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Nat Genet DOI:10.1038/s41588-020-00740-8

Improving the trans-ancestry portability of polygenic risk scores by prioritizing variants in predicted cell-type-specific regulatory elements.

Publication TypeJournal Article
Year of Publication2020
AuthorsAmariuta, T, Ishigaki, K, Sugishita, H, Ohta, T, Koido, M, Dey, KK, Matsuda, K, Murakami, Y, Price, AL, Kawakami, E, Terao, C, Raychaudhuri, S
JournalNat Genet
Volume52
Issue12
Pages1346-1354
Date Published2020 Dec
ISSN1546-1718
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 R). Our study identifies a crucial role for functional annotations such as IMPACT to improve the trans-ancestry portability of genetic data.

DOI10.1038/s41588-020-00740-8
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/33257898?dopt=Abstract

Alternate JournalNat Genet
PubMed ID33257898
Grant List1U01HG009088 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
U01 HG009379 / HG / NHGRI NIH HHS / United States
1R01AR063759 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
T32 HG002295 / HG / NHGRI NIH HHS / United States
U01 HG009379 / HG / NHGRI NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States