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, Cho Michael H, Aschard Hugues
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.
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
EBioMedicine. 2025 Mar;113:105609. doi: 10.1016/j.ebiom.2025.105609. Epub 2025 Feb 25.
Chronic Obstructive Pulmonary Disease (COPD) has a broad spectrum of clinical characteristics. The aetiology of these differences is not well understood. The objective of this study is to assess whether respiratory genetic variants cluster by phenotype and associate with COPD heterogeneity.
We clustered genome-wide association studies of COPD, lung function, and asthma and phenotypes from the UK Biobank using non-negative matrix factorization. We constructed cluster-specific genetic risk scores and tested these scores for association with phenotypes in non-Hispanic white subjects in the COPDGene study.
We identified three clusters from 482 variants and 44 traits from genetic associations in 379,337 UK Biobank participants. Variants from asthma, COPD, and lung function were found in all three clusters. Clusters displayed varying effects on white blood cell counts, height, and body mass index (BMI)-related phenotypes in the UK Biobank. In the COPDGene cohort, cluster-specific genetic risk scores were associated with differences in steroid use, BMI, lymphocyte counts, and chronic bronchitis, as well as variations in gene and protein expression.
Our results suggest that multi-phenotype analysis of obstructive lung disease-related risk variants may identify genetically driven phenotypic patterns in COPD.
MHC was supported by R01HL149861, R01HL135142, R01HL137927, R01HL147148, and R01HL089856. HA and HJ were supported by ANR-20-CE36-0009-02 and ANR-16-CONV-0005. The COPDGene study (NCT00608764) is supported by grants from the NHLBI (U01HL089897 and U01HL089856), by NIH contract 75N92023D00011, and by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion.
慢性阻塞性肺疾病（COPD）具有广泛的临床特征。这些差异的病因尚未完全明确。本研究的目的是评估呼吸基因变异是否按表型聚类，并与COPD的异质性相关。
我们使用非负矩阵分解对英国生物银行中COPD、肺功能、哮喘及相关表型的全基因组关联研究进行聚类。我们构建了特定聚类的遗传风险评分，并在COPDGene研究中的非西班牙裔白人受试者中测试这些评分与表型的关联。
我们从379,337名英国生物银行参与者的482个变异和44个遗传关联性状中识别出三个聚类。在所有三个聚类中均发现了来自哮喘、COPD和肺功能的变异。这些聚类在英国生物银行中对白细胞计数、身高和体重指数（BMI）相关表型表现出不同的影响。在COPDGene队列中，特定聚类的遗传风险评分与类固醇使用、BMI、淋巴细胞计数和慢性支气管炎的差异以及基因和蛋白质表达的变化相关。
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有助于识别COPD中由基因驱动的表型模式。
MHC由R01HL149861、R01HL135142、R01HL137927、R01HL147148和R01HL089856资助。HA和HJ由ANR-20-CE36-0009-02和ANR-16-CONV-0005资助。COPDGene研究（NCT00608764）由美国国立心肺血液研究所（U01HL089897和U01HL089856）、美国国立卫生研究院合同75N92023D00011以及COPD基金会提供资助，该基金会通过向一个行业咨询委员会提供资金，该委员会成员包括阿斯利康、拜耳制药、勃林格殷格翰、基因泰克、葛兰素史克、诺华、辉瑞和太阳药业。
