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Background <p>Whole genome sequence (WGS) data in multi-ancestry samples supports discovery of low-frequency or population-specific genetic variants associated with chronic obstructive pulmonary disease (COPD) and lung function.</p> Results <p>We performed single variant, structural variant, and gene-based analysis of pulmonary function (FEV<sub>1</sub>, FVC and FEV<sub>1</sub>/FVC) and COPD case–control status in 44,287 multi-ancestry participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We validated findings using the UK Biobank and assessed implicated genes using lung single-cell RNA-seq (scRNA-seq) data sets. Applying a genome-wide significance threshold (<i>P</i> &lt; 5 × 10<sup>–9</sup>), we replicated known loci and identified novel associations near <i>LY86</i>, <i>MAGI1, GRK7,</i> and <i>LINC02668</i>. Colocalization with gene expression quantitative trait loci (eQTL) from the Lung Tissue Research Consortium highlighted known candidate genes including <i>ADAM19, THSD4</i>, <i>C4B</i>, and <i>PSMA4</i>, which were not identified through other eQTL sources. Multi-ancestry analysis improved fine-mapping resolution (e.g., <i>HTR4</i> and <i>RIN3</i>). Gene-based analysis identified and replicated <i>HMCN1</i>. In human lung scRNA-seq data sets, lung epithelial cells and immune cell types showed enriched expression, while fibroblasts showed higher expression for <i>HMCN1</i>. CRISPR targeting <i>HMCN1</i> in IMR90 demonstrated reduced expression of collagen genes.</p> Conclusions <p>Large-scale multi-ancestry WGS analysis improves variant discovery and fine-mapping resolution for lung function and COPD and highlights biologically relevant genes and pathways.</p>

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Whole genome sequence analysis of pulmonary function and COPD in 44,287 multi-ancestry participants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月15日

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  • Wonji Kim,
  • Xiaowei Hu,
  • Kangjin Kim,
  • Sung Chun,
  • Peter Orchard,
  • Dandi Qiao,
  • Ingo Ruczinski,
  • Aabida Saferali,
  • Francois Aguet,
  • Lucinda Antonacci-Fulton,
  • Pallavi P. Balte,
  • Traci M. Bartz,
  • Wardatul Jannat Anamika,
  • Xiaobo Zhou,
  • JunYi Duan,
  • Jennifer A. Brody,
  • Brian E. Cade,
  • Martha L. Daviglus,
  • Harshavadran Doddapaneni,
  • Shannon Dugan-Perez,
  • Susan K. Dutcher,
  • Christian D. Frazar,
  • Stacey B. Gabriel,
  • Sina A. Gharib,
  • Namrata Gupta,
  • Brian D. Hobbs,
  • Silva Kasela,
  • Laura R. Loehr,
  • Ginger A. Metcalf,
  • Donna M. Muzny,
  • Elizabeth C. Oelsner,
  • Laura J. Rasmussen-Torvik,
  • Colleen M. Sitlani,
  • Joshua Smith,
  • Tamar Sofer,
  • Hanfei Xu,
  • Bing Yu,
  • David Zhang,
  • John Ziniti,
  • R. Graham Barr,
  • April P. Carson,
  • Myriam Fornage,
  • Lifang Hou,
  • Ravi Kalhan,
  • Robert Kaplan,
  • Tuuli Lappalainen,
  • Stephanie J. London,
  • Alanna C. Morrison,
  • George T. O’Connor,
  • Bruce M. Psaty,
  • Laura M. Raffield,
  • Susan Redline,
  • Stephen S. Rich,
  • Jerome I. Rotter,
  • Edwin K. Silverman,
  • Ani Manichaikul,
  • Michael H. Cho

摘要

Background

Whole genome sequence (WGS) data in multi-ancestry samples supports discovery of low-frequency or population-specific genetic variants associated with chronic obstructive pulmonary disease (COPD) and lung function.

Results

We performed single variant, structural variant, and gene-based analysis of pulmonary function (FEV1, FVC and FEV1/FVC) and COPD case–control status in 44,287 multi-ancestry participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We validated findings using the UK Biobank and assessed implicated genes using lung single-cell RNA-seq (scRNA-seq) data sets. Applying a genome-wide significance threshold (P < 5 × 10–9), we replicated known loci and identified novel associations near LY86, MAGI1, GRK7, and LINC02668. Colocalization with gene expression quantitative trait loci (eQTL) from the Lung Tissue Research Consortium highlighted known candidate genes including ADAM19, THSD4, C4B, and PSMA4, which were not identified through other eQTL sources. Multi-ancestry analysis improved fine-mapping resolution (e.g., HTR4 and RIN3). Gene-based analysis identified and replicated HMCN1. In human lung scRNA-seq data sets, lung epithelial cells and immune cell types showed enriched expression, while fibroblasts showed higher expression for HMCN1. CRISPR targeting HMCN1 in IMR90 demonstrated reduced expression of collagen genes.

Conclusions

Large-scale multi-ancestry WGS analysis improves variant discovery and fine-mapping resolution for lung function and COPD and highlights biologically relevant genes and pathways.