Molecular Psychiatry最新文献

{"title":"Integrative analysis of miRNA expression profiles reveals distinct and common molecular mechanisms underlying broad diagnostic groups of severe mental disorders","authors":"Pierre Solomon, Lalit Kaurani, Monika Budde, Jean-Baptiste Guiné, Dennis Manfred Krüger, Kevin Riquin, Tonatiuh Pena, Susanne Burkhardt, Cynthia Fourgeux, Kristina Adorjan, Maria Heilbronner, Janos L. Kalman, Mojtaba Oraki Kohshour, Sergi Papiol, Daniela Reich-Erkelenz, Sabrina K. Schaupp, Eva C. Schulte, Fanny Senner, Thomas Vogl, Ion-George Anghelescu, Volker Arolt, Bernhardt T. Baune, Udo Dannlowski, Detlef E. Dietrich, Andreas J. Fallgatter, Christian Figge, Georg Juckel, Carsten Konrad, Jens Reimer, Eva Z. Reininghaus, Max Schmauß, Carsten Spitzer, Jens Wiltfang, Jörg Zimmermann, Anna-Lena Schütz, Farahnaz Sananbenesi, Anne Sauvaget, Peter Falkai, Thomas G. Schulze, André Fischer, Urs Heilbronner, Jeremie Poschmann","doi":"10.1038/s41380-025-03018-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03018-9","url":null,"abstract":"<p>Micro RNAs (miRNAs) play a crucial role as regulators of various biological processes and have been implicated in the pathogenesis of mental disorders such as schizophrenia and bipolar disorders. In this study, we investigate the expression patterns of miRNAs in the PsyCourse Study (<i>n</i> = 1786), contrasting three broad diagnostic groups: Psychotic (Schizophrenia-spectrum disorders), Affective (Bipolar Disorder I, II and recurrent Depression), and neurotypic healthy individuals. Through comprehensive analyses, including differential miRNA expression, miRNA transcriptome-wide association study (TWAS), and predictive modelling, we identified multiple miRNAs unique to Psychotic and Affective groups as well as shared by both. Furthermore, we performed integrative analysis to identify the target genes of the dysregulated miRNAs and elucidate their potential roles in psychosis. Our findings reveal significant alterations of multiple miRNAs such as miR-584-3p and miR-99b-5p across the studied diagnostic groups, highlighting their role as molecular correlates. Additionally, the miRNA TWAS analysis discovered previously known and novel genetically dysregulated miRNAs confirming the relevance in the etiology of the diagnostic groups. Importantly, novel factors and putative molecular mechanisms underlying these groups were uncovered through the integration of miRNA-target gene interactions. This comprehensive investigation provides valuable insights into the molecular underpinnings of severe mental disorders, shedding light on the complex regulatory networks involving miRNAs.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"26 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons","authors":"Chuyu Chen, Meghan Masotti, Nathaniel Shepard, Vanessa Promes, Giulia Tombesi, Daniel Arango, Claudia Manzoni, Elisa Greggio, Sabine Hilfiker, Yevgenia Kozorovitskiy, Loukia Parisiadou","doi":"10.1038/s41380-025-03030-z","DOIUrl":"https://doi.org/10.1038/s41380-025-03030-z","url":null,"abstract":"<p>Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson’s disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson’s disease-associated leucine-rich repeat kinase 2 (LRRK2) has an essential role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor side effects of haloperidol. This work opens up new therapeutic avenues for dopamine-related disorders, such as psychosis, also furthering our understanding of Parkinson’s disease pathophysiology.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"32 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations among white matter microstructural changes and the development of emotional reactivity and regulation in infancy","authors":"Yicheng Zhang, Layla Banihashemi, Amelia Versace, Alyssa Samolyk, Mahmood Abdelkader, Megan Taylor, Gabrielle English, Vanessa J. Schmithorst, Vincent K. Lee, Richelle Stiffler, Haris Aslam, Ashok Panigrahy, Alison E. Hipwell, Mary L. Phillips","doi":"10.1038/s41380-025-03025-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03025-w","url":null,"abstract":"<p>Deficits in emotional reactivity and regulation assessed in infancy, including high levels of negative emotionality (NE), low positive emotionality (PE) and low soothability, can predict future affective and behavioral disorders. White matter (WM) tracts develop rapidly in the first postnatal year, paralleling the development of emotional regulation. During this period, examining the development of white matter microstructure in tracts connecting cortical and/or subcortical regions supporting emotional regulation, including the cingulum bundle (CB), uncinate fasciculus (UF), and