From genetics to biology: advancing mental health research in the Genomics ERA.

The Genomics Workgroup of the National Advisory Mental Health Council (NAMHC) recently issued a set of recommendations for advancing the NIMH psychiatric genetics research program and prioritizing subsequent follow-up studies. The report emphasized the primacy of rigorous statistical support from properly designed, well-powered studies for pursuing genetic variants robustly associated with disease. Here we discuss the major points NIMH program staff consider when assessing research applications based on common and rare variants, as well as genetic syndromes, associated with psychiatric disorders. These are broad guiding principles for investigators to consider prior to submission of their applications. NIMH staff weigh these points in the context of reviewer comments, the existing literature, and current investments in related projects. Following the recommendations of the NAMHC, statistical strength and robustness of the underlying genetic discovery weighs heavily in our funding considerations as does the suitability of the proposed experimental approach. We specifically address our evaluation of applications motivated in whole, or in part, by an association between human DNA sequence variation and a disease or trait relevant to the mission of the NIMH.

Genomewide association studies of suicide attempts in US soldiers.

Suicide is a global public health problem with particular resonance for the US military. Genetic risk factors for suicidality are of interest as indicators of susceptibility and potential targets for intervention. We utilized population-based nonclinical cohorts of US military personnel (discovery: N = 473 cases and N = 9778 control subjects; replication: N = 135 cases and N = 6879 control subjects) and a clinical case-control sample of recent suicide attempters (N = 51 cases and N = 112 control subjects) to conduct GWAS of suicide attempts (SA). Genomewide association was evaluated within each ancestral group (European-, African-, Latino-American) and study using logistic regression models. Meta-analysis of the European ancestry discovery samples revealed a genomewide significant locus in association with SA near MRAP2 (melanocortin 2 receptor accessory protein 2) and CEP162 (centrosomal protein 162); 12 genomewide significant SNPs in the region; peak SNP rs12524136-T, OR = 2.88, p = 5.24E-10. These findings were not replicated in the European ancestry subsamples of the replication or suicide attempters samples. However, the association of the peak SNP remained significant in a meta-analysis of all studies and ancestral subgroups (OR = 2.18, 95%CI 1.70, 2.80). Polygenic risk score (PRS) analyses showed some association of SA with bipolar disorder. The association with SNPs encompassing MRAP2, a gene expressed in brain and adrenal cortex and involved in neural control of energy homeostasis, points to this locus as a plausible susceptibility gene for suicidality that should be further studied. Larger sample sizes will be needed to confirm and extend these findings.

National Institutes of Health social and behavioral research in response to the SARS-CoV2 Pandemic.

The COVID-19 pandemic has been mitigated primarily using social and behavioral intervention strategies, and these strategies have social and economic impacts, as well as potential downstream health impacts that require further study. Digital and community-based interventions are being increasingly relied upon to address these health impacts and bridge the gap in health care access despite insufficient research of these interventions as a replacement for, not an adjunct to, in-person clinical care. As SARS-CoV-2 testing expands, research on encouraging uptake and appropriate interpretation of these test results is needed. All of these issues are disproportionately impacting underserved, vulnerable, and health disparities populations. This commentary describes the various initiatives of the National Institutes of Health to address these social, behavioral, economic, and health disparities impacts of the pandemic, the findings from which can improve our response to the current pandemic and prepare us better for future infectious disease outbreaks.

The trauma outcome process assessment model: a structural equation model examination of adjustment.

This investigation sought to operationalize a comprehensive theoretical model, the Trauma Outcome Process Assessment, and test it empirically with structural equation modeling. The Trauma Outcome Process Assessment reflects a robust body of research and incorporates known ecological factors (e.g., family dynamics, social support) to explain internalizing distress (e.g., anxiety, depression), externalizing distress (e.g., aggression), and recovery outcomes following traumatic events. Results revealed that expected relationships among the variables were significantly related in the expected direction, and the measures mapped well onto the expected latent constructs. Following optimal specification of the relationships within the Trauma Outcome Process Assessment, structural equation modeling revealed strong support for the Trauma Outcome Process Assessment as a comprehensive identification and treatment model to explain the differential outcomes of those exposed to traumatic stressors.

Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers.

