Saferali Aabida, Kim Wonji, Chase Robert P, Vollmers Chris, Silverman Edwin K, Cho Michael H, Castaldi Peter J, Hersh Craig P
Channing Division of Network Medicine, Brigham and Women's Hospital, USA.
Department of Biomolecular Engineering, Cellular, Cellular, and Developmental Biology, University of California Santa Cruz, USA.
HGG Adv. 2025 Aug 11:100493. doi: 10.1016/j.xhgg.2025.100493.
Genome-wide association studies (GWAS) have identified multiple genetic loci associated with chronic obstructive pulmonary disease (COPD). Here, we identify SNPs that are associated with alternative splicing (sQTL) and gene expression (eQTLs) to identify functions for COPD associated genetic variants. RNA sequencing on whole blood from 3743 subjects in the COPDGene Study and from lung tissue of 1241 subjects from the Lung Tissue Research Consortium (LTRC) was analyzed. Associations between all SNPs within 1000 kb of a gene (cis-) and splice and gene expression quantifications were tested using tensorQTL. We assessed colocalization with COPD-associated SNPs from a published GWAS[1]. After adjustment for multiple statistical testing, we identified 28,110 splice-sites corresponding to 3,889 unique genes that were significantly associated with genotype in COPDGene whole blood, and 58,258 splice-sites corresponding to 10,307 unique genes associated with genotype in LTRC lung tissue. To determine what proportion of COPD-associated SNPs were associated with transcriptional splicing, we performed colocalization analysis between COPD GWAS and sQTL data, and found that 38 genomic windows, corresponding to 32 COPD GWAS loci had evidence of colocalization between QTLs and COPD. The top five colocalizations between COPD and lung sQTLs include NPNT, FBXO38, HHIP, NTN4 and BTC. Overall, a total of 38 COPD GWAS loci contain evidence of sQTLs, suggesting that analysis of sQTLs in whole blood and lung tissue can provide insights into disease mechanisms.
全基因组关联研究（GWAS）已经确定了多个与慢性阻塞性肺疾病（COPD）相关的基因位点。在此，我们鉴定与可变剪接（sQTL）和基因表达（eQTL）相关的单核苷酸多态性（SNP），以确定COPD相关基因变异的功能。对慢性阻塞性肺疾病基因研究（COPDGene）中3743名受试者的全血以及肺组织研究联盟（LTRC）中1241名受试者的肺组织进行了RNA测序分析。使用张量QTL测试基因1000 kb内所有SNP（顺式）与剪接和基因表达定量之间的关联。我们评估了与已发表的GWAS中COPD相关SNP的共定位情况[1]。在对多重统计检验进行校正后，我们在COPDGene全血中鉴定出28,110个与基因型显著相关的剪接位点，对应3,889个独特基因；在LTRC肺组织中鉴定出58,258个与基因型相关的剪接位点，对应10,307个独特基因。为了确定COPD相关SNP中与转录剪接相关的比例，我们对COPD GWAS和sQTL数据进行了共定位分析，发现38个基因组窗口（对应32个COPD GWAS位点）在QTL和COPD之间存在共定位证据。COPD与肺sQTL之间的前五个共定位包括NPNT、FBXO38、HHIP、NTN4和BTC。总体而言，共有38个COPD GWAS位点包含sQTL证据，这表明对全血和肺组织中的sQTL进行分析可以为疾病机制提供见解。
