Genetic Analysis of Obstructive Sleep Apnea and Its Relationship with Severe COVID-19
Satu Strausz, Е.А. Агафонова, Varvara Tiullinen, Tuomo Kiiskinen, Martin Broberg, Sanni Ruotsalainen, Jukka Koskela, Adel Bachour, Tamar Sofer, Daniel J. Gottlieb, Aarno Palotie, Tuula Palotie, Samuli Ripatti, Hanna M. Ollila
Abstract
Abstract Rationale Although patients with obstructive sleep apnea (OSA) have a higher risk for coronavirus disease (COVID-19) hospitalization, the causal relationship has remained unexplored. Objectives To understand the causal relationship between OSA and COVID-19 by leveraging data from vaccination and electronic health records, genetic risk factors from genome-wide association studies, and Mendelian randomization. Methods We elucidated genetic risk factors for OSA using FinnGen (total N = 377,277), performing genome-wide association. We used the associated variants as instruments for univariate and multivariate Mendelian randomization (MR) analyses and computed absolute risk reduction against COVID-19 hospitalization with or without vaccination. Results We identified nine novel loci for OSA and replicated our findings in the Million Veteran Program. Furthermore, MR analysis showed that OSA was a causal risk factor for severe COVID-19 (P = 9.41 × 10−4). Probabilistic modeling showed that the strongest genetic risk factor for OSA at the FTO locus reflected a signal of higher body mass index (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 analysis showed that the causality for severe COVID-19 was driven by BMI (multivariate MR P = 5.97 × 10−6, β = 0.47). Finally, vaccination reduced the risk for COVID-19 hospitalization more in the patients with OSA than in the non-OSA controls, with respective absolute risk reductions of 13.3% versus 6.3%. 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.