There is currently only limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). The aim of our study is to identify genetic loci associated with OSA risk and to test if OSA and its comorbidities share a common genetic background. We conducted the first large-scale genome-wide association study of OSA using FinnGen Study (217,955 individuals) with 16,761 OSA patients identified using nationwide health registries. We estimated 8.3% [0.06-0.11] heritability and identified five loci associated with OSA (P < 5.0x10^-8): rs4837016 near GTPase activating protein and VPS9 domains 1 (GAPVD1), rs10928560 near C-X-C motif chemokine receptor 4 (CXCR4), rs185932673 near Calcium/calmodulin-dependent protein kinase ID (CAMK1D) and rs9937053 near Fat mass and obesity-associated protein (FTO) - a variant previously associated with body mass index (BMI). In a BMI-adjusted analysis, an association was observed for rs10507084 near Rhabdomyosarcoma 2 associated transcript (RMST)/NEDD1 gamma-tubulin ring complex targeting factor (NEDD1). We found genetic correlations between OSA and BMI (rg=0.72 [0.62-0.83]) and with comorbidities including hypertension, type 2 diabetes (T2D), coronary heart disease (CHD), stroke, depression, hypothyroidism, asthma and inflammatory rheumatic diseases (IRD) (rg > 0.30). Polygenic risk score (PRS) for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile and Mendelian randomization supported a causal relationship between BMI and OSA. Our findings support the causal link between obesity and OSA and joint genetic basis between OSA and comorbidities.

中文翻译：

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阻塞性睡眠呼吸暂停的遗传分析发现与心脏代谢健康密切相关

目前对阻塞性睡眠呼吸暂停（OSA）的遗传病因只有有限的了解。我们研究的目的是确定与OSA风险相关的遗传基因座，并测试OSA及其合并症是否具有共同的遗传背景。我们使用FinnGen研究（217,955个人）进行了首次大规模的OSA基因组范围的全基因组关联研究，该研究使用全国卫生登记所确定的16,761名OSA患者。我们估计了8.3％[0.06-0.11]的遗传力，并确定了与OSA相关的五个基因座（P <5.0x10 ^ -8）：GTPase激活蛋白和VPS9结构域1（GAPVD1）附近的rs4837016，CXC基序趋化因子受体4（CXCR4）附近的rs10928560。 ，钙/钙调蛋白依赖性蛋白激酶ID（CAMK1D）附近的rs185932673和脂肪和肥胖相关蛋白（FTO）附近的rs9937053-先前与体重指数（BMI）相关的变体。在BMI调整后的分析中，观察到横纹肌肉瘤2相关转录本（RMST）/ NEDD1γ-微管蛋白环复合物靶向因子（NEDD1）附近的rs10507084有关联。我们发现OSA和BMI之间存在遗传相关性（rg = 0.72 [0.62-0.83]），并伴有合并症，包括高血压，2型糖尿病（T2D），冠心病（CHD），中风，抑郁症，甲状腺功能减退症，哮喘和炎性风湿病（ IRD）（rg> 0.30）。BMI的多基因风险评分（PRS）显示最高和最低五分位数之间的OSA风险增加了1.98倍，孟德尔随机化支持了BMI与OSA之间的因果关系。