Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations-猫眼课题宝

DOI：

10.1101/355644

发表时间：

2018-06

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

P. Sakornsakolpat;D. Prokopenko;M. Lamontagne;N. Reeve;A. Guyatt;V. Jackson;N. Shrine;D. Qiao;Traci M. Bartz;D. Kim;Mi Kyeong Lee;J. Latourelle;Xingnan Li;J. Morrow;M. Obeidat;A. Wyss;Xiaobo Zhou;P. Bakke;R. G. Barr;Terri H. Beaty;S. Belinsky;G. Brusselle;J. Crapo;K. Jong;D. Demeo;T. Fingerlin;Sina A. Gharib;A. Gulsvik;I. Hall;J. Hokanson;Woojun Kim;D. Lomas;S. London;D. Meyers;George T. O’Connor;S. Rennard;D. Schwartz;P. Śliwiński;D. Sparrow;D. Strachan;R. Tal-Singer;Y. Tesfaigzi;J. Vestbo;J. Vonk;J. Yim;Y. Bossé;A. Manichaikul;L. Lahousse;E. Silverman;H. Boezen;L. Wain;M. Tobin;B. Hobbs;M. Cho

慢性阻塞性肺疾病（COPD）是全球呼吸系统死亡的主要原因。遗传风险位点为疾病发病机制提供了新的见解。为了扩大 COPD 遗传风险位点发现范围并确定细胞类型和表型关联，我们对英国生物库的 35,735 例病例和 222,076 例对照进行了全基因组关联研究，以及国际 COPD 遗传学联盟的其他研究。我们鉴定出 82 个 P 值 < 5×10−8 的位点； 47 种先前被描述为与慢性阻塞性肺病或基于人群的肺功能相关。在剩下的 35 个新基因座中，有 13 个与 SpiroMeta 联盟 79,055 名个体的肺功能相关。利用基因表达和调控数据，我们确定了肺组织、平滑肌和 II 型肺泡细胞中基因座的富集。我们发现 COPD 和哮喘之间有 9 个共享基因组区域，COPD 和肺纤维化之间有 5 个共享基因组区域。 COPD 遗传风险位点聚集成定量成像特征和合并症关联组。我们的分析为 COPD 的遗传易感性和异质性提供了进一步的支持。

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. To broaden COPD genetic risk loci discovery and identify cell type and phenotype associations we performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P value < 5×10−8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and alveolar type II cells. We found 9 shared genomic regions between COPD and asthma and 5 between COPD and pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations

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