122) versus moderate-to-high (n=140) exposure to maltreatment. Graph theory analysis revealed lower degree, strength, global efficiency, and maximum Laplacian spectra, higher pathlength, small-worldness and Laplacian skewness, and less deviation from artificial networks in subjects with moderate-to-high exposure to maltreatment. On balance, local clustering was similar in both groups, but the different clusters were more strongly interconnected in the no-to-low exposure group. History of major depression, anxiety and attention deficit hyperactivity disorder did not have a significant impact on global network measures over and above the effect of maltreatment. Maltreatment is an important factor that needs to be taken into account in studies examining the relationship between network differences and psychopathology.

Childhood Maltreatment, Depression, and Suicidal Ideation: Critical Importance of Parental and Peer Emotional Abuse during Developmental Sensitive Periods in Males and Females.

BACKGROUND: The adverse childhood experience (ACE) study found that risk for depression increased as a function of number of types of childhood maltreatment, and interpret this as a result of cumulative stress. An alternative hypothesis is that risk depends on type and timing of maltreatment. This will also present as a linear increase, since exposure to more types of abuse increases likelihood of experiencing a critical type of abuse at a critical age. METHODS: 560 (223M/337F) young adults (18-25 years) were recruited from the community without regard to diagnosis and balanced to have equal exposure to 0-4 plus types of maltreatment. The Maltreatment and Abuse Chronology of Exposure Scale assessed severity of exposure to 10 types of maltreatment across each year of childhood. Major depressive disorder (MDD) and current symptoms were evaluated by SCID, interview, and self-report. Predictive analytics assessed importance of exposure at each age and evaluated whether exposure at one or two ages was a more important predictor than number, severity, or duration of maltreatment across childhood. RESULTS: The most important predictors of lifetime history of MDD were non-verbal emotional abuse in males and peer emotional abuse (EA) in females at 14 years of age, and these were more important predictors across models than number of types of maltreatment (males: t 9 = 16.39, p < 10(-7); females t 9 = 5.78, p < 10(-4)). Suicidal ideation was predicted, in part, by NVEA and peer EA at age 14, but most importantly by parental verbal abuse at age 5 in males and sexual abuse at age 18 in females. CONCLUSION: This study provides evidence for sensitive exposure periods when maltreatment maximally impacts risk for depression, and provides an alternative interpretation of the ACE study results. These findings fit with emerging neuroimaging evidence for regional sensitivity periods. The presence of sensitive exposure periods has important implications for prevention, preemption, and treatment of MDD.