Younga Heather Lee

Summary Background Current psychiatric diagnoses lack biological grounding. Using transdiagnostic psychiatric dimensions derived through data-driven genetic studies with large-scale clinical health records of multiple physiological and clinical outcomes, we can gain new insights into biological similarity and differences between such dimensions, informing nosological discourse. Methods Here, we examined data from 108,182 individuals of European-like ancestry and 13,229 African-like ancestry across two healthcare biobanks. Genetic liabilities of individuals were estimated as polygenic scores for five first-order psychopathology factors (compulsive, thought, neurodevelopmental, substance use, internalizing disorders) and one second-order factor (hierarchical/p-factor). Phenome-wide and laboratory-wide association scans encompassed 1,520 medical phenotypes and 123 laboratory metrics, meta-analyzed across sites. People with lived experience were involved in the design, preparation, interpretation and reporting of this work. Outcomes We observed robust associations with up to 143 conditions (14 disease categories) for first-order factors and 221 conditions (15 categories) for the hierarchical factor (OR=0.75-1.94). Circulatory, digestive, and respiratory diseases were linked to neurodevelopmental, internalizing, and substance use liabilities. Metabolic conditions were negatively associated with thought and compulsive liabilities but positively associated with the remaining three factors. Laboratory results, particularly lipid and glucose metabolism markers, supported these differential findings. Immune markers also showed differential associations, with C-reactive protein and Complement C4 specifically linked to neurodevelopmental and thought factors, respectively. Similar trends emerged in the smaller African-like ancestry sample. Interpretation Overall, these findings support ongoing efforts to define biologically informed subtypes in psychiatry, such as immuno-metabolic profiles, which can facilitate patient stratification in clinical trials and support transdiagnostic precision psychiatry approaches. Funding The work was supported by funding from the participating institutions. BF's and NRM's contributions were supported by the European Community's Horizon 2020 Programme (H2020/2014-2020) under grant agreement No. 847879 (PRIME). NRM was also supported by the Netherlands Organisation for Scientific Research (NWO) Innovation Programme (Vidi grant No. 09150172410043). Research reported in this publication was also supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH124851. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.

Aims: Cross‐national research on mental health trajectories requires harmonised measures that are valid and comparable. However, measurement scales often differ between cohorts in item content and cultural context. This study aimed to develop a framework for harmonising mental health measures across international cohorts, focussing on depression and anxiety symptoms. Methods: We applied a structured, theory‐driven approach to align item content across two longitudinal ageing cohorts that used different self‐report instruments with heterogeneous item codings: ELSA‐UK and ELSA‐Brasil. Data were collected before, during, and after the COVID‐19 pandemic, providing a natural experiment for examining temporal changes in mental health. The harmonisation process involved: (1) mapping items to DSM‐5 symptom domains via expert review; (2) transforming response formats into harmonised ordinal indicators; (3) leveraging the Harmony AI tool to identify semantically equivalent items; and (4) testing measurement invariance across waves and cohorts using multi‐group confirmatory factor analysis (MGCFA). Results: Scalar invariance was achieved for depression in both longitudinal and cross‐cohort models, enabling meaningful latent mean comparisons between cohorts. For anxiety, scalar invariance was supported within but not across cohorts, likely due to the limited number of conceptually matching items. Conclusion: The proposed harmonisation framework demonstrates the feasibility of robust cross‐cultural comparisons of mental health constructs. Its success depends on the conceptual alignment and quality of available items. This approach provides a methodological template for future harmonisation efforts in global health and psychiatric epidemiology.