forceps minor (FM), can provide neural markers reflecting pathophysiological processes underlying early emotional regulation development. The Neurite Orientation Dispersion and Density Imaging (NODDI) model can be used to estimate with high intercellular specificity microstructural integrity and myelination using the neurite density index (NDI), and dispersion, using the orientation dispersion index (ODI). Examining relationships among changes in WM tract NODDI measures and changes in emotional reactivity and regulation during the first 3-to-9-months of age (<i>n</i> = 39), we showed that larger 3-to-9-month increases in right UF, FM, and left CB ODI were associated with larger decreases or smaller increases in soothability during this period, while a larger increase in right UF NDI was associated with a smaller increase in PE. These findings suggest that in infancy, larger microstructural changes in major WM tracts interconnecting neural networks supporting emotional regulation are associated with disrupted development of PE and soothability. These findings could provide early neural markers of child emotional dysregulation and may have implications for future affective or behavioral trajectories.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"50 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in discerning the mechanisms underlying depression and resiliency: relation to the neurobiology of stress and the effects of antidepressants","authors":"Philip W. Gold, Ma-Li Wong","doi":"10.1038/s41380-025-03019-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03019-8","url":null,"abstract":"<p>Depression denotes a dysregulated stress response with significant mental and health implications. This review examines the neurobiological mechanisms underlying depression and resilience, focusing on how stress mediators influence vulnerability to severe stressors contrasted with resilience. We analyze structural and functional alterations in key brain regions, genetic factors, and potential therapeutic interventions. Understanding these mechanisms offers insights into preventing depression onset instead of solely treating its manifestations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"20 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the implications of case selection methods for psychiatric molecular genetic studies","authors":"Kenneth S. Kendler, Henrik Ohlsson, Jan Sundquist, Kristina Sundquist","doi":"10.1038/s41380-025-03015-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03015-y","url":null,"abstract":"<p>Researchers selecting probands for molecular genetic studies confront a range of sampling issues with modest empirical guidance. In this paper, using cases of major depression (MD), anxiety disorders (AD) alcohol use disorder (AUD), drug use disorder (DUD), bipolar disorder (BD) and schizophrenia (SZ) from a large population cohort of all native Swedes born 1940–2003, we examine the implications of three proband selection decisions by exploring profiles of genetic risks assessed using the validated family genetic risk scores. The impact of censoring cases with comorbid diagnoses is quite variable, depending on the frequency of that disorder in the case sample and the genetic relationship of the censored to the primary disorder. In an MD cohort, censoring SZ cases produces only a focal small decrease in schizophrenia genetic risk while censoring AD cases produces a wide-spread reduction in genetic risk for MD and most other disorders. We examine the value of censoring cases of SZ, BD and MD whose onset was preceded by one to two years by first episodes of DUD or AUD. We do not see any increase in genetic risk for these “screened” cohorts. Secondary ascertainment, where disorder A is ascertained as a comorbid diagnosis in a sample collected for disorder B, can, in certain situations, produces large increases in the genetic risk for disorder B and associated disorders in cases of A. However, if disorder B is closely genetically related to disorder A (as seen with MD/AD and DUD/AUD pairings), the pattern differs dramatically and produces a general moderate elevation across the genetic risk profile. These findings provide guidelines for future investigators and suggest caution when screening out comorbid disorders and when utilizing secondary ascertainment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"32 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease","authors":"David Mengel, Ester Soter, Julia Maren Ott, Madeleine Wacker, Alejandra Leyva, Oliver Peters, Julian Hellmann-Regen, Luisa-Sophie Schneider, Xiao Wang, Josef Priller, Eike Spruth, Slawek Altenstein, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Niels