Whole Genome Sequence Analysis of Pulmonary Function and COPD in 44,287 Multi-ancestry Participants

Abstract Background Whole genome sequence (WGS) data in multi-ancestry samples provide the opportunity to identify low-frequency or population-specific genetic variants associated with chronic obstructive pulmonary disease (COPD) and lung function. Methods We performed single variant, structural variant, and gene-based analysis of pulmonary function (FEV 1 , FVC and FEV 1 /FVC) and COPD case-control status in 44,287 multi-ancestry participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We validated a subset of findings using the UK Biobank, implicated effector molecules, and examined cell-type specific expression in lung scRNA-seq data sets. Results Applying a genome-wide significance threshold ( P  < 5x10 -9 ) to our WGS analysis, we recapitulated evidence of association for previously reported loci, and further found evidence of association with lung function or COPD for novel regions located near LY86 , MAGI1 , and GRK7 . Colocalization with gene expression quantitative trait loci (eQTL) from the Lung Tissue Research Consortium provided new support for known candidate genes including ADAM19, THSD4 , C4B , and PSMA4 , which were not specifically identified through integration with eQTL from other sources. Multi-ancestry analysis improved fine-mapping resolution, notably for loci with strong linkage disequilibrium in European ancestry, such as those near HTR4 and RIN3 . In gene-based analysis of high-confidence loss of function variants, we found and replicated an association of HMCN1 . Single-cell datasets nominated lung epithelial cells and immune cell types from our association studies, and fibroblasts for HMCN1 . CRISPR targeting HMCN1 in IMR90 demonstrated reduced expression of collagen genes. Conclusions Our study demonstrates that genome-wide association study with larger multi-ancestry participants and WGS data helped to discover novel genomic regions and improved fine-mapping resolution for lung function and COPD.