Both sustained attention (SA) and executive functioning (EF) are critical for adaptive behavior and compromised across a range of psychiatric disorders, yet their etiological relationships remain underexplored. Here, we report the first multivariate characterization of molecular genetic influences on SA (vigilance, lapse recovery cost, lapse propensity) and EF (processing speed, response selection, working memory). In collaboration with 23andMe, we report previously unpublished genome-wide association studies of these phenotypes in a single cohort of more than 20,000 individuals enriched for diagnoses of major depressive disorder and bipolar disorder. We used Genomic Structural Equation Modeling to formally model patterns of genetic covariance among these task-based measures of cognition, and their relationships with other cognitive, clinical, and imaging-derived phenotypes. We identified two distinct latent genetic factors: one influencing EF and one influencing SA. Both the EF and SA factors were genetically correlated with cognitive and clinical phenotypes, with each latent factor uniquely linked to liability for psychiatric disorders, including attention-deficit/hyperactivity disorder. However, genetic correlations with imaging-derived neuroanatomical phenotypes were modest and non-significant after correction for multiple comparisons. Collectively, these results provide an initial multivariate genetic characterization of SA and EF, though replication in larger and more diverse samples will be important. They suggest that genetic influences on sustained attention are generally distinct from those that influence executive function. The EF and SA factors show distinct patterns of genetic overlap with multiple cognitive and psychiatric outcomes, underscoring the need for more granular cognitive phenotyping to generate new insights into the genetic architecture of cognition and the etiology of psychopathology.

Importance: The impact of COVID-19 containment policies (e.g., physical distancing, school closures) on population anxiety has been debated and difficult to resolve. Objective: To estimate the joint effects of state-level COVID-19 containment policies on anxiety symptoms during the early pandemic. Design: Retrospective analysis of a prospective cohort with cross-sectional outcome assessment. Setting: All of Us Research Program, a U.S. national research cohort. Participants: 40,610 adult participants who completed the All of Us COPE survey in July 2020. Exposures: Seven state-level COVID-19 containment policies (school closures, workplace closures, cancellation of public events, restrictions on gatherings, public transport closures, stay-at-home requirements, and restrictions on internal movement) measured from March 22 to May 23, 2020, via the Oxford COVID-19 Government Response Tracker (OxCGRT). Main outcomes and measures: The primary outcome was anxiety symptoms (GAD-7) in July 2020. Using quantile g-computation, we classified policies as anxiety-increasing or anxiety-decreasing by the sign of their training-set contributions, then re-estimated joint effects in a holdout testing set. Results: Among participants (64% female; mean age: 57.8 years), 13.3% (n=5398) reported moderate-to-severe anxiety (GAD-7 score 10-21) in July 2020. The joint effect of all seven containment policies was not significant (β = 1.88, 95% CI: -0.51 to 4.28, p = 0.12). An anxiety-increasing joint effect from 4 policies (school, workplace, public events, internal movement; β = 2.98, 95% CI: 0.30 to 5.66, p = 0.03) and an anxiety-decreasing joint effect from 3 policies (gatherings, public transport, stay-at-home; β = -1.10, 95% CI: -1.75 to -0.44, p = 0.002) reached significance. Effects were largest in adults 18-44 (anxiety-increasing β = 8.93, 95% CI: 1.50 to 16.37, p = 0.02; anxiety-decreasing β = -2.81, 95% CI: -4.98 to -0.64, p = 0.01), with no significant effects in adults 45 and older. Conclusions and Relevance: Modeling seven containment policies jointly showed no net anxiety effect, a result that masked opposing-direction effects. Partitioning by effect direction revealed significant joint effects exceeding single-policy estimates, with young-adult point estimates above the 4-point GAD-7 minimal clinically important difference (MCID) though lower CI bounds fell below it. These findings may inform the use of containment policies in future pandemics, given their differing association with population anxiety.

Importance: Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood. Objective: To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use. Design, Setting and Participants: Cross-sectional analysis of Mass General Brigham Biobank participants with metabolomic profiling, genomic data, and linked electronic health records. Exposures: Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD). Main Outcomes and Measures: 249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use. Results: Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 × 10 ^-4 ), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides (β = 0.04 to 0.05, all p< 4.4 ×10 ^-13 ) and glycoprotein acetyls (β = 0.05, all p< 2.2 ×10 ^-16 ). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions (β = 0.03 to 0.08, all p< 2.1 ×10 ^-4 ). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern. Conclusions and Relevance: Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity. Key findings: Question: Does genetic liability to psychiatric disorders influence peripheral metabolism independent of psychiatric diagnosis and treatment? Findings: In 25,290 participants, polygenic scores for major depressive disorder, posttraumatic stress disorder, and attention deficit hyperactivity disorder showed widespread associations with metabolic dysregulation, such as elevated triglycerides and systemic inflammation, which persisted after adjusting for diagnosis and medication use. Polygenic scores for schizophrenia and bipolar disorder showed minimal metabolite associations despite their well-established cardiometabolic burden. Meaning: Shared genetic pathways partially underlie psychiatric and cardiometabolic comorbidity, implicating transdiagnostic biomarker profiles.

