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Browsing by Author "Naamanka, Joonas"

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  • Naamanka, Joonas (2023)
    Objective: Anxiety disorders are the most prevalent psychiatric disorders, but their genetic architecture remains largely unknown. The main objective of this study is to increase the number of known loci through novel phenotyping. The subsequent results are followed with validating analyses, polygenic risk score (PRS) and linkage-disequilibrium score regression (LDSC). Methods: The participants were part of the FinnGen data release 7, totaling 309,136 individuals. First, a network model of non-organic, non-congenital psychiatric disorders was constructed to determine their comorbidity structure by utilizing community detection. Second, diagnoses were scored according to their network loading to the resulting anxiety community. Third, weighted sum scores were computed for the whole sample so that each different diagnosis added to the score by their network loading and this was used as the phenotype for GWAS. Fourth, case-control GWASs of core anxiety disorders and a broader anxiety related disorders were conducted with 10,289 and 33,865 cases, respectively. 186,192 individuals without a history of psychiatric disorders served as controls. Fifth, LDSCs were performed to obtain SNP-heritability estimates. Finally, a PRS of the anxiety sum score was computed and used to predict anxiety disorders in an independent sample of 12,584 individuals from FinnGen data release 9. Results: The network model revealed a comorbidity structure that resembles the current classification according to ICD-10. A community including all core anxiety and obsessive-compulsive disorder (OCD) diagnoses, and nothing else, emerged. Anxiety sum score GWAS discovered two genome-wide significant loci in intergenic regions of the genome. The core anxiety one detected one such locus in the gene SORCS3 and the broad anxiety GWAS identified four, one intergenic and three within genes, SEMA6D, RAB27B and CCDC36/KLHDC8B/CCDC71. Heritability estimates for anxiety sum score, core and broad anxiety were 1.98%, 13.1% and 9.5%, respectively. The PRS predicted anxiety disorders in the independent sample (OR = 1.42, p < .001). Conclusions: The network model suggests anxiety disorders tend to co-occur with each other, which includes OCDs. The anxiety sum score phenotype did not prove superior to traditional case-control approaches but did provide complementary findings that would have been otherwise missed. The anxiety sum score PRS performed comparably to other PRSs from other large GWASs, lending support to its validity.