Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities
| Autor: | Mallard, T. T., Linnér, R. K., Grotzinger, A. D., Sanchez-Roige, S., Seidlitz, J., Okbay, A., e Vlaming, R., Meddens, S. F. W., Bipolar Disorder Working Group of the PGC, Palmer, A. A., Davis, L. K., Tucker-Drob, E. M., Kendler, K. S., Keller, M. C., Koellinger, P. D., Harden, K. P., Gordon-Smith, Katherine, Perry, Amy, Jones, Lisa |
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| Přispěvatelé: | Applied Economics, Epidemiology, Economics, Tinbergen Institute, Amsterdam Neuroscience - Complex Trait Genetics, Gordon-Smith, Katherine, Perry, Amy, Jones, Lisa |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Psychosis
medicine.medical_specialty Population Genome-wide association study Disease psychiatric genetics SDG 3 - Good Health and Well-being pleiotropy genomics Medicine Bipolar disorder Psychiatry education education.field_of_study genome-wide association study neurodevelopment business.industry medicine.disease genetic correlation psychiatric disorders Schizophrenia transdiagnostic RC0321 Major depressive disorder medicine.symptom business Mania |
| Zdroj: | Cell Genomics, 2(6):100140 Bipolar Disorder Working Group of the Psychiatric Genomics Consortium 2022, ' Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities ', Cell Genomics, vol. 2, no. 6, 100140, pp. 1-19 . https://doi.org/10.1016/j.xgen.2022.100140 Cell Genomics, 2(6):100140. Cell Press Cell Genomics, 2(6):100140, 1-19. Cell Press |
| ISSN: | 2666-979X |
| DOI: | 10.1016/j.xgen.2022.100140 |
| Popis: | A single dimension of general psychopathology, p , has been hypothesized to represent a general liability that spans multiple types of psychiatric disorders and non-clinical variation in psychiatric symptoms across the lifespan. We conducted genome-wide association analyses of lifetime symptoms of mania, psychosis, irritability in 124,952 to 208,315 individuals from UK Biobank, and then applied Genomic SEM to model the genetic relationships between these psychiatric symptoms and clinically-defined psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder). Two dimensions of cross-cutting genetic liability emerged: general vulnerability to self-reported symptoms ( p self ) versus transdiagnostic vulnerability to clinically-diagnosed disease ( p clinician ). These were only modestly correlated ( r g = .344). Multivariate GWAS identified 145 and 11 independent and genome-wide significant loci for p clinician and p self , respectively, and improved polygenic prediction, relative to univariate GWAS, in hold-out samples. Despite the severe impairments in occupational and educational functioning seen in patients with schizophrenia and bipolar disorder, p self showed stronger and more pervasive genetic correlations with facets of socioeconomic disadvantage (educational attainment, income, and neighborhood deprivation), whereas p clinician was more strongly associated with medical disorders unrelated to the brain. Genetic variance in p clinician that was unrelated to general vulnerability to psychiatric symptoms was associated with less socioeconomic disadvantage, suggesting positive selection biases in clinical samples used in psychiatric GWAS. These findings inform criticisms of psychiatric nosology by suggesting that cross-disorder genetic liabilities identified in GWASs of clinician-defined psychiatric disease are relatively distinct from genetic liabilities operating on self-reported symptom variation in the general population. |
| Databáze: | OpenAIRE |
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