Hansen, Ayda Rostamzadeh, Emra Düzel, Wenzel Glanz, Enise I. Incesoy, Katharina Buerger, Daniel Janowitz, Michael Ewers, Robert Perneczky, Boris Rauchmann, Stefan Teipel, Ingo Kilimann, Christoph Laske, Sebastian Sodenkamp, Annika Spottke, Johanna Brustkern, Frederic Brosseron, Michael Wagner, Melina Stark, Luca Kleineidam, Kai Shao, Falk Lüsebrink, Renat Yakupov, Matthias Schmid, Stefan Hetzer, Peter Dechent, Klaus Scheffler, David Berron, Frank Jessen, Matthis Synofzik","doi":"10.1038/s41380-025-03021-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03021-0","url":null,"abstract":"<p>Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer’s disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"9 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic and genetic profiling of comorbidity patterns among substance dependence diagnoses","authors":"Gita A. Pathak, Robert H. Pietrzak, AnnMarie Lacobelle, Cassie Overstreet, Frank R. Wendt, Joseph D. Deak, Eleni Friligkou, Yaira Z. Nunez, Janitza L. Montalvo-Ortiz, Daniel F. Levey, Henry R. Kranzler, Joel Gelernter, Renato Polimanti","doi":"10.1038/s41380-025-03031-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03031-y","url":null,"abstract":"<p>This study investigated the genetic and epigenetic mechanisms underlying the comorbidity of five substance dependence diagnoses (SDs; alcohol, AD; cannabis, CaD; cocaine, CoD; opioid, OD; tobacco, TD). A latent class analysis (LCA) was performed on 22,668 individuals from six cohorts to identify comorbid DSM-IV SD patterns. In subsets of this sample, we tested SD-latent classes with respect to polygenic overlap of psychiatric and psychosocial traits in 7659 individuals of European descent and epigenome-wide changes in 886 individuals of African, European, and Admixed-American descents. The LCA identified four latent classes related to SD comorbidities: AD + TD, CoD + TD, AD + CoD + OD + TD (i.e., polysubstance addiction, PSU), and TD. In the epigenome-wide association analysis, <i>SPATA4</i> cg02833127 was associated with CoD + TD, AD + TD, and PSU latent classes. AD + TD latent class was also associated with CpG sites located on <i>ARID1B</i>, <i>NOTCH1</i>, <i>SERTAD4</i>, and <i>SIN3B</i>, while additional epigenome-wide significant associations with CoD + TD latent class were observed in <i>ANO6</i> and <i>MOV10</i> genes. PSU-latent class was also associated with a differentially methylated region in <i>LDB1</i>. We also observed shared polygenic score (PGS) associations for PSU, AD + TD, and CoD + TD latent classes (i.e., attention-deficit hyperactivity disorder, anxiety, educational attainment, and schizophrenia PGS). In contrast, TD-latent class was exclusively associated with posttraumatic stress disorder-PGS. Other specific associations were observed for PSU-latent class (subjective wellbeing-PGS and neuroticism-PGS) and AD + TD-latent class (bipolar disorder-PGS). In conclusion, we identified shared and unique genetic and epigenetic mechanisms underlying SD comorbidity patterns. These findings highlight the importance of modeling the co-occurrence of SD diagnoses when investigating the molecular basis of addiction-related traits.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"42 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiovascular diseases and depression: A meta-analysis and Mendelian randomization analysis","authors":"Jun Zeng, Yuting Qiu, Chengying Yang, Xinrong Fan, Xiangyu Zhou, Chunxiang Zhang, Sui Zhu, Yang Long, Yan Wei, Kenji Hashimoto, Lijia Chang","doi":"10.1038/s41380-025-03003-2","DOIUrl":"https://doi.org/10.1038/s41380-025-03003-2","url":null,"abstract":"<p>Depression is a common psychiatric symptom among patients with cardiovascular disease (CVD), adversely affecting their health. Despite the identification of various contributing factors, the precise mechanisms linking CVD and depression remain elusive. This study conducted a meta-analysis to investigate the association between CVD and depression. Furthermore, a bidirectional Mendelian randomization (MR) analysis was undertaken to clarify the causal relationship between the two conditions. The meta-analysis included 39 studies, encompassing 63,444 patients with CVD, 12,308 of whom were diagnosed with depression. The results revealed a significant association between CVD and depression or anxiety, with an estimated overall prevalence of depression in CVD patients of 20.8%. Subgroup analyses showed that the prevalence of depression in patients with coronary artery disease and heart failure was 19.8 and 24.7%, respectively. According to a random-effects model, depressive symptoms were linked to an increase in unadjusted