European Neuropsychopharmacology最新文献

{"title":"SHARED GENETIC RISK FOR INTERNALIZING AND EXTERNALIZING DISORDERS IN MEXICAN ADOLESCENTS: THE MODERATING EFFECT OF ADVERSITY","authors":"Gabriela Martinez-Levy ,&nbsp;Zuriel Ceja ,&nbsp;Jackson Thorp ,&nbsp;Jill A. Rabinowits ,&nbsp;I-Tzu Hung ,&nbsp;Nathaniel Thomas ,&nbsp;Miguel E. Rentería ,&nbsp;Carlos Cruz Fuentes ,&nbsp;Corina Benjet","doi":"10.1016/j.euroneuro.2025.08.474","DOIUrl":"10.1016/j.euroneuro.2025.08.474","url":null,"abstract":"<div><div>Internalizing (INT) and externalizing (EXT) disorders are heritable conditions that frequently co-occur. Large-scale genome-wide association studies (GWAS) have enhanced our understanding of the polygenic architecture of these disorders; yet genetic factors associated with their comorbidity remain unclear. Here, we leverage large-scale GWAS summary statistics on INT and EXT (Thorp et al., 2021; Karlsson Linnér et al., 2021) to examine the association of shared and unique genetic liability for INT and EXT disorders in relation to phenotypic comorbidity, and explored whether childhood adversity, a well-established risk factor for these disorders moderated these associations. Participants were Mexican adolescents (n=1,134 evaluated within the framework of an epidemiological study with the Composite International Diagnostic Interview. Genomic structural equation modeling (gSEM) was used to identify common vs. unique variance associated with INT, EXT, and comorbidity of these traits. Polygenic risk scores (PGS) were subsequently created based on these results. Model fit indices supported a bifactor gSEM model (AIC = 750.978, CFI = 0.973, SRMR = 0.052) comprised of a General Psychopathology (GP) factor influencing all traits and orthogonal specific factors for externalizing and internalizing traits. The GP-PGS was significantly associated with EXT (OR = 1.3, p &lt; 0.001) and comorbid INT-EXT (OR = 1.42, p &lt; 0.000) outcomes. Adversities, such as parental psychopathology and neglect/abuse were associated with greater risk for all psychiatric outcomes (p &lt; 0.001), while Parental Loss (p &lt; 0.001) was specifically associated with EXT disorders (p &lt; 0.000). A significant interaction was identified between GP-PGS and Loss adversity in predicting INT disorders (OR = 1.63, p &lt; 0.016), such that the experience of loss adversity was more influential for participants with higher levels of GP genetic liability. Our results indicate the predictive utility of trans-diagnostic, genetically informed models and the importance of considering specific adversities in understanding psychiatric risk for INT and EXT comorbidity.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 11"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STUDYING BRAIN BIOLOGY IN LIVING PEOPLE","authors":"Alexander Charney","doi":"10.1016/j.euroneuro.2025.08.517","DOIUrl":"10.1016/j.euroneuro.2025.08.517","url":null,"abstract":"<div><div>A goal of biomedical research is to advance knowledge of the molecular basis of human brain function. One way to achieve this goal is through studies of cells and molecules in samples of human brain tissue. As brain samples from living people (“LIV samples”) are largely unavailable for research, most such studies are conducted using brain samples from postmortem donors (“PM samples”). This practice, while necessary, is subject to four key limitations. First, the extent to which PM samples faithfully represent LIV samples at the molecular level has not been rigorously investigated. Second, in contrast to the living brain, the postmortem brain is by definition not capable of any meaningful function – therefore, the molecular basis of human brain functions like perception, mood, and memory cannot be fully established using PM samples. Third, the postmortem state is unsuitable for studying the molecular relationship between the brain and more readily accessible tissues - most importantly, the blood - and this hinders biomarker discovery. Fourth, valuable information about PM sample donors (e.g., neuroimaging data, deep clinical phenotyping information) is often not available to researchers, thus precluding comprehensive understanding of how functions emerge from the biological, electrophysiological, and anatomical features of the human brain.