John M. Hettema’s research while affiliated with Texas A&M Health Science Center and other places

Posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD) share ostensibly similar and sometimes overlapping symptoms that complicate diagnostic assessment and conceptualization. While varying models for the symptom structure of PTSD have been proposed – including the presently used 4-factor and a more fine-grained 7-factor model – little research has focused on youth and even less is known about how these symptoms relate to one another when OCD is present. The present study used confirmatory factor analysis (CFA) and network analysis to compare PTSD symptom relations among 2,066 trauma-exposed youth aged 8-20 enrolled in the Texas Childhood Trauma Research Network, of which 10.9% met diagnostic criteria for OCD. CFA model fit was strongest for the 7-factor PTSD model, and multigroup CFA found no evidence that the structure differed as a function of OCD diagnosis, sex, nor age group. Internal consistency in the 7-factor model ranged from poor to good (α=0.59—0.80), while all clusters of the 4-factor model demonstrated adequate internal consistency (α=0.75—0.89). Network analysis revealed unique associations between PTSD and OCD. Specifically, having OCD was linked to more Negative Affect (edge=0.15) and Anhedonia (edge=0.16), which are both part of the 4-factor Negative Alterations in Cognitions and Mood symptom cluster. While the clinical relevance of the 7-factor model is still unclear, it evidenced mixed empirical support in the present sample and provided greater nuance when examining links between PTSD and OCD.

We are in the midst of an opioid epidemic. In the United States, more than a third of the country knows someone who has died from an opioid overdose. Prescription opioids (e.g., oxycodone, hydrocodone, and fentanyl) are commonly used and misused, and it has been estimated that approximately 8-12% of individuals who misuse opioids will subsequently develop an opioid use disorder (OUD). While emphasis has been placed on understanding OUD and the associated adverse effects, there remains a critical gap in systematically characterizing the multifactorial pathways (e.g., behavioral, clinical, genetic, and socio-demographic characteristics) that contribute to the transition from initial use to misuse to OUD. To address this gap, we introduce the Prescription Opioid Medication Survey (POMS), an online 120-item assessment that compiles multiple validated and standardized instruments. POMS is intended for individuals with any lifetime prescription opioid use. POMS captures various aspects of prescription opioid use including data on opioid use patterns, subjective effects (e.g., euphoria, nausea), problematic use, withdrawal, OUD, overdose, treatment history, and remission. It also addresses comorbid risk factors such as surgical history, chronic pain, other substance use disorders (SUD; e.g., nicotine, alcohol, cannabis, stimulants), other addictive behaviors (i.e., gambling, sexual behaviors, and gaming), and family history of SUD and other addictive behaviors. Mental health assessments, including screening for depression and anxiety, self-reports of eight psychiatric disorders (anxiety, depression, bipolar, schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, eating disorders) and related mental health conditions (e.g., loneliness, suicide, trauma) are included, along with data on personality traits (e.g., risk-taking, delay discounting, wisdom) and socio-demographic factors. POMS is intended to be administered in clinical settings and large population-based cohorts, facilitating data collection that can enable discoveries to inform better prevention and intervention strategies for OUD.

Psychiatric disorders are highly heritable and polygenic, influenced by environmental factors and often comorbid. Large-scale genome-wide association studies (GWASs) through consortium efforts have identified genetic risk loci and revealed the underlying biology of psychiatric disorders and traits. However, over 85% of psychiatric GWAS participants are of European ancestry, limiting the applicability of these findings to non-European populations. Latin America and the Caribbean, regions marked by diverse genetic admixture, distinct environments and healthcare disparities, remain critically understudied in psychiatric genomics. This threatens access to precision psychiatry, where diversity is crucial for innovation and equity. This Review evaluates the current state and advancements in psychiatric genomics within Latin America and the Caribbean, discusses the prevalence and burden of psychiatric disorders, explores contributions to psychiatric GWASs from these regions and highlights methods that account for genetic diversity. We also identify existing gaps and challenges and propose recommendations to promote equity in psychiatric genomics.