Biomarkers can potentially improve the diagnosis, monitoring, and treatment of posttraumatic stress disorder (PTSD). However, PTSD biomarkers that are scalable and easily integrated into real-world clinical settings have not been identified. The analysis was conducted between June to November 2024 using genomic samples and laboratory test results recorded in the Mass General Brigham (MGB) Health System. The analysis included 23,743 European ancestry participants from the nested MGB Biobank study. The first exposure was polygenic risk score (PRS) for PTSD, calculated using the largest available European ancestry genome-wide association study (GWAS), employing a Bayesian polygenic scoring method. The second exposure was a clinical diagnosis of PTSD, determined by the presence of two or more instances of PTSD-related diagnostic codes in the longitudinal electronic health records (EHR). The primary outcomes were the inverse normal quantile transformed, median lab values of 241 laboratory traits with non-zero h²_SNP estimates. Sixteen unique laboratory traits across the cardiometabolic, hematologic, hepatic, and immune systems were implicated in both genomic and phenotypic lab-wide association scans (LabWAS). Two-sample Mendelian randomization analyses provided evidence of potential unidirectional causal effects of PTSD liability on hepatic (decreased albumin and total bilirubin), cardiometabolic (decreased HDL cholesterol and increased VLDL cholesterol), and hematologic (decreased mean platelet volume) markers. These findings demonstrate the potential of a triangulation approach to uncover scalable and clinically relevant biomarkers for PTSD.

Background: Both the COVID-19 pandemic and containment policies caused widespread psychological distress, yet their independent effects remain unclear. Disentangling these effects could inform future responses that balance physical and mental health. This study sought to estimate the effect of lifting versus maintaining containment policies on psychological distress, independent of pandemic severity. Methods: We conducted a state-level longitudinal analysis using the Behavioral Risk Factor Surveillance System (BRFSS), a representative survey of US adults, restricted to the pandemic period preceding widespread vaccine availability (April 2020 to April 2021). The exposure was lifting versus maintaining containment policies (school closures, workplace closures, event cancellations, and full lockdown) from the Oxford COVID-19 Government Response Tracker. Exposure was measured during periods of low (14 days) pandemic severity. The primary outcome was prevalence of psychological distress, derived from a BRFSS survey item corresponding to a PHQ-4 score ≥6. Findings: Three causal inference approaches yielded consistent evidence of transient policy-lifting effects: (1) synthetic control analysis of Maine showed a temporary 5.5 percentage-point reduction in psychological distress lasting three months before returning to counterfactual levels; (2) within-state fixed effects found immediately after lifting full lockdown, distress decreased by 5.68 [-8.67, −2.69] percentage points, declining by 30 days (−3.24 [-6.88, 0.39]) and negligible at 60 days (−0.94 [-3.77, 1.89]); (3) target trial emulation detected no significant effects from lifting versus maintaining policies for 90 days. Interpretation: Lifting containment policies in the first year of the pandemic produced immediate but transient reductions in psychological distress. These results suggest that extended containment policies were unlikely to account for persistent increases in distress during this period.

