Genetic Analysis of Obstructive Sleep Apnea and Its Relationship with Severe COVID-19

Rationale: While patients with obstructive sleep apnea (OSA) have a higher risk for COVID-19 hospitalization, the causal relationship has remained unexplored. Objectives: To understand the causal relationship between OSA and COVID-19 leveraging data from vaccination and electronic health records, genetic risk factors from genome-wide association studies (GWAS) and Mendelian randomization. Methods: We elucidated genetic risk factors for OSA using FinnGen (N total = 377,277 individuals) performing genome-wide association. We used the associated variants as instruments for univariate and multivariate Mendelian randomization (MR) analyses and computed absolute risk reduction (ARR) against COVID-19 hospitalization with or without vaccination. Measurements and Main Results: We identified 9 novel loci for OSA and replicated our findings in the Million Veterans Program. Furthermore, MR analysis showed that OSA was a causal risk factor for severe COVID-19 (P=9.41x10-4). Probabilistic modelling showed that the strongest genetic risk factor for OSA at the FTO locus reflected a signal of higher BMI, whereas BMI independent association was seen with the earlier reported SLC9A4 locus and a MECOM locus which is a transcriptional regulator with 210-fold enrichment in the Finnish population. Similarly, Multivariate MR (MVMR) analysis showed that the causality for severe COVID-19 was driven by body mass index (BMI), (P MVMR = 5.97x10-6, beta=0.47). Finally, vaccination reduced the risk for COVID-19 hospitalization more in the OSA patients than in the non-OSA controls: ARR = 13.3% vs. ARR = 6.3% in the OSA vs. non-OSA population. Conclusions: Our analysis identified novel genetic risk factors for OSA and showed that OSA is a causal risk factor for severe COVID-19. The effect is predominantly explained by higher BMI and suggests BMI-dependent effects at the level of individual variants and at the level of comorbid causality.