Understanding how excessive fear responses develop and persist is critical. Research using laboratory models of fear learning offers valuable insights on etiology. In this study, the influence of genetic and environmental etiology of baseline startle response and fear learning was examined, focusing on fear acquisition and generalization processes using the fear conditioning paradigm measuring fear‐potentiated startle (FPS) in a sample of adolescents and young adult twins (15–20 years old). Participants (N = 794) completed fear acquisition and generalization training that consisted of quasi‐randomly presented rings of gradually increasing size. The extreme sizes served as conditioned danger cues (CS+) paired with electric shock as the unconditioned stimulus and conditioned safety cues (CS−), with rings of intermediary size serving as generalization stimuli. As an index of fear learning, FPS was measured using the magnitude of eyeblink startle reflex to a sound probe. Twin model estimates indicated that both pre‐acquisition startle (startle probe responses to stimuli prior to conditioning) and FPS (startle probe responses after conditioning during acquisition and generalization) exhibited modest to moderate heritability (26%–43%), aligning with previous studies on FPS. We also observed that the genetic influences on FPS were highly correlated with pre‐acquisition startle, indicating minimal genetic innovation on FPS. This finding implies that fear responses might be regulated, from a genetic perspective, by general startle response as opposed to specific fear‐learning‐related factors. We discuss the resulting implications for measurement of biomarkers for fear and anxiety disorders.

The Psychiatric Genomics Consortium (PGC) has fueled discoveries of common and rare genetic variation contributing to liability to 13 psychiatric and neurodevelopmental conditions. This narrative review reflects on major findings from the past half decade of research by this international group of investigators in five priority areas: discovery of common variants using GWAS; rare variation and its interplay with polygenic risk; leveraging genetics to go beyond diagnostic boundaries; ascribing functional attributes to genomic discoveries; and developing and implementing processes for data sharing, outreach to various communities, and training. The insights gained in these domains frame the agenda for the next phase of PGC research. In addition to accelerating integrative common and rare variant-, within- and across-disorder findings for multiple psychiatric and neurodevelopmental conditions, the next phase will elucidate genetic etiologies in multiple ancestral populations, leverage rapidly accumulating multi-modal functional genomics data to gain mechanistic understanding, and attempt to bring genetic findings to clinically actionable phenotypes, such as treatment response, and address the developmental unfolding of genetic risk.

The Psychiatric Genomics Consortium (PGC) has fueled discoveries of common and rare genetic variation contributing to liability to 13 psychiatric and neurodevelopmental conditions. This narrative review reflects on major findings from the past half decade of research by this international group of investigators in five priority areas: discovery of common variants using GWAS; rare variation and its interplay with polygenic risk; leveraging genetics to go beyond diagnostic boundaries; ascribing functional attributes to genomic discoveries; and developing and implementing processes for data sharing, outreach to various communities, and training. The insights gained in these domains frame the agenda for the next phase of PGC research. In addition to accelerating integrative common and rare variant-, within- and across-disorder findings for multiple psychiatric and neurodevelopmental conditions, the next phase will elucidate genetic etiologies in multiple ancestral populations, leverage rapidly accumulating multi-modal functional genomics data to gain mechanistic understanding, and attempt to bring genetic findings to clinically actionable phenotypes, such as treatment response, and address the developmental unfolding of genetic risk.

Psychiatric disorders display high levels of comorbidity and genetic overlap. Genomic methods have shown that even for schizophrenia and bipolar disorder, two disorders long-thought to be etiologically distinct, the majority of genetic signal is shared. Furthermore, recent cross-disorder analyses have uncovered over a hundred pleiotropic loci shared across eight disorders. However, the full scope of shared and disorder-specific genetic basis of psychopathology remains largely uncharted. Here, we address this gap by triangulating across a suite of cutting-edge statistical genetic and functional genomic analyses applied to 14 childhood and adult onset psychiatric disorders (1,056,201 cases). Our analyses identify and characterize five underlying genomic factors that explain the majority of the genetic variance of the individual disorders (~66% on average) and are associated with 268 pleiotropic loci. We observed particularly high levels of polygenic overlap and local genetic correlation and very few disorder-specific loci for two factors defined by: (i) schizophrenia and bipolar disorder (SB factor), and by (ii) major depression, PTSD, and anxiety (internalizing factor). At the functional level, we applied multiple methods which demonstrated that the shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the internalizing factor was associated with oligodendrocyte biology. By comparison, the genetic signal shared across all 14 disorders was enriched for broad biological processes (e.g., transcriptional regulation). These results indicate increasing differentiation of biological function at different levels of shared cross-disorder risk, from quite general vulnerability to more specific pathways associated with subsets of disorders. These observations may inform a more neurobiologically valid psychiatric nosology and implicate novel targets for therapeutic developments designed to treat commonly occurring comorbid presentations.