</div><div>The Living Brain Project (LBP) was designed to help address these limitations. The LBP is a translational research framework predicated upon the deep brain stimulation (DBS) procedure. From each LBP study participant the following is obtained: samples of the prefrontal cortex (PFC), peripheral blood samples obtained simultaneously with the PFC, intracranial electrical recordings, neuroimaging, and deep clinical phenotyping. To date, analyses of LBP data have identified (1) the safety of the PFC biopsy approach, (2) widespread biological differences between LIV samples and PM samples, (3) biological signatures of neurotransmission, (4) complex patterns of molecular communication between the brain and the blood, and (5) relationships between brain biology and structure. Overall, the LBP framework provides a blueprint for the safe, ethical, and scalable study of brain biology in living people and enables the investigation of fundamental questions about the brain that were previously unable to be studied.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 30"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SEX DIFFERENCES IN THE ASSOCIATION OF APOE HAPLOTYPES, LDL CHOLESTEROL, AND DEMENTIA IN THE ELECTRONIC HEALTH RECORD","authors":"Freida Blostein ,&nbsp;Ky'Era Actkins ,&nbsp;Maria Niarchou ,&nbsp;Peter Straub ,&nbsp;Nancy Cox ,&nbsp;Lea Davis","doi":"10.1016/j.euroneuro.2025.08.522","DOIUrl":"10.1016/j.euroneuro.2025.08.522","url":null,"abstract":"<div><div>The APOE gene exhibits sex differences in associations with Alzheimer’s disease and related dementias (ADRDS): APOE ε4 is more strongly associated with ADRD in females than males while APOE ε2 may be more neuroprotective in females than males. Additionally, APOE regulates lipid biology, and lipid traits exhibit sex differences across the lifespan. In an agnostic scan for sex differences in the genetic architecture of clinical laboratory traits, we detected stronger inverse associations between APOE ε2 and median LDL cholesterol value across the medical record in females than in males. We followed-up on this association by performing interaction and mediation analyses for &gt;77,000 participants with whole genome sequencing data and LDL cholesterol measurements in the Vanderbilt University Medical Center genetic biobank, BioVU. Sex modified the association of APOE haplotypes with LDL cholesterol, with stronger associations in females than males for both APOE ε4 (increased LDL cholesterol) and APOE ε2 (decreased LDL cholesterol). Although females were much less likely to have statin medication records, the interaction between APOE and sex on LDL cholesterol was not explained by differences in statin records. Similarly, sex modified associations with dementia, with stronger associations in females. Higher LDL was associated with dementia among females without statin record and among all males regardless of statin record status. In preliminary mediation analyses, LDL cholesterol mediated 3% (95%CI: 1.5%, 2.4%) of the effect of the APOE ε3/ε4 (relative to ε3/ε3) haplotype on dementia for males. For females without statin record, LDL cholesterol mediated 8% (3%, 16%) of the effect of the APOE ε3/ε4 (relative to ε3/ε3) haplotype on dementia. Our results suggest sex differences in APOE influence cholesterol biology and dementia.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 31-32"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"THE IMPACT OF RARE GENETIC VARIANTS ON BRAIN STRUCTURE AND RISK FOR NEUROPSYCHIATRIC DISORDERS","authors":"Rune Bøen,&nbsp;Kathleen O’Hora,&nbsp;Hoki Fung,&nbsp;Leila Kushan,&nbsp;Elizabeth Bondy,&nbsp;Charles Schleifer,&nbsp;Carolyn Amir,&nbsp;Jee Won Kang,&nbsp;Haley Wang,&nbsp;Dylan Hughes,&nbsp;ENIGMA 22q11DS Working Group,&nbsp;Carrie Bearden","doi":"10.1016/j.euroneuro.2025.08.514","DOIUrl":"10.1016/j.euroneuro.2025.08.514","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Rare recurrent copy number variants (CNVs) have been implicated in atypical neurodevelopment and elevated risk for neuropsychiatric disorders. Among these, CNVs at the 22q11.2 locus (i.e., deletions or duplications on the long arm of chromosome 22) represent one of the most robust genetic risk factors for developmental neuropsychiatric conditions. The 22q11.2 deletion, occurring in ∼1 in 3,600 live births, is associated with markedly increased risk for autism spectrum disorder and schizophrenia. In contrast, the reciprocal 22q11.2 duplication, found in ∼1 in 1,200 live births, confers elevated risk for autism spectrum disorder but is associated with a reduced risk of schizophrenia relative