Understanding the genetics behind obstructive sleep apnea (OSA) could lead to better care for excessive daytime sleepiness, according to a study led by Pavithra Nagrajan of Brigham and Women’s Hospital. The researchers used whole-genome sequencing data for 11,619 individuals of diverse race and ethnic backgrounds, identified from the NHLBI Trans-Omics for Precision Medicine programme. The team sought outcomes of the Apnea-Hypopnea Index (AHI) and the exposure Epworth Sleepiness Scale (≤10: non-EDS; >10: EDS). The results showed that one novel locus (rs35370454) was identified that mapped to IFRD1, whose overexpression has been linked to sleep restriction and hypomethylation with narcolepsy. The team also found two novel loci rs13118183, rs281851 that mapped to genes MARCHF1 and CCDC3 in the 1 df test of interaction effect. The next step will be to conduct replication analysis using independent imputed samples.
OSA is a disorder that involves hypopnea and apnea during sleep and results in decreased oxygen saturation. OSA is connected to cognitive impairment and cardiovascular disease, which can lead to reduced quality of life, economic burden, and increased mortality. Excessive daytime sleepiness is one of the primary symptoms of OSA, specifically hypothesized to represent a more severe subtype.
Although there is considerable heritability of this condition and past genome-wide association studies, the genetic mechanisms causing OSA are still not understood. Because chronic sleep insufficiency and a pro-inflammatory state reflect excessive daytime sleepiness, it could interact with genetic variants to modify the risk of OSA.
The research team used the GENESIS R package to perform two-stage rank normalization, adjusted for age, sex, body mass index (BMI), ancestral PCs, cohort, and genetic relatedness, and rescaled residuals to a unit variance, separately in each study or ancestry group. They also used GEM software to perform gene-EDS interaction analyses which included 1df tests of marginal SNP effect and interaction effect of SNPxEDS on AHI, respectively, and 2df test of joint significance of both. Finally, they used robust standard errors with a significance threshold of p < 5×10−8. Overall, the team found one novel locus, two novel loci, and pathways to genes related to sleep regulation and hypomethylation with narcolepsy, and cellular insulin sensitivity related to OSA severity. “By modelling the modification effect of [excessive daytime sleepiness] on [obstructive sleep apnea], we identified three novel loci. This approach may be useful in understanding the genetic factors that vary across OSA subtypes,” the authors concluded. In nutshell, the research team sought to explore the interplay between genetics and obstructive sleep apnea. The research could result in better outcomes for patients concerned with excessive daytime sleepiness. The team used whole-genome sequencing data for over 11,000 individuals of diverse backgrounds to identify a novel locus linked with sleep restriction and hypomethylation with narcolepsy. Two novel loci were found that mapped to genes, MARCHF1 and CCDC3, that may inhibit cellular insulin sensitivity and promote NF-KB, respectively. Moving forward, the team will conduct replication analysis using independent imputed samples.
