Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrumResearch in context
Summary: Background: Psychotic major depressive disorder (MDD), a subtype of MDD characterised by psychotic symptoms that occur exclusively during mood episode, is clinically significant yet underexplored genetically due to its rarity. This study comprehensively examines the genetic basis of psycho...
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2025-02-01
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| author | Thuy-Dung Nguyen Joeri J. Meijsen Robert Sigström Ralf Kuja-Halkola Ying Xiong Arvid Harder Kaarina Kowalec Joëlle A. Pasman Carolina Scarpa Elin Hörbeck Lina Jonsson Sara Hägg Niamh Mullins Kevin S. O’Connell Christina Dalman Dorte Helenius Richard Zetterberg Henrik Larsson Paul Lichtenstein Ole A. Andreassen Thomas Werge Alfonso Buil Mikael Landén Patrick F. Sullivan Yi Lu |
| author_facet | Thuy-Dung Nguyen Joeri J. Meijsen Robert Sigström Ralf Kuja-Halkola Ying Xiong Arvid Harder Kaarina Kowalec Joëlle A. Pasman Carolina Scarpa Elin Hörbeck Lina Jonsson Sara Hägg Niamh Mullins Kevin S. O’Connell Christina Dalman Dorte Helenius Richard Zetterberg Henrik Larsson Paul Lichtenstein Ole A. Andreassen Thomas Werge Alfonso Buil Mikael Landén Patrick F. Sullivan Yi Lu |
| author_sort | Thuy-Dung Nguyen |
| collection | DOAJ |
| description | Summary: Background: Psychotic major depressive disorder (MDD), a subtype of MDD characterised by psychotic symptoms that occur exclusively during mood episode, is clinically significant yet underexplored genetically due to its rarity. This study comprehensively examines the genetic basis of psychotic MDD and elucidates its position within the mood-psychotic spectrum. Methods: This population-based cohort study used Swedish and Danish registry data for over 5.1 M individuals born between 1958 and 1993/1996. Specialist-diagnosed psychotic MDD was defined using ICD-10 sub-codes of MDD, F32.2/F32.3. We estimated familial aggregation/coaggregation using generalised estimating equations, heritability and genetic correlations using structural equation modelling. We also analysed ∼30,000 genotyped MDD cases from the UK Biobank and a Swedish cohort to explore which polygenic risk score (PRS) may predispose individuals to psychotic MDD. Findings: With over 10,000 psychotic MDD identified from the two nationwide patient registers, this study highlights the familial aggregation of psychotic MDD, co-aggregation with mood and psychotic disorders, and its stronger genetic correlation with schizophrenia compared to non-psychotic MDD. The familial risks increased with closer biological relatedness, suggesting genetic influence. Pedigree-heritability of psychotic MDD was 30.17% (95% CI 23.53–36.80%). While the genetic correlation between psychotic and non-psychotic MDD was high (0.82, 95% CI 0.73–0.92), the psychotic subgroup showed a higher genetic correlation with schizophrenia than non-psychotic MDD (0.67 vs 0.46, p-value 7.55∗10−4). Within 30,000 genotyped MDD cases, individuals with psychotic MDD had higher mean PRS for schizophrenia and BD but a lower MDD PRS than non-psychotic MDD. PRS for BD type-I was associated with increased odds of psychotic MDD, while BD type-II PRS showed no significant association with psychotic MDD. Interpretation: This study provides evidence for the genetic basis of psychotic MDD, underscoring its unique position bridging the spectrum of mood and psychotic disorders. These findings advance our understanding of the aetiology of psychotic MDD and contribute to the limited body of evidence on this phenotype by utilising large-scale population-based data. Funding: European Research Council; US National Institutes of Mental Health; European Union Horizon 2020 Program; Swedish Research Council; Research Council of Norway; Swedish Foundation for Strategic Research; Hjärnfonden. |
| format | Article |
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| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | EBioMedicine |
| spelling | doaj-art-7c1d491ce69341aabcb81851efd3b1cc2025-01-31T05:11:53ZengElsevierEBioMedicine2352-39642025-02-01112105576Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrumResearch in contextThuy-Dung Nguyen0Joeri J. Meijsen1Robert Sigström2Ralf Kuja-Halkola3Ying Xiong4Arvid Harder5Kaarina Kowalec6Joëlle A. Pasman7Carolina Scarpa8Elin Hörbeck9Lina Jonsson10Sara Hägg11Niamh Mullins12Kevin S. O’Connell13Christina Dalman14Dorte Helenius15Richard Zetterberg16Henrik Larsson17Paul Lichtenstein18Ole A. Andreassen19Thomas Werge20Alfonso Buil21Mikael Landén22Patrick F. Sullivan23Yi Lu24Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Global Public Health, Karolinska Institutet, Stockholm, SwedenInstitute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, DenmarkDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Affective Clinic, Sahlgrenska University Hopsital, Gothenburg, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; College of Pharmacy, University of Manitoba, Winnipeg, CanadaDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, Amsterdam UMC Location University of Amsterdam, Amsterdam, the NetherlandsDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Psychiatry “ASST Fatebenefratelli-Sacco”, University of Milan, Milan, ItalyDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA; Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl., New York, USANORMENT, Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, NorwayDepartment of Global Public Health, Karolinska Institutet, Stockholm, Sweden; Center for Epidemiology and Community Medicine, Stockholm, SwedenInstitute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, DenmarkInstitute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, DenmarkDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenNORMENT, Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo and Oslo University Hospital, Oslo, NorwayInstitute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, DenmarkInstitute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, DenmarkDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, USADepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden; Corresponding author. Nobels Väg 12A, Solna 17177, Sweden.Summary: Background: Psychotic major depressive disorder (MDD), a subtype of MDD characterised by psychotic symptoms that occur exclusively during mood episode, is clinically significant yet underexplored genetically due to its rarity. This study comprehensively examines the genetic basis of psychotic MDD and elucidates its position within the mood-psychotic spectrum. Methods: This population-based cohort study used Swedish and Danish registry data for over 5.1 M individuals born between 1958 and 1993/1996. Specialist-diagnosed psychotic MDD was defined using ICD-10 sub-codes of MDD, F32.2/F32.3. We estimated familial aggregation/coaggregation using generalised estimating equations, heritability and genetic correlations using structural equation modelling. We also analysed ∼30,000 genotyped MDD cases from the UK Biobank and a Swedish cohort to explore which polygenic risk score (PRS) may predispose individuals to psychotic MDD. Findings: With over 10,000 psychotic MDD identified from the two nationwide patient registers, this study highlights the familial aggregation of psychotic MDD, co-aggregation with mood and psychotic disorders, and its stronger genetic correlation with schizophrenia compared to non-psychotic MDD. The familial risks increased with closer biological relatedness, suggesting genetic influence. Pedigree-heritability of psychotic MDD was 30.17% (95% CI 23.53–36.80%). While the genetic correlation between psychotic and non-psychotic MDD was high (0.82, 95% CI 0.73–0.92), the psychotic subgroup showed a higher genetic correlation with schizophrenia than non-psychotic MDD (0.67 vs 0.46, p-value 7.55∗10−4). Within 30,000 genotyped MDD cases, individuals with psychotic MDD had higher mean PRS for schizophrenia and BD but a lower MDD PRS than non-psychotic MDD. PRS for BD type-I was associated with increased odds of psychotic MDD, while BD type-II PRS showed no significant association with psychotic MDD. Interpretation: This study provides evidence for the genetic basis of psychotic MDD, underscoring its unique position bridging the spectrum of mood and psychotic disorders. These findings advance our understanding of the aetiology of psychotic MDD and contribute to the limited body of evidence on this phenotype by utilising large-scale population-based data. Funding: European Research Council; US National Institutes of Mental Health; European Union Horizon 2020 Program; Swedish Research Council; Research Council of Norway; Swedish Foundation for Strategic Research; Hjärnfonden.http://www.sciencedirect.com/science/article/pii/S2352396425000209Psychotic major depressive disorderPsychotic disordersGeneticEpidemiology |
| spellingShingle | Thuy-Dung Nguyen Joeri J. Meijsen Robert Sigström Ralf Kuja-Halkola Ying Xiong Arvid Harder Kaarina Kowalec Joëlle A. Pasman Carolina Scarpa Elin Hörbeck Lina Jonsson Sara Hägg Niamh Mullins Kevin S. O’Connell Christina Dalman Dorte Helenius Richard Zetterberg Henrik Larsson Paul Lichtenstein Ole A. Andreassen Thomas Werge Alfonso Buil Mikael Landén Patrick F. Sullivan Yi Lu Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrumResearch in context EBioMedicine Psychotic major depressive disorder Psychotic disorders Genetic Epidemiology |
| title | Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrumResearch in context |
| title_full | Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrumResearch in context |
| title_fullStr | Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrumResearch in context |
| title_full_unstemmed | Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrumResearch in context |
| title_short | Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrumResearch in context |
| title_sort | genetic insights into psychotic major depressive disorder bridging the mood psychotic disorder spectrumresearch in context |
| topic | Psychotic major depressive disorder Psychotic disorders Genetic Epidemiology |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425000209 |
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