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• W4387476664 abstract "Anxiety disorder and major depressive disorder (MDD) have been found to co-occur, respond to the same treatments and share pathogenetic mechanisms and genetic liability. It may therefore be informative to conduct genetic studies of an internalising disorder phenotype that combines both anxiety disorder and MDD. We identified a range of ways to define anxiety disorder and MDD in UK Biobank and used these to derive a combined internalising disorder phenotype. We examined the association of both common and rare genetic variation with these phenotype definitions across different ethnic groups. We established eight ways of defining anxiety, MDD and internalising disorders, using self-reported medical history, self-reported medication use, electronic healthcare records (HER, eg primary care records and hospital admission records) and specialised diagnostic instruments (ie CIDI-SF). Then, the effect of both common and rare genetic variation on these phenotypes was assessed. To assess the effect of common variation, ancestry adjusted polygenic risk scores (PRS) of MDD and anxiety were computed and their accuracy for predicting the phenotypes was examined. To examine if combining different phenotype definitions would better capture genetic liability, the association of these PRSs with the number of phenotypes endorsed was also assessed. Finally, to examine rare genetic variation, the association of 33 copy number variants (CNVs), which have been previously implicated in neurodevelopmental disorders, with the phenotypes was also assessed. The eight definitions of anxiety disorder, MDD, and internalising disorders were highly intercorrelated. Both MDD and anxiety PRS were significantly associated with all phenotypes, with the association being stronger for the combined internalising phenotype. There was no significant difference between the performance of MDD PRS and anxiety PRS at predicting the phenotypes. Both PRSs performed better at predicting stricter phenotypes based on diagnostic instruments compared to self-reported and EHR-derived phenotypes (AUC 0.631, 0.596 and 0.578, respectively). The prediction accuracy increased with the number of definitions endorsed (AUC ranging from 0.549 for one defintion to 0.626 ≥5 definitions). Carrying any of the CNVs was significantly associated with EHR-derived and self-reported definitions of the anxiety, MDD and internalising phenotypes, but no individual CNV was associated with any of the phenotypes. These results indicate that combining MDD and anxiety disorder into a combined internalising phenotype disorder could be beneficial in genetic analyses. Stricter phenotypes were found to have a stronger polygenic component but were not associated with rare variants. This suggests that the different ways of defining internalising disorders may capture different genetic liability. Endorsing multiple definitions resulted in better polygenic prediction, which could indicate that combining information from multiple sources might result in a more genetically robust phenotype." @default.
• W4387476664 created "2023-10-11" @default.
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• W4387476664 date "2023-10-01" @default.
• W4387476664 modified "2023-10-16" @default.
• W4387476664 title "T21. A GENETIC EXPLORATION OF DEFINITIONS OF INTERNALISING DISORDERS IN UK BIOBANK" @default.
• W4387476664 doi "https://doi.org/10.1016/j.euroneuro.2023.08.308" @default.
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