| Title: | Development and validation of a multiancestry and multitrait polygenic risk score for lung cancer |
| Journal: | Nature Communications |
| Published: | 27 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42364979/ |
| DOI: | https://doi.org/10.1038/s41467-026-74964-3 |
| URL: | https://www.nature.com/articles/s41467-026-74964-3_reference.pdf |
Publication 20701
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Abstract
Polygenic risk scores (PRSs) quantify genetic susceptibilities, yet ancestry imbalance in genome-wide association studies (GWASs) limits the accuracy of monoracial PRSs in non-European populations. Here, we perform a multiancestry GWAS meta-analysis for lung cancer (76,953 cases and 1,886,372 controls), identifying 87 conditionally independent genome-wide significant loci, including two unreported cytobands. We use a PRS construction method, PRS-CSx, to develop a multiancestry PRS (PRSMA$${{{{\rm{PRS}}}}}_{{{{\rm{MA}}}}}$$) which outperforms 32 published PRSs. To enhance predictive power, we construct a multitrait PRS (PRSMT$${{{{\rm{PRS}}}}}_{{{{\rm{MT}}}}}$$) using CatBoost, integrating 32 cross-trait PRSs across three ancestries. Combining PRSMA$${{{{\rm{PRS}}}}}_{{{{\rm{MA}}}}}$$ and PRSMT$${{{{\rm{PRS}}}}}_{{{{\rm{MT}}}}}$$, we generate PRSMAMT$${{{{\rm{PRS}}}}}_{{{{\rm{MAMT}}}}}$$ and validate it in independent cohorts (OncoArray, TRICL and All of Us). PRSMAMT$${{{{\rm{PRS}}}}}_{{{{\rm{MAMT}}}}}$$ demonstrates superior discriminability in European, Asian, and African populations, improves risk stratification, and identifies approximately 10% additional lung cancer cases in the UK Biobank. Individuals with elevated PLCOm2012 scores and high genetic risk exhibit a 12.64-fold higher cumulative risk than those with low scores and low genetic risk, supporting precision prevention strategies.</p>
7 Authors
- Yixin Zhang
- Jinglan Dai
- Pan Gu
- Yang Zhao
- David C. Christiani
- Feng Chen
- Sipeng Shen
Enabling scientific discoveries that improve human health