| Summary: | Abstract Background The relationship between schizophrenia (SCZ) and lung cancer (LC) remains inadequately understood, necessitating further exploration through a genetic perspective. Methods Utilizing extensive genome-wide association study databases, a comprehensive multi-level genetic analytical framework was implemented to examine the genetic association patterns between SCZ and distinct LC subtypes. Initially, genome-wide genetic correlations were assessed through linkage disequilibrium score regression and high-definition likelihood approaches. Subsequently, local variance association analysis (LAVA) was employed to identify key genomic regions exhibiting significant genetic associations. Mendelian randomization (MR) was employed to assess causal effects. Finally, the degree of genetic overlap and shared genetic loci between these diseases were quantitatively evaluated by integrating the conditional/conjunctional false discovery rate methodology. Results Genetic correlation analyses demonstrated significant positive associations between SCZ and LC, particularly its squamous cell subtype, at the genome-wide level, whereas no statistically significant associations were detected concerning lung adenocarcinoma or small cell lung cancer. Moreover, LAVA identified distinct genetic association patterns within multiple chromosomal segments. A systematic evaluation incorporating a joint false discovery rate confirmed the existence of genetic overlap phenomena between these diseases and successfully pinpointed multiple shared pathogenic risk loci. Conclusion This study furnishes novel theoretical evidence regarding the comorbidity mechanisms linking various LC subtypes with SCZ from a genetic perspective, thereby enhancing the comprehension of their intrinsic interconnections.
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