to the general population. These reciprocal CNVs thus provide a unique model to investigate the neurobiological mechanisms underlying vulnerability and resilience to neuropsychiatric disorders. This presentation will highlight preliminary results showing that 22q11.2 CNVs are associated with substantial distribution shifts and regional brain structural variability beyond mean differences, as measured by magnetic resonance imaging, compared to controls. A novel neurodevelopmental model of the mechanisms underlying these alterations will also be discussed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Magnetic resonance imaging data of 22q11.2 CNV carriers and unrelated, typically developing controls were derived from an ongoing longitudinal study (111 22q11.2 deletion carriers, 109 controls and 38 22q11.2 duplication carriers) and the world’s largest multi-site study on 22qDel (438 22q11.2 deletion carriers and 412 controls). Brain structural measures include cortical thickness, cortical surface area, cortical folding, intracranial volume, white matter volume and gray matter volume.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;22q11.2 deletion carriers show widespread increased cortical thickness and lower cortical surface area, characterized by a complete distribution shift in these measures compared to controls. The 22q11.2 deletion carriers also showed greater gray matter volume relative to white matter volume, which was related to individual differences in cortical surface area. In addition, there was a significant dosage effect (i.e., linear association between brain measures and copies of the 22q11.2 locus) on cortical folding (positive association) and cortical thickness (negative association).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Discussion and Conclusion&lt;/h3&gt;&lt;div&gt;The 22q11.2 CNVs yield large effects on brain structure, resulting in a distribution shift in brain phenotypes among 22q11.2 deletion carriers. We posit that the consistently observed increased cortical thickness and lower cortical surface area in 22q11.2 deletion may represent increased neuronal density in deep cortical layers and reduced neuronal density in upper cortical layers. In contrast, 22q11.2 duplication may yield increased neuronal density in upper cortical layers, resulting in a thinner ","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 28-29"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The genetics of treatment-resistant depression: controversies and perspectives.","authors":"Alessandro Serretti","doi":"10.1016/j.euroneuro.2025.07.012","DOIUrl":"10.1016/j.euroneuro.2025.07.012","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"1-2"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clozapine in treatment-resistant early-onset schizophrenia: A two-year follow-up retrospective observational study.","authors":"Giuseppe Albanesi, Giada Trovini, Susanna Pacifici, Nicola Annarumma, Lavinia Marcucci, Silvia Orecchio, Carmine Gelormini, Giorgio Di Lorenzo, Sergio De Filippis","doi":"10.1016/j.euroneuro.2025.07.010","DOIUrl":"10.1016/j.euroneuro.2025.07.010","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"19-20"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EPIGENOME-WIDE ASSOCIATION STUDIES IDENTIFY NOVEL EPIGENETIC SIGNATURES OF ANXIETY","authors":"Shaunna Clark ,&nbsp;Lea Zillich ,&nbsp;Miriam Schiele ,&nbsp;Katharina Domschke","doi":"10.1016/j.euroneuro.2025.08.463","DOIUrl":"10.1016/j.euroneuro.2025.08.463","url":null,"abstract":"<div><div>Anxiety disorders are a highly prevalent public health burden that significantly impair daily functioning and decrease quality of life. While they are moderately heritable, environmental factors also contribute and may interact with genetics to confer risk for anxiety disorders. A growing body of research suggests that DNA methylation may play a role as it is involved in critical adaptations to changing environments and thus may confer risk for anxiety disorders by invoking a maladaptive response to environmental triggers. A recent systematic review of epigenome-wide association studies of anxiety disorders found no overlapping DNA methylation sites across studies, which is likely due to small sample sizes in individual studies. Here, we aim to overcome this limitation by combining data from existing studies.