A cross-trait study of lung cancer and its related respiratory diseases based on large-scale exome sequencing population.

BACKGROUND: Genome-wide association studies (GWASs) explain the genetic susceptibility between diseases and common variants. Nevertheless, with the appearance of large-scale sequencing profiles, we could explore the rare coding variants in disease pathogenesis.

METHODS: We estimated the genetic correlation of nine respiratory diseases and lung cancer in the UK Biobank (UKB) by linkage disequilibrium score regression (LDSC). Then, we performed exome-wide association studies at single-variant level and gene-level for lung cancer and lung cancer-related respiratory diseases using the whole-exome sequencing (WES) data of 427,934 European participants. Cross-trait meta-analysis was conducted by association analysis based on subsets (ASSET) to identify the pleiotropic variants, while in-silico functional analysis was performed to explore their function. Causal mediation analysis was used to explore whether these pleiotropic variants lead to lung cancer is mediated by affecting the chronic respiratory diseases.

RESULTS: Five respiratory diseases [emphysema, pneumonia, asthma, chronic obstructive pulmonary disease (COPD), and fibrosis] were genetically correlated with lung cancer. We identified 102 significant independent variants at single-variant levels for lung cancer and five lung cancer-related diseases. 15:78590583:G>A (missense variant in CHRNA5 ) was shared in lung cancer, emphysema, and COPD. Meanwhile, 14 significant genes and 87 suggestive genes were identified in gene-based association tests, including HSD3B7 (lung cancer), SRSF2 (pneumonia), TNXB (asthma), TERT (fibrosis), MOSPD3 (emphysema). Based on the cross-trait meta-analysis, we detected 145 independent pleiotropic variants. We further identified abundant pathways with significant enrichment effects, demonstrating that these pleiotropic genes were functional. Meanwhile, the proportion of mediation effects of these variants ranged from 6 to 23 (emphysema: 23%; COPD: 20%; pneumonia: 20%; fibrosis: 7%; asthma: 6%) through these five respiratory diseases to the incidence of lung cancer.

CONCLUSIONS: The identified shared genetic variants, genes, biological pathways, and potential intermediate causal pathways provide a basis for further exploration of the relationship between lung cancer and respiratory diseases.