Ziyatdinov Andrey, Hobbs Brian D, Kanaan-Izquierdo Samir, Moll Matthew, Sakornsakolpat Phuwanat, Shrine Nick, Chen Jing, Song Kijoung, Bowler Russell P, Castaldi Peter J, Tobin Martin D, Kraft Peter, Silverman Edwin K, Julienne Hanna, Aschard Hugues, Cho Michael H
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
medRxiv. 2023 Feb 21:2023.02.20.23286186. doi: 10.1101/2023.02.20.23286186.
Chronic Obstructive Pulmonary Disease (COPD) has a simple physiological diagnostic criterion but a wide range of clinical characteristics. The mechanisms underlying this variability in COPD phenotypes are unclear. To investigate the potential contribution of genetic variants to phenotypic heterogeneity, we examined the association of genome-wide associated lung function, COPD, and asthma variants with other phenotypes using phenome-wide association results derived in the UK Biobank. Our clustering analysis of the variants-phenotypes association matrix identified three clusters of genetic variants with different effects on white blood cell counts, height, and body mass index (BMI). To assess the potential clinical and molecular effects of these groups of variants, we investigated the association between cluster-specific genetic risk scores and phenotypes in the COPDGene cohort. We observed differences in steroid use, BMI, lymphocyte counts, chronic bronchitis, and differential gene and protein expression across the three genetic risk scores. Our results suggest that multi-phenotype analysis of obstructive lung disease-related risk variants may identify genetically driven phenotypic patterns in COPD.
慢性阻塞性肺疾病（COPD）有一个简单的生理诊断标准，但临床特征范围广泛。COPD表型这种变异性背后的机制尚不清楚。为了研究基因变异对表型异质性的潜在影响，我们利用英国生物银行得出的全表型关联结果，研究了全基因组关联的肺功能、COPD和哮喘变异与其他表型之间的关联。我们对变异-表型关联矩阵的聚类分析确定了三组对白细胞计数、身高和体重指数（BMI）有不同影响的基因变异。为了评估这些变异组的潜在临床和分子影响，我们在COPDGene队列中研究了特定聚类的遗传风险评分与表型之间的关联。我们观察到在三种遗传风险评分中，类固醇使用、BMI、淋巴细胞计数、慢性支气管炎以及基因和蛋白质表达差异方面存在差异。我们的结果表明，对阻塞性肺病相关风险变异进行多表型分析可能会识别出COPD中由基因驱动的表型模式。