</div><div>As the Psychiatric Genomics Consortium Anxiety Epigenetics Workgroup, we will conduct the largest cross-sectional meta-analysis of epigenome-wide association studies of anxiety disorders to date, involving over 18,434 participants (3,577 anxiety cases and 14,857 controls) from 12 cohorts. DNA methylation was assayed from blood using Illumina HumanMethylation 450 or MethylationEPIC (850K) Beadchips, or enrichment-based sequencing approaches. Within each cohort, DNA methylation will be regressed on anxiety case status, sex, age, estimated blood cell proportions, ancestry, smoking, and any cohort-specific comorbidities (e.g., depression). An inverse variance-weighted meta-analysis will be performed. Primary analyses will focus on current clinically assessed anxiety disorder diagnoses (i.e., cases had at least one current anxiety disorder diagnosis), while replication efforts will examine self-reported anxiety diagnoses. Secondary analyses will focus on identifying methylation sites specific to individual anxiety disorders as, for example, panic disorder may have different methylation signatures than fear-related disorders like specific phobias.</div><div>Preliminary results identified 28 sites significantly associated with anxiety case status (p &lt; 9.0 × 10-08). The top finding was located in PFKP, a key regulator of glycolysis, which may impact anxiety by altering glucose metabolism in brain regions involved in emotion regulation. Characterization of top findings suggested potential dysregulation of cellular stress response systems as well as immune and inflammatory pathways. Replication efforts and disorder-specific analyses are ongoing. Although further work is needed, our preliminary results suggest DNA methylation as a promising approach to study biological mechanisms in anxiety research.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 4-5"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GENETICALLY SHAPED ENVIRONMENTS: THE ROLE OF ACTIVE AND EVOCATIVE GENE-ENVIRONMENT CORRELATIONS IN MENTAL HEALTH","authors":"Emma Sprooten Chair ,&nbsp;Meike Bartels Co-chair ,&nbsp;Matthew Keller Discussant","doi":"10.1016/j.euroneuro.2025.08.476","DOIUrl":"10.1016/j.euroneuro.2025.08.476","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Environmental and lifestyle factors influencing mental health—e.g. SES, diet, sleep, home environment, activieties—are heritable. This gives rise to gene-environment correlation (rGE). rGE can bias genetic effect sizes, Mendelian randomisation studies, and gene-environment interaction estimates. rGEs can also reveal new mechanisms through which genetic risk is expressed. In this symposium we present several studies that explore (active and evocative) rGE using quantitative genetics and GWAS-based approaches, in different cohorts across the world.&lt;/div&gt;&lt;div&gt;Margherita Malanchini will address different forms of gene-environment interplay influencing internalising and externalising problems in childhood and adolescence. The effects of 13 polygenic scores for psychopathology (G), a combination of environmental exposures (E), their additive effect (G+E), interaction (G × E), and correlation (rGE) were examined in 3,337 16-year-olds from the Twins Early Development Study. Results indicated both GxE and rGE, and suggested that individuals may seek or create environments that align with their genetic propensities, which complicates the interpretion of G × E.&lt;/div&gt;&lt;div&gt;Next, Luciana Tovo-Rodrigues will explore recent evidence on the joint contribution of genetic liability and exposure to childhood maltreatment to ADHD symptomatology in young adulthood. Analyses were based on the 2004 Pelotas Birth Cohort, a landmark longitudinal study in Brazil that followed 4,231 individuals from birth. Findings indicated that individuals with higher polygenic scores for ADHD are more likely to have experienced adverse childhood environments. Mediation analysis suggested an evocative rGE mechanism.&lt;/div&gt;&lt;div&gt;Third, Yingjie Shi wil present findings from the longitudinal ABCD study examining how genetic, familial, and dozens of lifestyle and environmental factors contribute—individually and collectively—to adolescent mental health. Lifestyle, especially sleep, had the largest unique influence on internalizing and externalizing problems, while family and school environments were particularly important for externalizing behaviors. Longitudinal analyses revealed widespread bidirectional relationships between lifestyle/environment and mental health traits.