Abstract
There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed to identify genetic loci associated with OSA risk, and to test if OSA and its comorbidities share a common genetic background.
We conducted the first large-scale genome-wide association study of OSA using the FinnGen study (217 955 individuals) with 16 761 OSA patients identified using nationwide health registries.
We estimated 0.08 (95% CI 0.06–0.11) heritability and identified five loci associated with OSA (p<5.0×10−8): rs4837016 near GAPVD1 (GTPase activating protein and VPS9 domains 1), rs10928560 near CXCR4 (C-X-C motif chemokine receptor type 4), rs185932673 near CAMK1D (calcium/calmodulin-dependent protein kinase ID) and rs9937053 near FTO (fat mass and obesity-associated protein; a variant previously associated with body mass index (BMI)). In a BMI-adjusted analysis, an association was observed for rs10507084 near RMST/NEDD1 (rhabdomyosarcoma 2 associated transcript/NEDD1 γ-tubulin ring complex targeting factor). We found high genetic correlations between OSA and BMI (rg=0.72 (95% CI 0.62–0.83)), and with comorbidities including hypertension, type 2 diabetes, coronary heart disease, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic disease (rg>0.30). The polygenic risk score for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile, and Mendelian randomisation supported a causal relationship between BMI and OSA.
Our findings support the causal link between obesity and OSA, and the joint genetic basis between OSA and comorbidities.
Abstract
Five OSA-associated loci were found, highlighting the causal link between obesity and OSA, and providing evidence for non-BMI-dependent effects. OSA comorbidities were correlated genetically for OSA, showing these diseases may have a shared genetic basis. https://bit.ly/36Rfq1Y
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.04644-2020
This article has supplementary material available from erj.ersjournals.com
Data availability: The FinnGen individual-level data may be accessed through applications to the Finnish biobanks’ FinnBB portal, Finngenious (www.finbb.fi). Summary data can be accessed through the FinnGen site www.finngen.fi/en/access_results. The full genotyping and imputation protocol for FinnGen is described at https://doi-org.libproxy.helsinki.fi/10.17504/protocols.io.nmndc5e
Author contributions: S. Ripatti and T. Palotie supervised the study. S. Ruotsalainen, S. Strausz, H.M. Ollila, M. Kurki and J. Karjalainen performed the statistical and bioinformatics analyses. A.S. Havulinna and T. Kiiskinen phenotyped the study samples. S. Strausz and E. Luonsi collected the data for the chart review. S. Strausz, H.M. Ollila and S. Ruotsalainen wrote the manuscript with feedback from all authors.
Conflict of interest: S. Strausz has nothing to disclose.
Conflict of interest: S. Ruotsalainen has nothing to disclose.
Conflict of interest: H.M. Ollila has nothing to disclose.
Conflict of interest: J. Karjalainen has nothing to disclose.
Conflict of interest: T. Kiiskinen has nothing to disclose.
Conflict of interest: M. Reeve has nothing to disclose.
Conflict of interest: M. Kurki has nothing to disclose.
Conflict of interest: N. Mars has nothing to disclose.
Conflict of interest: A.S. Havulinna has nothing to disclose.
Conflict of interest: E. Luonsi has nothing to disclose.
Conflict of interest: D. Mansour Aly has nothing to disclose.
Conflict of interest: E. Ahlqvist has nothing to disclose.
Conflict of interest: M. Teder-Laving has nothing to disclose.
Conflict of interest: P. Palta has nothing to disclose.
Conflict of interest: L. Groop has nothing to disclose.
Conflict of interest: R. Mägi has nothing to disclose.
Conflict of interest: A. Mäkitie has nothing to disclose.
Conflict of interest: V. Salomaa has received honoraria from Novo Nordisk and Sanofi for consultations and has ongoing research collaboration with Bayer AG (all unrelated to this study).
Conflict of interest: A. Bachour has nothing to disclose.
Conflict of interest: T. Tuomi has nothing to disclose.
Conflict of interest: A. Palotie has nothing to disclose.
Conflict of interest: T. Palotie has nothing to disclose.
Conflict of interest: S. Ripatti has nothing to disclose.
Support statement: This work was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (grants 312062 to S. Ripatti and 312074 to A. Palotie), Academy of Finland (grants 285380 to S. Ripatti, 128650 to A. Palotie and 309643 to H.M. Ollila), Finnish Foundation for Cardiovascular Research (S. Ripatti, V. Salomaa and A. Palotie), Sigrid Jusélius Foundation (S. Ripatti and A. Palotie), University of Helsinki HiLIFE (Fellow grants 2017–2020 to S. Ripatti) and Foundation and the Horizon 2020 Research and Innovation Programme (grant 667301 (COSYN) to A. Palotie); Oskar Öfflund Foundation and Yrjö Jahnsson Foundation (H.M. Ollila), and Finnish Dental Society Apollonia (S. Strausz). The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and 11 industry partners (AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Celgene Corp., Celgene International II Sàrl, Genentech Inc., Merck Sharp & Dohme Corp., Pfizer Inc., GSK, Sanofi, Maze Therapeutics Inc., Janssen Biotech Inc.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received August 10, 2020.
- Accepted November 4, 2020.
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