Common genetic basis and causality between central nervous system disease and cancer

The epidemiological associations between central nervous system diseases and cancers have been widely studied, but the shared genetic basis and etiology between these joint phenotypes remain unclear. To explore this issue, we utilized genome-wide association study summary data to investigate the shared genetic architecture and causality between 10 central nervous system diseases and 14 cancers. We employed multiple statistical genetic approaches, including global and local genetic correlation, Mendelian randomization, shared loci and genes, and shared tissues and cell-types to systematically and robustly explore the common genetic basis and causal relationships between central nervous system diseases and cancers. Our results revealed genetic correlations between schizophrenia and both lung cancer and breast cancer, including estrogen receptor-positive breast cancer, as well as between neuroticism and both lung cancer and ovarian cancer, including serous ovarian cancer. We found causal relationships between schizophrenia and lung cancer (OR = 1.14, P = 0.009) and breast cancer (OR = 1.05, P = 3.00 × 10^-5). When the whole genome was partitioned, significant local correlations of schizophrenia with breast cancer and lung cancer were further discovered within 14 specific genomic regions. Using cross-trait meta-analysis, we identified 24 pleiotropic loci associated with the two joint phenotypes. Using summary-data-based Mendelian randomization, we further identified eight functional genes shared between schizophrenia and both breast cancer and lung cancer, neuroticism and ovarian cancer. Additionally, we observed consistent patterns of single-nucleotide polymorphism heritability enrichment for schizophrenia and lung cancer in T lymphocytes. Our study provides insights into the genetic underpinnings and causal relationships of comorbidities between central nervous system diseases and cancers.