Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in...

Area of Science:

• Genetics
• Sleep Medicine
• Genomics

Background:

• Obstructive sleep apnea (OSA) is a prevalent heritable sleep disorder with significant sexual dimorphism in prevalence and progression.
• Existing genetic studies for OSA have limitations, including focus on single ethnic groups and unexplained heritability.
• The apnea-hypopnea index (AHI) quantifies OSA severity, with potential differences in genetic associations between rapid eye movement (REM) and non-REM (NREM) sleep stages.

Purpose of the Study:

• To identify novel genetic association signals for OSA by analyzing NREM/REM-specific AHI.
• To conduct sex-specific analyses in multiethnic populations to account for the sexual dimorphism in OSA.
• To explore gene-by-sex interactions influencing AHI.

Main Methods:

• Genome-wide association tests were performed on up to 19,733 participants across African, Asian, European, and Hispanic/Latino American ancestries from 7 studies.
• Sex-specific analyses were conducted for NREM and REM AHI.
• Replication analysis was performed in an independent physiological research study.

Main Results:

• A significant quantitative trait locus (rs12936587) on chromosome 17 was identified for NREM AHI specifically in men (P = 1.7 × 10⁻⁸), and this finding was replicated.
• This locus is near the RAI1 gene and includes PEMT1, SREBF1, and RASD1, previously linked to cardiovascular disease, lipid metabolism, and specific genetic syndromes with sleep abnormalities.
• Suggestive gene-by-sex interactions were found, indicating that genetic variants for AHI may differ between sexes.

Conclusions:

• A novel genetic locus associated with NREM AHI in men was discovered, contributing to understanding the unexplained heritability of OSA.
• The findings support the hypothesis that sex-specific genetic factors influence OSA severity, aligning with observed clinical sexual dimorphism.
• Further research into this locus and gene-by-sex interactions is warranted to elucidate the genetic architecture of OSA.