The Shared Genetic Architectures Between Lung Cancer and Multiple Polygenic Phenotypes in Genome-Wide Association Studies

Background: Prior genome-wide association studies have identified numerous lung cancer risk loci and reveal substantial etiologic heterogeneity across histologic subtypes. Analyzing the shared genetic architecture underlying variation in complex traits can elucidate common genetic etiologies across phenotypes. Exploring pairwise genetic correlations between lung cancer and other polygenic traits can reveal the common genetic etiology of correlated phenotypes. Methods: Using cross-trait linkage disequilibrium score regression, we estimated the pairwise genetic correlation and heritability between lung cancer and multiple traits using publicly available summary statistics. Identified genetic relationships were also examined after excluding genomic regions known to be associated with smoking behaviors, a major risk factor for lung cancer. Results: We observed several traits showing moderate single nucleotide polymorphism–based heritability and significant genetic correlations with lung cancer. We observed highly significant correlations between the genetic architectures of lung cancer and emphysema/chronic bronchitis across all histologic subtypes, as well as among lung cancer occurring among smokers. Our analyses revealed highly significant positive correlations between lung cancer and paternal history of lung cancer. We also observed a strong negative correlation with parental longevity. We observed consistent directions in genetic patterns after excluding genomic regions associated with smoking behaviors. Conclusions: This study identifies numerous phenotypic traits that share genomic architecture with lung carcinogenesis and are not fully accounted for by known smoking-associated genomic loci. Impact: These findings provide new insights into the etiology of lung cancer by identifying traits that are genetically correlated with increased risk of lung cancer.

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