Wonji Kim

Postdoctoral Research Fellow
Channing Division of Network Medicine
Wonji Kim*, Xiaowei Hu, Bing Yu, Laura J. Rasmussen-Torvik, Sina A. Gharib, Brian Cade, Josée Dupuis, Robert Kaplan, Solomon Musani, Jennifer Brody, Stephanie J. London, Ravi Kalhan, Susan Redline, Bruce M. Psaty, George T. O’Connor, Adolfo Correa, Edwin K. Silverman, Dandi Qiao, Ani Manichaikul, Michael H. Cho and the TOPMed Investigators
Whole Genome Sequence Analysis of Pulmonary Function and COPD for 44,403 Multi-ethnic participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program

Background: Large scale whole genome sequence (WGS) data in multi-ethnic samples provide the opportunity to identify novel associated variants and regions for Chronic obstructive pulmonary disease (COPD) and lung function, reflecting lower frequencies or population-specific signals.

Methods: We performed WGS analysis of pulmonary function (FEV1, FVC and FEV1/FVC) and COPD case-control status in 44,403 multi-ethnic participants from the NHLBI Trans-Omics for Precision Medicine Program. We performed single variant analysis and gene-based analysis using GENESIS implemented on the DNANexus platform. To identify which variants/genes were novel, we tested each significant variant/gene adding known variants within 2Mb as covariates. We also validated a subset of findings using exome sequence data from the UK Biobank.

Results: In the single variant analysis, we identified 21 significant regions including 1,045 variants in the multi-ethnic analysis at a genome-wide significance level of 5×10-9. Among these, 28 variants in 5 regions were significant after conditioning on known GWAS variants, identifying novel signals within/near MAGI1, RNF7, GRK7 and ADAMTSL3. In the gene-based analysis, we identified 5 significantly associated protein-coding genes; TTC22, HMCN1, GZMM, DMAP1 and ENSG00000285868 for the variants annotated as loss-of-function with high-confidence. Of these genes, HMCN1 and DMAP1 were significantly associated with FEV1/FVC in the conditional analysis, and the association with HMCN1 was replicated in the UK Biobank with p-values of 9.62×10-30 in European ancestry.

Conclusions: Our findings complement large-scale GWAS studies with a focus on low frequency variants, and indicate that novel genetic regions can be discovered with larger multi-ethnic sample sizes with WGS data.