| Title: | Genetic analyses of eight complex diseases using predicted continuous representations of disease |
| Journal: | Cell Reports Methods |
| Published: | 25 Jul 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40714005/ |
| DOI: | https://doi.org/10.1016/j.crmeth.2025.101115 |
Publication 16108
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Abstract
We evaluated whether predicted continuous disease representations could enhance genetic discovery beyond case-control genome-wide association study (GWAS) phenotypes across eight complex diseases in up to 485,448 UK Biobank participants. Predicted phenotypes had high genetic correlations with case-control phenotypes (median rg = 0.66) but identified more independent associations (median 306 versus 125). While some predicted phenotype associations were spurious, multi-trait analysis of GWAS-boosted case-control phenotypes identified a median of 46 additional variants per disease, of which a median of 73% replicated in FinnGen, 37% reached genome-wide significance in a UK Biobank/FinnGen meta-analysis, and 45% had supporting evidence. Predicted phenotypes also identified 14 genes targeted by phase I-IV drugs not identified by case-control phenotypes, and combined polygenic risk scores (PRSs) using both phenotypes improved prediction performance, with a median 37% increase in Nagelkerke's R2. Predicted phenotypes represent composite biomarkers complementing case-control approaches in genetic discovery, drug target prioritization, and risk prediction, though efficacy varies across diseases.</p>
9 Keywords
- Case-Control Studies
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Multifactorial Inheritance
- Phenotype
- Polymorphism, Single Nucleotide
9 Authors
- Robert Chen
- Ghislain Rocheleau
- Ben Omega Petrazzini
- Iain S. Forrest
- Joshua K. Park
- Áine Duffy
- Ha My T. Vy
- Daniel Jordan
- Ron Do
1 Application
| Application ID | Title |
|---|---|
| 16218 | Dissecting the genetic and phenotypic architecture of cardiovascular disease |
Enabling scientific discoveries that improve human health