&lt;/div&gt;&lt;div&gt;Fourth, Meike Bartels will present two studies of the Netherlands Twin Register converging on evidence that genetic predisposition for wellbeing contributes to shaping supportive environments, consistent with active rGE. A large-scale longitudinal survey showed that higher teenage wellbeing predicts better psychosocial outcomes in early adulthood, with attenuated within-family effects suggesting genetically influenced environmental selection. In a second, Ecological Momentary Assessment study, individuals with higher momentary wellbeing experienced less subsequent social mismatch, indicating that affective states shape social interactions.&lt;/div&gt;&lt;div&gt;Together, these findings from different analyses techniq","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 12-13"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GENETIC SUSCEPTIBILITY AND CHILDHOOD MALTREATMENT IN ATTENTION-DEFICIT/HYPERACTIVITY DISORDER: FINDINGS FROM A GLOBAL SOUTH BIRTH COHORT","authors":"","doi":"10.1016/j.euroneuro.2025.08.478","DOIUrl":"10.1016/j.euroneuro.2025.08.478","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 13"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"QUANTIFYING INDIVIDUAL DEPRESSIVE SYMPTOM BURDEN OVER THE LIFE COURSE USING AREA UNDER THE CURVE (AUC): AN ALTERNATIVE PHENOTYPE FOR GENOME-WIDE ASSOCIATION STUDIES (GWAS)","authors":"Esme Elsden,&nbsp;Rita Dargham,&nbsp;Alex S.F. Kwong,&nbsp;Mark Adams,&nbsp;Xueyi Shen,&nbsp;Andrew McIntosh","doi":"10.1016/j.euroneuro.2025.08.484","DOIUrl":"10.1016/j.euroneuro.2025.08.484","url":null,"abstract":"<div><div>Depression can be a chronic, fluctuating condition, yet most research relies on cross-sectional estimates of symptom severity that fail to capture individual trajectories over time. This project used longitudinal population data and multilevel growth curve models to quantify individual-level depressive symptom burden using AUC methods. This approach provides a scalable, interpretable, and theoretically grounded alternative to the prior cross-sectional phenotype of depression.</div><div>This project used data from the UK Biobank of ∼490,000 adults with repeated measures of the 2-item Patient Health Questionnaire (PHQ-2) across eight occasions. A mixed-effect model was fitted via MLwiN in Stata 18.5. The models included fixed effects for age, age-squared and age-cubed, and random intercepts and slopes for age to capture individual deviations in symptom onset and linear change. Age was centred around the grand mean to improve interpretability and reduce collinearity between polynomial terms.</div><div>Person-specific predicted symptom trajectories were derived from the estimated model parameters, incorporating both fixed and random effects. The AUC was then calculated for each individual using the trapezoidal rule, integrating predicted PHQ-2 scores across observed time points. This resulted in a continuous measure of cumulative depressive symptom burden—scaled for comparability across individuals with varying follow-up durations. The resulting distribution of AUC values captures substantial inter-individual variability, with higher scores reflecting longer duration and greater intensity of symptoms over time. This phenotype was then used to run a GWAS using REGENIE, controlling for principal components, removing SNPs with genotype missingness &gt; 10%, INFO &lt; 0.1, and HWE p &gt; 1e-15. REGENIE uses a two-step method that enables rapid whole-genome regression modelling. 2 lead SNPs were identified.</div><div>This method addresses three key limitations of traditional phenotyping approaches: (1) it preserves longitudinal structure and avoids arbitrary cutoffs, (2) it enables comparison of lifetime symptom burden across individuals, and (3) it accommodates varying observation schedules through flexible multilevel modelling.</div><div>We discuss the implications of using AUC as a phenotypic summary in psychiatric genomics. For example, how the cumulative burden derived from model-based predictions may serve as a more stable and interpretable outcome for a Genome-Wide Association Study compared to timepoint-specific symptom scores. Our work demonstrates how longitudinal modelling combined with AUC integration provides a powerful tool for capturing dynamic mental health processes over the life course.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 16"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}