OBJECTIVES: Poor cardiovascular health (CVH) and the high prevalence of depressive symptoms represent significant public health concerns, underscoring the importance of examining their association. This study aimed to investigate the association between CVH, as defined by the American Heart Association’s 2022 Life’s Essential 8 (LE8) framework, and depressive symptoms.METHODS: This study used data from the 2014, 2016, 2018, and 2020 Korea National Health and Nutrition Examination Survey. Overall CVH, measured using LE8, was categorized into 3 groups: low score (0–<50), moderate score (50–<80), and high score (80–100). LE8 comprises 2 subdomains: health behaviors and health factors. Depressive symptoms were defined as a total score ≥10 on the Patient Health Questionnaire-9. Multiple logistic regression analyses were performed, adjusting for sex, age, socioeconomic status, and current drinking status.RESULTS: Among 17,294 adults, 257 male and 681 female reported significant depressive symptoms. Compared with individuals in the low LE8 category (reference), the odds ratio (OR) for depressive symptoms was 0.29 (95% confidence interval [CI], 0.21 to 0.40) for those in the high LE8 category. The OR for depressive symptoms was 0.39 (95% CI, 0.29 to 0.53) for individuals with a high health behavior score compared with those with a low health behavior score. In contrast, the health factor score was not significantly associated with depressive symptoms.CONCLUSIONS: These findings suggest that overall CVH, particularly the health behavior subdomain, was associated with lower odds of depressive symptoms. Prospective longitudinal studies are warranted to validate these findings and clarify the directionality of the observed associations.

Background: Childhood adversity and trauma are prevalent risk factors for the development of mental health conditions. This two-part paper describes the conceptual basis and pilot implementation of a tiered model of pediatric population mental health, highlighting the local socioecological context in which it was developed and the trauma-informed approach used. Methods: Using retrospective record review of three datasets from the primary and secondary care pediatric clinics of a large academic medical center, which were harmonized to cover the study period from July 1, 2023 to June 30, 2024, we conducted descriptive analyses of patients across three levels: pediatric primary care ( n = 9535), an integrated primary care program, which embeds mental health clinicians in primary care ( n = 267), and family-centered trauma-informed psychotherapies in secondary care ( n = 63), designed to address emotion dysregulation in pre-adolescent children. Demographics and lifetime history of trauma and adversity (assessed with a comprehensive 19-item list coded based on standardized screeners) were assessed through electronic medical records. Results: Relative to the pediatric primary care population, more patients in the integrated primary care program and trauma-informed psychotherapies identified as White. Using our 19-item assessment, the lifetime prevalence of adversity or trauma was nearly universal among patients in the integrated primary care (94.4%) and trauma-informed psychotherapy (98.4%) programs. However, the lifetime prevalence of childhood adversities differed significantly across the two programs (integrated primary care: 76.8%; trauma-informed psychotherapy: 98.4%) when we assessed prevalence based only on the 10-item Adverse Childhood Experiences Questionnaire (Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, Koss MP, Marks JS, Am J Prev Med 14:245–58, 1998). There was a higher prevalence of family and parent-related adversities in the trauma-informed psychotherapy program. Conclusions: Findings support the need for trauma-informed, population mental health approaches in pediatric care. Developmentally tailored, family-centered, transdiagnostic screening and interventions are essential. Study findings, including gaps in programmatic fiscal sustainability, suggest avenues for policy reform to support and scale trauma-informed programs like ours. Programs seeking to implement trauma-informed approaches should leverage implementation and participatory research to ensure effectiveness and equitable accessibility for patients of diverse identities.

This study explored the genetic links between 11 immune-mediated diseases and 13 psychiatric disorders, addressing the limited understanding of what links these illnesses. Utilizing genomic structural equation modeling, we investigated whether 14 immune markers (e.g., C-reactive protein [CRP], interleukin-6 [IL-6]) mediated associations between latent genomic factors of immune-mediated diseases (e.g., autoimmune) and psychiatric disorders (e.g., internalizing). While the literature extensively describes the psychiatric relevance of CRP, results indicated this is better explained by its biological precursor, IL-6. Six immune markers significantly mediated 11 psychiatric-immune disease genetic relationships. For example, IL-6 mediated 60% of the genetic link between an internalizing factor and Crohn’s disease. Identified markers often evinced mediating effects for multiple disorder clusters, while at the same time showing some specificity in their associations. These findings provide mechanistic insight by pinpointing the immune markers that may be most critical to the psychiatric-immune disease link, which notably did not include CRP.