O'Neal Wanda K, Gallins Paul, Pace Rhonda G, Dang Hong, Wolf Whitney E, Jones Lisa C, Guo XueLiang, Zhou Yi-Hui, Madar Vered, Huang Jinyan, Liang Liming, Moffatt Miriam F, Cutting Garry R, Drumm Mitchell L, Rommens Johanna M, Strug Lisa J, Sun Wei, Stonebraker Jaclyn R, Wright Fred A, Knowles Michael R
Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: wanda_o'
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Am J Hum Genet. 2015 Feb 5;96(2):318-28. doi: 10.1016/j.ajhg.2014.12.022. Epub 2015 Jan 29.
Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent Pseudomonas aeruginosa (P. aeruginosa) lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity. Therefore, we utilized gene expression association from lymphoblastoid cells lines from 754 p.Phe508del CF-affected homozygous individuals to identify genes and pathways. LPAR6, a G protein coupled receptor, associated with lung disease severity (false discovery rate q value = 0.0006). Additional pathway analyses, utilizing a stringent permutation-based approach, identified unique signals for all three phenotypes. Pathways associated with lung disease severity were annotated in three broad categories: (1) endomembrane function, containing p.Phe508del processing genes, providing evidence of the importance of p.Phe508del processing to explain lung phenotype variation; (2) HLA class I genes, extending previous GWAS findings in the HLA region; and (3) endoplasmic reticulum stress response genes. Expression pathways associated with lung disease were concordant for some endosome and HLA pathways, with pathways identified using GWAS associations from 1,978 CF-affected individuals. Pathways associated with age of onset of persistent P. aeruginosa infection were enriched for HLA class II genes, and those associated with MI were related to oxidative phosphorylation. Formal testing demonstrated that genes showing differential expression associated with lung disease severity were enriched for heritable genetic variation and expression quantitative traits. Gene expression provided a powerful tool to identify unrecognized heritable variation, complementing ongoing GWASs in this rare disease.
囊性纤维化（CF）表型的变异，包括肺部疾病严重程度、持续性铜绿假单胞菌（P. aeruginosa）肺部感染的发病年龄以及胎粪性肠梗阻（MI）的存在，已部分由全基因组关联研究（GWAS）作出解释。预计仅靠GWAS不足以揭示与CF表型多样性相关的所有遗传性状。因此，我们利用来自754名p.Phe508del纯合CF患者的淋巴母细胞系的基因表达关联来鉴定基因和通路。LPAR6，一种G蛋白偶联受体，与肺部疾病严重程度相关（错误发现率q值 = 0.0006）。利用基于严格排列的方法进行的额外通路分析，为所有三种表型鉴定出独特信号。与肺部疾病严重程度相关的通路分为三大类：（1）内膜功能，包含p.Phe508del加工基因，为p.Phe508del加工对解释肺部表型变异的重要性提供了证据；（2）HLA I类基因，扩展了先前在HLA区域的GWAS研究结果；（3）内质网应激反应基因。与肺部疾病相关的表达通路在一些内体和HLA通路方面是一致的，这些通路是使用来自1978名CF患者的GWAS关联鉴定出来的。与持续性铜绿假单胞菌感染发病年龄相关的通路富含HLA II类基因，而与MI相关的通路与氧化磷酸化有关。正式测试表明，显示与肺部疾病严重程度相关的差异表达的基因富含可遗传的基因变异和表达数量性状。基因表达提供了一个强大的工具来识别未被认识的可遗传变异，对这种罕见疾病正在进行的GWAS起到补充作用。
