Polygenic Risk for Major Depression: Diagnostic Specificity and Developmental Trajectories in an Admixed Youth Cohort.

Prolonged Childhood and Adolescent Loneliness in First-Episode Psychosis: Synergistic Polygenic Effects and Functional Outcomes.

Prolonged CAL is linked to higher risk of FEP, preferentially affective psychosis in females, poorer functioning, and developmental potentiation of polygenic liability.

Polygenic risk scores in major depressive disorder: A systematic review across diagnostic, treatment, course/severity, and subtype domains.

BACKGROUND Major depressive disorder (MDD) is heterogeneous across diagnostic, treatment-related, course/severity, and subtype domains. Polygenic risk score (PRS) studies have examined these domains, but differences in PRS sources, samples, methods, and endpoint definitions have fragmented the evidence. We synthesised findings and examined potential contributors to heterogeneity. METHODS PubMed/MEDLINE, Embase, PsycINFO, and Web of Science were searched for studies published from January 2016 through 25 November 2025. Result records were synthesised using SWiM, and certainty was assessed with an adapted GRADE framework. RESULTS Sixty studies contributed 493 retained records; 450 were descriptively classified as positive, null, or reverse, although records were not independent. Positive findings accounted for 44/56 diagnostic, 61/273 treatment-related, 64/100 course/severity, and 14/21 subtype records. For MDD/depression-derived PRSs and case-control MDD status, all 10 contributing studies showed higher liability in cases (exploratory exact sign test p = 0.002; FDR q = 0.004). The same PRS group showed positive findings for overall depressive symptom severity (14/18), although the study-level test was imprecise (5/5 studies; p = 0.063). Pharmacological response/remission findings for these PRSs were mostly null or directionally mixed (10 positive, 18 null, and 9 reverse). Treatment-resistant depression (TRD) findings differed by operational definition. Atypical and psychotic subtype signals arose mainly from single-study PRS and endpoint contrasts. CONCLUSIONS PRS evidence was clearest for MDD diagnostic status and showed a tentative pattern for overall symptom burden. Treatment and subtype findings were less consistent or less replicated. Larger, ancestrally diverse studies with standardised endpoints and transparent PRS methods are needed.

Discordance Between Genetic Ancestry and Self-Reported Race Impacts Inference of Neuropsychiatric Burden in Alzheimer's Disease

Ancestry-Calibrated Polygenic Risk Scores Predict PTSD Trajectories in Recent Trauma Survivors and Interact with Neighborhood Resources

Objective: Polygenic risk scores (PRS) for posttraumatic stress disorder (PTSD) often account for a low amount of variance. Ancestry-related differences in PRS scale and variance limit cross-group comparisons. This methodological challenge further complicates gene-by-environment (GxE) analyses, given that socioenvironmental exposures are inequitably distributed across ethnoracial groups. We constructed an ancestry-calibrated polygenic risk score (AC-PRS) for PTSD in the largest longitudinal study of trauma survivors to date and investigated GxE interactions. Method: Recent trauma survivors (N=1,801) provided a blood specimen for genotyping. Six PTSD trajectories were previously identified from PTSD Checklist for DSM-5 (PCL-5) scores at 2-weeks, 8-weeks, 3-months, and 6-months post-trauma. Greenspace (normalized difference vegetation index [NDVI) and socioeconomic disadvantage (area deprivation index [ADI]) were derived from residential addresses. Logistic regressions examined interactions between newly developed AC-PRS and neighborhood factors on trajectories after adjusting for sociodemographic and trauma-related covariates. Secondary linear models considered GxE interactions on 6-month PCL-5 scores. Results: AC-PRS performed well across ethnoracial groups, explaining significant variability in PTSD trajectories (R2=.053). ADI moderated the association between AC-PRS and the likelihood of assignment in a high nonremitting trajectory of PTSD symptoms and severity of symptoms at 6-months (ps < .05). There were no NDVI x AC-PRS interactions in any models. Conclusions: AC-PRS captures genetic risk for PTSD in admixed trauma survivors, demonstrating good discrimination between nonremitting and resilient courses of PTSD. However, neighborhood disadvantage may modify utility of PRS for PTSD, warranting careful consideration when applying these scores across contexts.

Genome-wide association analyses of borderline personality disorder identify 11 loci and highlight shared risk with mental and somatic disorders

BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, antisocial behavior, and measures of suicide and self-harm.

Investigation of polygenic risk scores and subphenotypes in social anxiety disorder

Social anxiety disorder (SAD) is a common anxiety disorder (ANX) with moderate heritability that often co-occurs with other mental disorders. Until now, sample sizes in genetic analyses of SAD have been limited, so that the genetic basis of SAD and its subphenotypes is still largely unknown. In a large cohort comprising n = 1,194 SAD patients derived from five German cohorts and n = 3,409 controls from the Heinz Nixdorf Recall Study, we computed polygenic risk scores (PRS) at six p-thresholds using PRSice-2 based on large-scale genome-wide association studies for depression, major depressive disorder (MDD), ANX, schizophrenia (SCZ), bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), autism spectrum disorder (ASD), and alcohol dependence (AD). We used general linear models to examine the association between the PRS and SAD status. In SAD subsamples, we investigated whether the PRS are associated with SAD subphenotypes (i.e., SAD severity, current depressive symptoms, comorbid MDD) using correlation analyses and a general linear model. Results were corrected for multiple testing. The SAD status was significantly associated with PRS for depression, MDD, ANX, SCZ, BD, AN, and ASD (pBH-adjusted<0.05), but not with PRS for ADHD and AD. In SAD subsamples, the subphenotype analyses revealed no significant associations after correction for multiple testing (pBH-adjusted>0.05). Our results support that SAD seems to be genetically highly overlapping with other mental disorders, which might underline a common psychopathological factor. No significant association was found with SAD severity, current depressive symptoms or comorbid MDD. A better understanding of the genetic architecture of SAD may help to develop new diagnostic and treatment approaches.