HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.

HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.

Lung cancer remains the most common cause of cancer death globally. Dysregulation of immune response and inflammatory signaling is known to play an important role in lung tumorigenesis, but the causal drivers of this process have yet to be elucidated. To identify circulating inflammatory and immune-related proteins that influence risk for lung cancer we related genetically predicted plasma levels for 85 inflammation and immune proteins with susceptibility to lung cancer. Mendelian randomization (MR) analyses in 29,266 cases and 56,450 controls identified a candidate causal marker, IL-18, which conferred lower risk of lung cancer (OR per standard deviation increase: 0.85 [95% CI: 0.79-0.92]), in particular for adenocarcinoma (OR: 0.80 [95% CI: 0.72-0.89]). We subsequently validated this association using polygenic IL-18 predictions in the UK Biobank (HR highest vs. lowest quartile: 0.83 [95% CI: 0.72-0.95]) and using pre-diagnostic blood concentrations of IL-18 in 732 cases and 732 controls after controlling for the inhibitory role of IL-18BP (OR highest vs. lowest quartile: 0.63 [95% CI: 0.41-0.91]). Genetic colocalization suggested that IL-18 may act on lung cancer risk locally via lung tissue expression, and joint MR and tumor microenvironment analyses highlight CD8 T cells and NK cells as potential mediators. In addition to risk, IL-18 expression in adenocarcinoma tumor tissue was found to be associated with all-cause mortality in 480 TCGA samples after controlling for IL-18BP (HR per SD: 0.87 [95% CI: 0.78, 0.98]), which is in line with recent studies showing anti-tumor effects of IL-18. Our comprehensive genomic triangulation study thus highlights the potential for IL-18 as an aetiological biomarker and targetable for immune-oncology therapies.