Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health
Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health
复制标题
DOI：
10.1183/13993003.03091-2020
复制
发表时间：
2021-05-01
影响因子：
24.3
通讯作者：
Ripatti, Samuli
中科院分区：
文献类型：
--
作者：
Strausz, Satu;Ruotsalainen, Sanni;Ripatti, Samuli
目前对阻塞性睡眠呼吸暂停（OSA）的遗传病因学了解有限。我们的目的是确定与OSA风险相关的遗传位点，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（217955人）进行了第一次大规模的OSA全基因组关联研究，其中16761例OSA患者使用全国健康登记处确定。我们估计0.08（95%CI 0.06-0.11）的遗传力，并确定了与OSA相关的5个位点（p < 5.0x10（-8））：GAPVD 1附近的rs 4837016（GT3活化蛋白和VPS 9结构域1），靠近CXCR 4的rs 10928560（C-X-C基序趋化因子受体4型），rs 185932673靠近CAMK 1D（钙/钙调素非依赖性蛋白激酶ID）和FTO附近的rs 9937053（脂肪量和肥胖相关蛋白;以前与体重指数（BMI）相关的变体）。在BMI调整分析中，观察到rs 10507084与RMST/NEDD 1（横纹肌肉瘤2相关转录物/NEDD 1 γ微管蛋白环复合物靶向因子）的相关性。我们发现OSA与BMI之间存在高度的遗传相关性（r（g）=0.72（95%CI 0.62-0.83）），并与包括高血压、2型糖尿病、冠心病、中风、抑郁症、甲状腺功能减退症、哮喘和炎性风湿性疾病在内的合并症存在高度的遗传相关性（rg > 0.30）。BMI的多基因风险评分显示，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BMI和OSA之间的因果关系。我们的研究结果支持肥胖和OSA之间的因果关系，以及OSA和合并症之间的共同遗传基础。
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 (217955 individuals) with 16761 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 < 5.0x10(-8)): rs4837016 near GAPVD1 (GTPase activating protein and VPS9 domains 1), rs10928560 near CXCR4 (C-X-C motif chemokine receptor type 4), rs185932673 near CAMK1D (calcium/calmodulindependent protein kinase ID) and rs9937053 near FTO (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 RMST/NEDD1 (rhabdomyosarcoma 2 associated transcript/NEDD1 gamma tubulin ring complex targeting factor). We found high genetic correlations between OSA and BMI (r(g)=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 (rg > 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.