Abstract
Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Iron and heme metabolism, implicated in ventilatory control and OSA comorbidities, was associated with OSA phenotypes in recent admixture mapping and gene enrichment analyses. However, its causal contribution was unclear. In this study, we performed pathway-level transcriptional Mendelian randomization (MR) analysis to investigate the causal relationships between iron and heme related pathways and OSA. In primary analysis, we examined the expression level of four iron/heme Reactome pathways as exposures and four OSA traits as outcomes using cross-tissue cis-eQTLs from the Genotype-Tissue Expression portal and published genome-wide summary statistics of OSA. We identify a significant putative causal association between up-regulated heme biosynthesis pathway with higher sleep time percentage of hypoxemia (p = 6.14 × 10–3). This association is supported by consistency of point estimates in one-sample MR in the Multi-Ethnic Study of Atherosclerosis using high coverage DNA and RNA sequencing data generated by the Trans-Omics for Precision Medicine project. Secondary analysis for 37 additional iron/heme Gene Ontology pathways did not reveal any significant causal associations. This study suggests a causal association between increased heme biosynthesis and OSA severity.
Highlights
Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. 4School of Biomedical Informatics, Center for Precision Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. 5VA Boston Healthcare System, Boston, MA, USA. 6Department of Medicine, Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, University of Washington, Seattle, WA, USA. 7Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. 8Department of Biostatistics, Harvard T
We identified a significant putative causal association between increased heme biosynthesis pathway expression and higher sleep time% of S pO2 < 90% ( β = 0.012, p = 6.14 × 1 0–3)
Associations were suggested between increased heme biosynthesis pathway expression with higher apnea hypopnea index (AHI) ( β = 0.007, p = 0.189), lower average SpO2 ( β = − 0.008, p = 0.078) and minimum S pO2 ( β = − 0.008, p = 0.095) (Table 1 and Fig. 3)
Summary
Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. 4School of Biomedical Informatics, Center for Precision Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. 5VA Boston Healthcare System, Boston, MA, USA. 6Department of Medicine, Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, University of Washington, Seattle, WA, USA. 7Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. 8Department of Biostatistics, Harvard T. Gene set enrichment analyses in recent transcriptome-wide studies identified that the heme metabolic pathway was associated with OSA traits and was up-regulated in individuals with more severe disease or in response to withdrawal of continuous positive airway pressure (CPAP) t reatment[9,10]. It is not clear whether the iron or heme related genes and pathways are causally associated with OSA, or rather are biomarkers of disease activity or severity. We implement a novel pathway-based MR approach to investigate the causal relationship between expression levels of iron/heme related pathways
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