<a name="PFgenetics"></a>

<!-- Last updated: January 24, 2024 -->

Collaborative genetic studies of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by the build-up of scar tissue in the lungs. It is believed that the damage to the alveolar epithelium is followed by an aberrant wound healing response leading to the deposition of dense fibrotic tissue, reducing the lungs’ flexibility and inhibiting gas transfer. IPF still has limited therapeutic interventions and a high mortality rate within 3-5 years from diagnosis.

To date, genome-wide association studies (GWAS) of IPF susceptibility have associated common variants (minor allele frequency [MAF]>5%) near genes involved in host defence, telomere maintenance, cell-cell adhesion and signalling in disease susceptibility. Common variants near MUC5B and TOLLIP genes also show association with survival time after diagnosis of IPF (1,2).

<!-- --------------------------------- SECTION -------------------------------- -->

Publicly available datasets

<ul> <li><a href="#study1">3-way meta-GWAS of IPF susceptibility (2020)</a></li> <li><a href="#study2">5-way meta-GWAS of IPF susceptibility (2021)</a></li> <li><a href="#study3">GWAS of longitudinal lung function and gas transfer in individuals with IPF (2022)</a></li> <li><a href="#study4">GWAS of IPF of transplant-free survival (2022)</a></li> <li><a href="#study5">Genome-wide SNP-sex interaction analysis of susceptibility to IPF (2024)</a></li> <li><a href="#study6">7-way meta-GWAS of IPF susceptibility imputed with TopMed (2025)</a></li> </ul> <!-- --------------------------------- SECTION -------------------------------- -->

<a name="study1"></a>

3-way meta-GWAS of IPF susceptibility (2020)

Building up on published GWAS results (1,3,4) and novel study samples, we have performed a large GWAS of IPF susceptibility (5) to identify novel genes and further advance in the understanding of IPF pathogenesis and risk. The discovery stage of the study comprised up to 2,668 IPF cases and 8,591 controls and replication was pursued in an additional 1,456 IPF cases and 11,874 controls.

<p align="center"> <img src="https://github.com/genomicsITER/PFgenetics/blob/master/images/Figure_susceptibility_GWAS-IPF.png" width="auto"/> </p> <p><br></p> <!--  -->

Sample sizes for genome-wide analyses

Access to the results of this study

To help advance IPF research and allow the wider research community to access to the most accurate effect sizes for genetic variants on a genome-wide scale, the variant summary data from the discovery stage of the study by Allen et al. (5; https://doi.org/10.1164/rccm.201905-1017OC) <!--(1.31 Gb)--> can be accessed from the GWAS catalog (study accession 31710517).<!-- after an internal assessment of formal requests received. -->

<!-- ## What type of results would be made available? No individual level data will be made available. Granted requests will have access to a file with the GWAS meta-analysis variant summary data with information for the following descriptors: • **rsid** • **chromosome_position** [According to GRCh37/hg19 reference] • **non_effect_allele** • **effect_allele** • **effect_allele_frequency** [Frequency taken from across all three studies included in the meta-analysis] • **studies_included** [This is a piece of text that is Y if it is in the study and N if it is not. For example if the variant was in all three studies it would read Y:Y:Y (with UK first, Chicago second and Colorado last), if it was in the UK and Chicago but not included in Colorado it would read Y:Y:N] • **imputation_quality_by_study** [The imputation r2 by study in the same order as the studies_included column] • **effect_direction_by_study** [A piece of text with a plus sign (+) if the effect allele was associated with an increased risk of IPF (i.e. beta > 0) and a minus sign (–) if associated with a decreased risk of IPF (i.e. beta < 0) by study. For example if the effect allele had lower risk in the UK study but higher risk in the Chicago and Colorado studies it would read -:+:+] • **beta** [This is the beta from the meta-analysis] • **standard_error** [This is the standard error from the meta-analysis] • **p** [This is the p value from the meta-analysis] --> <p align="right"> <a href="#PFgenetics" title="Up"> <img src="https://github.com/genomicsITER/PFgenetics/blob/master/images/home-icon.png" style="float: right; margin: 10px; padding: 2px;" /> </a> </p> <br> <br> <!-- --------------------------------- SECTION -------------------------------- -->

<a name="study2"></a>

5-way meta-GWAS of IPF susceptibility (2021)

To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk GWAS (6). We utilised the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals. A total of 4,125 IPF cases, 20,464 controls, and 7,554,248 genetic variants were included in the analysis.