all-cause mortality compared with non-depressed patients. The MR analysis, employing the inverse-variance weighted method as the primary tool for causality assessment, identified significant associations between various CVD types and depression or anxiety phenotypes. These findings underscore the significant relationship between CVD and depression or anxiety, leading to an elevated risk of all-cause mortality. Moreover, the MR analysis provides the first genetically-informed evidence suggesting that depression plays a critical role in the development and progression of certain CVD subtypes. This emphasizes the need for addressing depressive symptoms in CVD patients to prevent or reduce adverse cardiovascular outcomes.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"88 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Animal studies reveal downregulation of the Beclin-1 autophagy pathway as shared mechanism in Autism Spectrum Disorder: a systematic review and meta-analysis","authors":"A Abromeit, CR Hooijmans, C LeMaoult, CM Drion, MJH Kas","doi":"10.1038/s41380-025-03028-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03028-7","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with complex etiology, involving genetic and environmental influences on brain development and behavior. Dysregulation of mammalian target of rapamycin (mTOR) signaling alters neuronal growth and synaptic plasticity, and has emerged as a potential underlying pathway in ASD.</p><h3 data-test=\"abstract-sub-heading\">Goal and methods</h3><p>To investigate mTOR dysregulation as a common mechanism in ASD, we performed a systematic review, and a meta-analysis of 192 studies examining mTOR signaling in diverse genetic and environmental animal models.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Our random-effects model identified significant alterations in mTOR pathway-related proteins. For several proteins (p-AKT, PTEN, p-mTOR, p-EIF4e, LC3-II, p-S6K and p-S6), subgroup analyses revealed clear species-, sex-, age-, or brain region-specific effects. Interestingly, Beclin-1 was consistently downregulated across all subgroups.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Our findings support mTOR-pathway dysregulation in ASD. The observed consistent downregulation of Beclin-1 highlights autophagy as a common mechanism, and provides new leads for novel ASD biomarker and treatment development.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The moderation of genetic risk for ten major psychiatric and substance use disorders by the genetic aptitude for educational attainment","authors":"Kenneth S. Kendler, Henrik Ohlsson, Jan Sundquist, Kristina Sundquist","doi":"10.1038/s41380-025-03022-z","DOIUrl":"https://doi.org/10.1038/s41380-025-03022-z","url":null,"abstract":"<p>We seek to clarify the impact of the Genetic Aptitude for Educational Attainment (GAEA) on risk for 10 psychiatric disorders divided into 4 groups: Internalizing, Externalizing, Eating/Compulsive and Psychotic. Educational attainment and psychiatric and substance use disorder information were obtained from national Swedish registries. GAEA and disorder-specific family genetic risk score (FGRS) were calculated from extended pedigrees. In males, information on IQ and resilience was obtained from the Swedish conscript registry. Affected individuals were born in Sweden from 1973–1995 to Swedish born parents. Controlling for disorder specific FGRS, GAEA were negatively and substantially associated with risk for externalizing and internalizing disorders, minimally associated with psychotic disorder risk and positively and modestly associated with risk for eating/compulsive disorders. While the majority of GAEA effect on risk for externalizing disorders was mediated through impact on IQ, for internalizing disorders, mediation was largely through resilience. For externalizing and internalizing disorders, interactions between GAEA and disorder specific FGRS were robust and negative – the slope of disorder risk with increasing genetic liability was steepest in those with low GAEA. For eating disorders, interactions were modest and positive –the slope of risk with increasing genetic liability being steepest in individuals with high GAEA. We found that the impact of GAEA on risk for psychiatric and substance can be substantial and varies widely across disorders in magnitude, direction, and mediation. GAEA also often interacts, sometimes robustly, with disorder specific genetic risk factors. Comprehensive risk models for psychiatric disorders should consider the inclusion of GAEA.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"64 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}