Improving the trans-ancestry portability of polygenic risk scores by prioritizing variants in predicted cell-type-specific regulatory elements
- 30 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 52 (12), 1346-1354
- https://doi.org/10.1038/s41588-020-00740-8
Abstract
Poor trans-ancestry portability of polygenic risk scores is a consequence of Eurocentric genetic studies and limited knowledge of shared causal variants. Leveraging regulatory annotations may improve portability by prioritizing functional over tagging variants. We constructed a resource of 707 cell-type-specific IMPACT regulatory annotations by aggregating 5,345 epigenetic datasets to predict binding patterns of 142 transcription factors across 245 cell types. We then partitioned the common SNP heritability of 111 genome-wide association study summary statistics of European (average n ≈ 189,000) and East Asian (average n ≈ 157,000) origin. IMPACT annotations captured consistent SNP heritability between populations, suggesting prioritization of shared functional variants. Variant prioritization using IMPACT resulted in increased trans-ancestry portability of polygenic risk scores from Europeans to East Asians across all 21 phenotypes analyzed (49.9% mean relative increase in R2). Our study identifies a crucial role for functional annotations such as IMPACT to improve the trans-ancestry portability of genetic data.Keywords
Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (1U01HG009088, U01 HG009379, 1R01AR063759, T32 HG002295)
This publication has 65 references indexed in Scilit:
- Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studiesNature Genetics, 2013
- Linking disease associations with regulatory information in the human genomeGenome Research, 2012
- An integrated encyclopedia of DNA elements in the human genomeNature, 2012
- A Better Coefficient of Determination for Genetic Profile AnalysisGenetic Epidemiology, 2012
- Bayesian inference analyses of the polygenic architecture of rheumatoid arthritisNature Genetics, 2012
- Mechanisms Limiting Body Growth in MammalsEndocrine Reviews, 2011
- Common SNPs explain a large proportion of the heritability for human heightNature Genetics, 2010
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- Common polygenic variation contributes to risk of schizophrenia and bipolar disorderNature, 2009
- PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage AnalysesAmerican Journal of Human Genetics, 2007