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  • Integrative analyses for the identification of idiopathic pulmonary fibrosis-associated genes and shared loci with other diseases

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Interstitial lung disease
Original research
Integrative analyses for the identification of idiopathic pulmonary fibrosis-associated genes and shared loci with other diseases
  1. Ming Chen1,
  2. Yiliang Zhang1,
  3. Taylor Adams2,
  4. Dingjue Ji3,
  5. Wei Jiang1,
  6. Louise V Wain4,5,
  7. Michael Cho6,7,
  8. Naftali Kaminski2,
  9. Hongyu Zhao1,3
  1. 1 Biostatistics, Yale University School of Public Health, New Haven, Connecticut, USA
  2. 2 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
  3. 3 Program of Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA
  4. 4 National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK
  5. 5 Department of Health Sciences, University of Leicester, Leicester, UK
  6. 6 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  7. 7 Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Hongyu Zhao, Biostatistics, Yale University, New Haven, Connecticut, USA; hongyu.zhao{at}yale.edu

Abstract

Background Although genome-wide association studies (GWAS) have identified many genomic regions associated with idiopathic pulmonary fibrosis (IPF), the causal genes and functions remain largely unknown. Many single-cell expression data have become available for IPF, and there is increasing evidence suggesting a shared genetic basis between IPF and other diseases.

Methods We conducted integrative analyses to improve the power of GWAS. First, we calculated global and local genetic correlations to identify IPF genetically associated traits and local regions. Then, we prioritised candidate genes contributing to local genetic correlation. Second, we performed transcriptome-wide association analysis (TWAS) of 44 tissues to identify candidate genes whose genetically predicted expression level is associated with IPF. To replicate our findings and investigate the regulatory role of the transcription factors (TF) in identified candidate genes, we first conducted the heritability enrichment analysis in TF binding sites. Then, we examined the enrichment of the TF target genes in cell-type-specific differentially expressed genes (DEGs) identified from single-cell expression data of IPF and healthy lung samples.

Findings We identified 12 candidate genes across 13 genomic regions using local genetic correlation, including the POT1 locus (p value=0.00041), which contained variants with protective effects on lung cancer but increasing IPF risk. We identified another 13 novel genes using TWAS. Two TFs, MAFK and SMAD2, showed significant enrichment in both partitioned heritability and cell-type-specific DEGs.

Interpretation Our integrative analysis identified new genes for IPF susceptibility and expanded the understanding of the complex genetic architecture and disease mechanism of IPF.

  • idiopathic pulmonary fibrosis

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. We gratefully acknowledge all the studies and databases that made GWAS summary data, expression data and annotation data available as listed in the supplemental file. This research was conducted by using the UK Biobank resource under application numbers 29900. All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/thorax-2021-217703

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. We gratefully acknowledge all the studies and databases that made GWAS summary data, expression data and annotation data available as listed in the supplemental file. This research was conducted by using the UK Biobank resource under application numbers 29900. All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Twitter @VivianC41985421, @kaminskimed

    • Contributors MC and YZ contributed to study concept and design, data analysis and manuscript writing. TA contributed to IPF single-cell data processing and manuscript writing. DJ and WJ contributed to data analysis. LVW and MC provided critical interpretation of the findings. NK and HZ contributed to study concept, design, and statistical support. All authors contributed to reviewing and editing of the manuscript and approved the final version of the manuscript. MC is guarantor for the work.

    • Funding LVW holds a GSK/British Lung Foundation Chair in Respiratory Research. The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. MHC is supported by R01HL135142, R01 HL137927, R01 HL089856, R01 HL147148. NK is supported by R01HL127349, R01HL141852, U01HL145567, UH2HL123886, and a generous gift from Three Lakes Partners. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. HZ is supported by NIH grant R01 GM134005 and NSF grant DMS 1902903.

    • Competing interests LVW has received funding from GSK and Orion, outside of the submitted work. MHC has received grant support from GSK and Bayer, consulting or speaking fees from Genentech, AstraZeneca, and Illumina. NK served as a consultant to Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, Astra Zeneca, Veracyte, Augmanity and CSL Behring, over the last 3 years, reports Equity in Pliant and a grant from Veracyte and non-financial support from MiRagen and Astra Zeneca. NK has IP on novel biomarkers and therapeutics in IPF licensed to Biotech.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.