Show Notes
Saferali A et al., Human Genetics and Genomics Advances - Overlap between COPD genetic association results and transcriptional quantitative trait loci. RNA-seq in human lung (LTRC) and blood (COPDGene) reveals COPD-associated variants colocalize with splicing QTLs, implicating FBXO38 cryptic exon NMD and BTC exon4 isoform shifts. Key terms: COPD, sQTL, FBXO38, Betacellulin (BTC), long-read RNA-seq.
Study Highlights:
The study analyzed RNA-seq from COPDGene whole blood (n≈3,743) and LTRC lung tissue (n=1,241) using LeafCutter for splicing and tensorQTL for cis associations, followed by Moloc colocalization and targeted Oxford Nanopore long-read sequencing. Authors identified 58,258 lung splice sites and widespread eQTLs/sQTLs, and found 38 genomic windows (corresponding to 33 GWAS loci) with strong colocalization between QTLs and COPD GWAS signals. Top colocalizations in lung sQTLs included NPNT, FBXO38, HHIP, NTN4, and BTC, and long-read data resolved isoform changes for FBXO38 and BTC. Functionally, FBXO38 cryptic exon inclusion is associated with predicted nonsense-mediated decay and decreased expression, and BTC exon 4 inclusion alters isoform ratios that affect the EGF-like domain.
Conclusion:
Multiple COPD GWAS associations colocalize with sQTLs and eQTLs in lung and blood, identifying candidate genes such as FBXO38 and BTC and implicating splicing-mediated mechanisms in COPD risk.
Music:
Enjoy the music based on this article at the end of the episode.
Article title:
Overlap between COPD genetic association results and transcriptional quantitative trait loci
First author:
Saferali A
Journal:
Human Genetics and Genomics Advances
DOI:
10.1016/j.xhgg.2025.100493
Reference:
Saferali A., Kim W., Chase R.P., NHLBI TransOmics in Precision Medicine (TOPMed), Vollmers C., Silverman E.K., Cho M.H., Castaldi P.J., Hersh C.P. Overlap between COPD genetic association results and transcriptional quantitative trait loci. Human Genetics and Genomics Advances. 2026 Jan 15;7:100493. https://doi.org/10.1016/j.xhgg.2025.100493.
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/
Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
Official website https://basebybase.com
On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
Episode link: https://basebybase.com/episodes/copd-sqtl-fbxo38-btc
QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-16.
QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive transcript content describing COPD genetic architecture, sQTL/eQTL mapping in lung tissue (LTRC) and whole blood (COPDGene), the LeafCutter/TensorQTL/Moloc pipeline, FBXO38 cryptic exon and NMD, BTC exon 4 splicing, long-read validation, and translational implications.
- transcript topics: COPD genetic architecture and regulatory mechanisms; sQTL/eQTL mapping in lung tissue (LTRC) and whole blood (COPDGene); LeafCutter splicing analysis; TensorQTL cis associations; Moloc colocalization; FBXO38 cryptic exon and nonsense-mediated decay
QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 6
- metadata issues found: 0
Metadata Audited:
- article_doi
- article_title
- article_journal
- license
- episode_title
- episode_number
- season
- publish_description_text
Factual Items Audited:
- 38 colocalization windows across 33 COPD GWAS loci with high posterior probability of shared causality (CPP>0.8)
- 58,258 lung splice sites identified in LTRC; 10,615 genes associated
- FBXO38: COPD-risk rs7730971 associated with a 158 bp cryptic exon; introduces premature stop codon and likely subjected to nonsense-mediated decay; reduced FBXO38 expression
- BTC: COPD-risk allele promotes increased inclusion of exon 4; shifts BTC isoform ratios and affects EGF-like domain
- Oxford Nanopore long-read sequencing validated FBXO38 and BTC isoforms
- Bulk RNA-seq in blood (COPDGene) and lung (LTRC) acknowledged as a limitation; single-cell follow-up suggested
QC result: Pass.