IMPORTANCE: Posttraumatic stress disorder (PTSD) is a prevalent, serious public health concern, particularly in the military. The identification of genetic risk factors for PTSD may provide important insights into the biological foundation of vulnerability and comorbidity. OBJECTIVE: To discover genetic loci associated with the lifetime risk for PTSD in 2 cohorts from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). DESIGN, SETTING, AND PARTICIPANTS: Two coordinated genome-wide association studies of mental health in the US military contributed participants. The New Soldier Study (NSS) included 3167 unique participants with PTSD and 4607 trauma-exposed control individuals; the Pre/Post Deployment Study (PPDS) included 947 unique participants with PTSD and 4969 trauma-exposed controls. The NSS data were collected from February 1, 2011, to November 30, 2012; the PDDS data, from January 9 to April 30, 2012. The primary analysis compared lifetime DSM-IV PTSD cases with trauma-exposed controls without lifetime PTSD. Data were analyzed from March 18 to December 27, 2015. MAIN OUTCOMES AND MEASURES: Association analyses for PTSD used logistic regression models within each of 3 ancestral groups (European, African, and Latino American) by study, followed by meta-analysis. Heritability and genetic correlation and pleiotropy with other psychiatric and immune-related disorders were estimated. RESULTS: The NSS population was 80.7% male (6277 of 7774 participants; mean [SD] age, 20.9 [3.3] years); the PPDS population, 94.4% male (5583 of 5916 participants; mean [SD] age, 26.5 [6.0] years). A genome-wide significant locus was found in ANKRD55 on chromosome 5 (rs159572; odds ratio [OR], 1.62; 95% CI, 1.37-1.92; P = 2.34 × 10-8) and persisted after adjustment for cumulative trauma exposure (adjusted OR, 1.64; 95% CI, 1.39-1.95; P = 1.18 × 10-8) in the African American samples from the NSS. A genome-wide significant locus was also found in or near ZNF626 on chromosome 19 (rs11085374; OR, 0.77; 95% CI, 0.70-0.85; P = 4.59 × 10-8) in the European American samples from the NSS. Similar results were not found for either single-nucleotide polymorphism in the corresponding ancestry group from the PPDS sample, in other ancestral groups, or in transancestral meta-analyses. Single-nucleotide polymorphism-based heritability was nonsignificant, and no significant genetic correlations were observed between PTSD and 6 mental disorders or 9 immune-related disorders. Significant evidence of pleiotropy was observed between PTSD and rheumatoid arthritis and, to a lesser extent, psoriasis. CONCLUSIONS AND RELEVANCE: In the largest genome-wide association study of PTSD to date, involving a US military sample, limited evidence of association for specific loci was found. Further efforts are needed to replicate the genome-wide significant association with ANKRD55-associated in prior research with several autoimmune and inflammatory disorders-and to clarify the nature of the genetic overlap observed between PTSD and rheumatoid arthritis and psoriasis.

Psychological outcomes and measurement of maternal posttraumatic stress disorder during the perinatal period.

For many parents, labor, delivery, and/or the perinatal and neonatal periods present significant stressors that result in clinically significant parental feelings of psychological distress or trauma. This review article identifies known preexisting risk, and protective, factors for such distress, focusing on individual variables and familial or other social support networks. Research describing the full range of possible psychological reactions is also presented, loosely categorized as representing psychological outcomes of resiliency or growth, externalized distress, and internalized distress. These outcomes are viewed as neither linear nor mutually exclusive, and specific implications for each outcome are presented. The primary focus of this review is on the most well understood internalizing distress outcome during the perinatal period, maternal posttraumatic stress reactions. The utility of a brief, freely available measure quantifying such distress is also overviewed, including standards for its usage. Healthcare and particularly nursing staff are encouraged to attend to the range of possible psychological outcomes that may emerge during the perinatal period, identifying distressed mothers, so that they may be referred for care. The review concludes by presenting recommended future directions for research regarding the measurement of posttraumatic stress disorder in parents.

Positive and negative adjustment and social support of sexual assault survivors.

The roles of positive (i.e., growth) and negative (i.e., posttraumatic stress symptoms and general symptomatology) adjustment following adult sexual assault experience(s) were examined using a standardized definition of abuse. These reactions were explored in association with positive and negative support from formal and informal providers. Finally, using standardized measures, the collective impact of positive and negative support, formal and informal support were investigated in predicting positive and negative psychological adjustment. Both forms of informal support were found to be associated with positive outcomes. Only negative informal support was associated with posttraumatic stress symptoms. First responders should consider whether support resources are appropriate to victims' needs.

Ethical issues pertaining to research in the aftermath of disaster.

In January 2003, The New York Academy of Medicine and the National Institute of Mental Health sponsored a meeting entitled "Ethical Issues Pertaining to Research in the Aftermath of Disaster." The purpose of the meeting was to bring together various experts to examine evidence concerning the impact of research on trauma-exposed participants, review the applicable ethical principles and policies concerning protection of human subjects, and offer guidance to investigators, IRBs, public health and local officials, and others interested in assuring that research in the aftermath of a disaster is conducted in a safe and ethical manner. This article summarizes the group's key findings and outlines potential considerations for those working in this field.