Pavithra Nagrajan

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A better understanding of how genetics play into obstructive sleep apnea (OSA) could enable better care for excessive daytime sleepiness.¹

A team, led by Pavithra Nagrajan, Brigham and Women’s Hospital, investigated gene by sleepiness interaction analysis by OSA.

OSA

There are a range of symptoms involved with OSA including excessive daytime sleepiness, which is postulated to represent a more severe subtype. There are significant heritability and past GWASs, but genetic mechanisms are still unclear.

Because excessive daytime sleepiness reflects chronic sleep insufficiency and a pro-inflammatory state, it could interact with genetic variants to modify the risk of OSA.

The data was presented during the SLEEP 2023 Annual Meeting in Indianapolis.

The Study

In the study, the investigators used whole-genome sequencing data for 11,619 individuals of a diverse race and ethnic background. The patients were identified from the NHLBI Trans-Omics for Precision Medicine program.

The investigators sought outcomes of the Apnea-Hypopnea Index (AHI) and the exposure Epworth Sleepiness Scale (>10: EDS, <=10: non-EDS).

The investigators used GENESIS R package to perform 2-stage rank normalization, adjusting for age, sex, body mass index (BMI), ancestral PCs, cohort, and genetic relatedness, and rescaling residuals to a unit variance, separately in each study or ancestry group.

They also used GEM software to perform gene-EDS interaction analyses, including 1 df tests of marginal SNP effect and interaction effect of SNPxEDS on AHI, respectively, and 2 df test of joint significance of both.

Finally, they used robust standard errors with a significance threshold of P <5x10-8.

The results show 1 novel locus (rs35370454) was identified by the 1 df test of marginal SNP effect, which mapped to IFRD1, whose overexpression has been linked to sleep restriction and hypomethylation with narcolepsy.

They also found 2 novel loci (rs13118183, rs281851) that mapped to genes MARCHF1 and CCDC3 in the 1 df test of interaction effect.

However, the 2 df joint test did not show any additional novel loci.

Finally, CCDC3 has shown to repress inflammatory activity of TNF-alpha, a cytokine postulated involved in sleep regulation and MARCHF1 has shown to inhibit cellular insulin sensitivity and promotes NF-KB, with degree of activation positively correlating with OSA severity.

“By modeling the modification effect of EDS on OSA we identified 3 novel loci,” the authors wrote. “This approach may be useful in understanding the genetic factors that vary across OSA subtypes. For next steps, we seek to conduct replication analysis using independent imputed samples.”

References:

Pavithra Nagarajan and others, 0034 Genetic Variants for Obstructive Sleep Apnea Identified after Modeling Interactions with Daytime Sleepiness, Sleep, Volume 46, Issue Supplement_1, May 2023, Pages A15–A16, https://doi.org/10.1093/sleep/zsad077.0034