The shared genetic architectures between lung cancer and multiple polygenic phenotypes in genome-wide association studies.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
BACKGROUND: Prior genome-wide association studies have identified numerous lung cancer risk loci and reveal substantial etiologic heterogeneity across histological 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 SNP-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 histological 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.
View details for DOI 10.1158/1055-9965.EPI-20-1635
View details for PubMedID 33771847
Partitioned glioma heritability shows subtype-specific enrichment in immune cells.
BACKGROUND: Epidemiological studies of adult glioma have identified genetic syndromes and 25 heritable risk loci that modify individual risk for glioma, as well increased risk in association with exposure to ionizing radiation and decreased risk in association with allergies. In this analysis we assess whether there is shared genome-wide genetic architecture between glioma and atopic/autoimmune diseases.METHODS: Using summary statistics from a glioma genome-wide association studies (GWAS) meta-analysis, we identified significant enrichment for risk variants associated with gene expression changes in immune cell populations. We also estimated genetic correlations between glioma and autoimmune, atopic, and hematologic traits using LDscore regression, which leverages genome-wide single nucleotide polymorphism (SNP) associations and patterns of linkage disequilibrium.RESULTS: Nominally significant negative correlations were observed for glioblastoma and primary biliary cirrhosis (rg=-0.26, p=0.0228), and for non-glioblastoma gliomas and celiac disease (rg=-0.32, p=0.0109). Our analyses implicate dendritic cells (GB pHM= 0.0306 and non-GB pHM=0.0186) in mediating both glioblastoma and non-glioblastoma genetic predisposition, with glioblastoma-specific associations identified in natural killer (NK) (pHM=0.0201) and stem cells (pHM=0.0265).CONCLUSIONS: This analysis identifies putative new associations between glioma and autoimmune conditions with genomic architecture that is inversely correlated with that of glioma and that T cells, NK cells, and myeloid cells are involved in mediating glioma predisposition. This provides further evidence that increased activation of the acquired immune system may modify individual susceptibility to glioma.
View details for DOI 10.1093/neuonc/noab072
View details for PubMedID 33743008
- Genetic correlation analysis identifies glioma heritability enrichment in immune cell types and novel protective associations with auto-immune conditions AMER ASSOC CANCER RESEARCH. 2020
- Genetic correlation between lung cancer and environmental exposures AMER ASSOC CANCER RESEARCH. 2020