睡眠呼吸暂停的全基因组嗜睡相互作用分析。

IF 4.9 2区医学 Q1 Medicine

Sleep Pub Date : 2025-07-28 DOI:10.1093/sleep/zsaf212

Pavithra Nagarajan, Nuzulul Kurniansyah, Jiwon Lee, Sina A Gharib, Yushan Xu, Yiyan Zhang, Brian Spitzer, Tariq Faquih, Hufeng Zhou, Eric Boerwinkle, Han Chen, Daniel J Gottlieb, Xiuqing Guo, Nancy L Heard-Costa, Bertha A Hidalgo, Daniel Levy, Peter Y Liu, Hao Mei, Rebecca Montalvan, Sutapa Mukherjee, Kari E North, George T O'Conner, Lyle J Palmer, Sanjay R Patel, Bruce M Psaty, Shaun M Purcell, Laura M Raffield, Stephen S Rich, Jerome I Rotter, Richa Saxena, Albert V Smith, Katie L Stone, Xiaofeng Zhu, Brian E Cade, Tamar Sofer, Susan Redline, Heming Wang

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引用次数: 0

摘要

研究目的：睡眠呼吸暂停患者的一个亚群报告了受环境和社会行为因素影响的白天过度嗜睡（EDS），这一群体可能具有较高的心血管风险。然而，目前尚不清楚是否有和没有EDS的睡眠呼吸暂停有不同的遗传基础。在这项研究中，我们对睡眠呼吸暂停严重程度的诊断指标——呼吸暂停低通气指数（AHI）进行了基因-EDS相互作用分析，以了解EDS对其潜在遗传风险的影响。方法：利用多民族Trans-Omics for Precision Medicine （TOPMed）数据（N=11619）分别对常见变异和基于基因的罕见变异进行发现交互分析，并对其他TOPMed输入数据（N=8904）进行复制和meta分析。采用1自由度（1df） GxE检验和2df关节GxE检验。另外进行了性别分层分析。结果：发现分析发现了两个常见的内含子变异- rs13118183 （CCDC3）和rs281851 (MARCHF1) -以及三个罕见的变异基因集，定位于SCUBE2， TMEM26和CPS4FL -与EDS相互作用。meta分析显示EDS与11个罕见变异基因集相互作用，这些基因集分别为UBLCP1、MED31、RAP1GAP、CPNE5、MYMX、YY1、ZNF773、YBEY、IQCB1、PI4K2B和CORO1A。结论：基因位点揭示了心血管风险、胰岛素抵抗、硫胺素缺乏和白藜芦醇机制的联系。发现的遗传信号可能为睡眠呼吸暂停患者过度困倦亚型提供相关的生物学途径。

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Genome-wide Gene by Sleepiness Interaction Analysis for Sleep Apnea.

Study objectives: Excessive daytime sleepiness (EDS), influenced by environmental and social-behavioral factors, is reported by a subset of patients with sleep apnea - a group that may be at elevated cardiovascular risk. However, it is unclear whether sleep apnea with and without EDS have distinct genetic underpinnings. In this study, we perform gene-by-EDS interaction analyses for apnea hypopnea index (AHI), a diagnostic marker of sleep apnea severity, to understand EDS's influence on its underlying genetic risk.

Methods: Discovery interaction analyses for common variants and gene-based rare variants were conducted respectively using multi-ethnic Trans-Omics for Precision Medicine (TOPMed) (N=11619) data, followed by replication and subsequent meta-analysis in additional TOPMed-imputed data (N=8904). The 1 degree-of-freedom (1df) GxE test and the 2df joint G, GxE tests were utilized. Sex-stratified analyses were additionally performed.

Results: Discovery analysis revealed two common intronic variants- rs13118183 (CCDC3) and rs281851 (MARCHF1) - and three rare variant gene sets mapped to SCUBE2, TMEM26, and CPS4FL - to exhibit interaction with EDS. Meta-analysis revealed EDS interaction with 11 rare variant gene sets mapped to UBLCP1, MED31, RAP1GAP, CPNE5, MYMX, YY1, ZNF773, YBEY, IQCB1, PI4K2B, and CORO1A.

Conclusion: Genetic loci reveal connections to cardiovascular risk, insulin resistance, thiamine deficiency, and resveratrol mechanism. Discovered genetic signals may offer insight into pertinent biological pathways for sleep apnea patients with an excessively sleepy subtype.

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来源期刊

Sleep Medicine-Neurology (clinical)

CiteScore

8.70

自引率

10.70%

发文量

期刊介绍： SLEEP® publishes findings from studies conducted at any level of analysis, including: Genes Molecules Cells Physiology Neural systems and circuits Behavior and cognition Self-report SLEEP® publishes articles that use a wide variety of scientific approaches and address a broad range of topics. These may include, but are not limited to: Basic and neuroscience studies of sleep and circadian mechanisms In vitro and animal models of sleep, circadian rhythms, and human disorders Pre-clinical human investigations, including the measurement and manipulation of sleep and circadian rhythms Studies in clinical or population samples. These may address factors influencing sleep and circadian rhythms (e.g., development and aging, and social and environmental influences) and relationships between sleep, circadian rhythms, health, and disease Clinical trials, epidemiology studies, implementation, and dissemination research.