Dept of Oral and Maxillofacial Diseases, Helsinki University Hospital, Helsinki, Finland.
Orthodontics, Dept of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Eur Respir J. 2021 May 6;57(5). doi: 10.1183/13993003.03091-2020. Print 2021 May.
There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed 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 the FinnGen study (217 955 individuals) with 16 761 OSA patients identified using nationwide health registries.We estimated 0.08 (95% CI 0.06-0.11) heritability and identified five loci associated with OSA (p<5.0×10): rs4837016 near (GTPase activating protein and VPS9 domains 1), rs10928560 near (C-X-C motif chemokine receptor type 4), rs185932673 near (calcium/calmodulin-dependent protein kinase ID) and rs9937053 near (fat mass and obesity-associated protein; 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/NEDD1 γ-tubulin ring complex targeting factor). We found high genetic correlations between OSA and BMI (r=0.72 (95% CI 0.62-0.83)), and with comorbidities including hypertension, type 2 diabetes, coronary heart disease, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic disease (r>0.30). The polygenic risk score for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile, and Mendelian randomisation supported a causal relationship between BMI and OSA.Our findings support the causal link between obesity and OSA, and the joint genetic basis between OSA and comorbidities.
目前，人们对阻塞性睡眠呼吸暂停（OSA）的遗传病因学了解有限。我们旨在确定与 OSA 风险相关的遗传基因座，并检验 OSA 及其合并症是否具有共同的遗传基础。
我们利用 FinnGen 研究（217955 人）进行了首次大规模的 OSA 全基因组关联研究，该研究使用全国健康登记册确定了 16761 例 OSA 患者。
我们估计 OSA 的遗传度为 0.08（95%CI 0.06-0.11），并确定了与 OSA 相关的五个基因座（p<5.0×10）：rs4837016 位于附近（GTP 酶激活蛋白和 VPS9 结构域 1），rs10928560 位于附近（C-X-C 基序趋化因子受体 4），rs185932673 位于附近（钙/钙调蛋白依赖性蛋白激酶 ID）和 rs9937053 位于附近（脂肪量和肥胖相关蛋白；该变体先前与体重指数（BMI）相关）。在 BMI 调整分析中，观察到 rs10507084 位于附近的关联/（横纹肌肉瘤 2 相关转录物/NEDD1 γ-微管蛋白环复合物靶向因子）。
我们发现 OSA 与 BMI 之间存在高度的遗传相关性（r=0.72（95%CI 0.62-0.83）），并且与高血压、2 型糖尿病、冠心病、中风、抑郁症、甲状腺功能减退、哮喘和炎症性风湿性疾病等合并症存在高度遗传相关性（r>0.30）。BMI 的多基因风险评分显示，最高五分位数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 BMI 和 OSA 之间存在因果关系。
我们的研究结果支持肥胖与 OSA 之间的因果关系，以及 OSA 与合并症之间的共同遗传基础。