<p align="center"> <img src="https://github.com/genomicsITER/PFgenetics/blob/master/images/Figure_susceptibility_GWASIPF-5way.png" width="auto"/> </p> <p><br></p> <!--  -->

Sample sizes for genome-wide analyses

Access to the results of this study

To help advance IPF research and allow the wider research community to access to the most accurate effect sizes for genetic variants on a genome-wide scale, the variant summary data resulting from this second meta-analysis by Allen et al. (6; https://doi.org/10.1101/2021.12.06.21266509) <!-- (roughly 0.8 Gb) --> can be accessed from the GWAS catalog (study accession 35688625). <!-- after an internal assessment of formal requests received. -->

<!-- ## What type of results would be made available? No individual level data will be made available. Granted requests will have access to a file with the GWAS meta-analysis variant summary data with information for the following descriptors: • **chromosome_position** [According to GRCh37/hg19 reference] • **rsid** • **non_effect_allele** • **effect_allele** • **maf** [Minor allele frequency taken from across all five studies included in the meta-analysis] • **Studies** [Number of studies contributing to the result] • **n** [This is the sample size. Note, as not all variants were included in all studies, this value varies by SNP] • **Direction** [Effect direction by study. A piece of text with a plus sign (+) if the effect allele was associated with an increased risk of IPF (i.e. beta > 0) and a minus sign (–) if associated with a decreased risk of IPF (i.e. beta < 0) by study (in the order UK, Colorado, Chicago, UUS and then Genentech). If the variant was not included in the analysis, this is recorded with a question mark (?)] • **beta** [This is the beta from the meta-analysis] • **standard_error** [This is the standard error from the meta-analysis] • **p** [This is the p value from the meta-analysis] --> <p align="right"> <a href="#PFgenetics" title="Up"> <img src="https://github.com/genomicsITER/PFgenetics/blob/master/images/home-icon.png" style="float: right; margin: 10px; padding: 2px;" /> </a> </p> <br> <br> <!-- --------------------------------- SECTION -------------------------------- -->

<a name="study3"></a>

GWAS of longitudinal lung function and gas transfer in individuals with IPF (2022)

To identify genetic variants associated with progressive forms of IPF, we performed a GWAS of longitudinal measures of FVC and DLco to identify variants that lead to a more rapid decline in lung capacity or gas transfer after a diagnosis of IPF (7; https://doi.org/10.1016/S2213-2600(22)00251-X). The discovery stage was performed over three studies (US, UK and UUS). The FVC analysis comprised up to 1,048 IPF cases who had a total of 4,560 FVC measures recorded and the discovery stage of the DLco analysis comprised of 729 cases with a total of 2,795 DLco measures recorded. Follow-up analyses were performed in an independent dataset (the CleanUP-IPF study).

<p align="center"> <img src="https://github.com/genomicsITER/PFgenetics/blob/master/images/Figure_decline_GWASIPF.png" width="auto"/> </p> <p><br></p> <!--  -->

Sample sizes for genome-wide analyses

Access to the results of this study

To help advance IPF research and allow the wider research community to access to the most accurate effect sizes for genetic variants on a genome-wide scale, the variant summary data from the discovery stage of the study by Allen et al. (7; https://doi.org/10.1016/S2213-2600(22)00251-X) <!-- (470Mb each) --> can be accessed from the GWAS catalog (study accession 35985358). <!-- after an internal assessment of formal requests received. -->

<!-- ## What type of results would be made available? No individual level data will be made available. Granted requests will have access to both the longitudinal FVC and longitudinal DLco analyses in files with the following descriptors: • **chromosome** • **position** [According to GRCh37/hg19 reference] • **rsid** • **non_effect_allele** • **effect_allele** • **eaf** [Effect Allele Frequency from across all three studies included in the meta-analysis] • **n_studies** [The num