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

Amariuta, Tiffany; Ishigaki, Kazuyoshi; Sugishita, Hiroki; Ohta, Toshio; Koido, Masaru; Dey, Kushal K.; Matsuda, Koichi; Murakami, Yoshinori; Price, Alkes L.; Kawakami, Eiryo; Terao, Chikashi; Raychaudhuri, Soumya

doi:10.1038/s41588-020-00740-8

Cited by 151 publications

(157 citation statements)

References 63 publications

Supporting

Mentioning

145

Contrasting

Order By: Relevance

“…Many recent efforts have demonstrated that functional annotation of the reference genome improves the fine-mapping of disease variants (55)(56)(57)(58). The unique advantage of EN-TEx is that the genetic variants and their functional annotations are determined for the same individual.…”

Section: Discussionmentioning

confidence: 99%

The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models

Rozowsky¹,

Moore²,

Pratt³

et al. 2021

Preprint

View full text Add to dashboard Cite

Evaluating the impact of genetic variants on transcriptional regulation is a central goal in biological science that has been constrained by reliance on a single reference genome. To address this, we constructed phased, diploid genomes for four cadaveric donors (using longread sequencing) and systematically charted noncoding regulatory elements and transcriptional activity across more than 25 tissues from these donors. Integrative analysis revealed over a million variants with allele-specific activity, coordinated, locus-scale allelic imbalances, and structural variants impacting proximal chromatin structure. We relate the personal genome analysis to the ENCODE encyclopedia, annotating allele- and tissue-specific elements that are strongly enriched for variants impacting expression and disease phenotypes. These experimental and statistical approaches, and the corresponding EN-TEx resource, provide a framework for personalized functional genomics.

show abstract

Section: Discussionmentioning

confidence: 99%

The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models

Rozowsky¹,

Moore²,

Pratt³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Characterization of these variants will allow a better understanding of gene regulation and disease etiology. Indeed, mounting evidence suggests that genetic variants underlying disease associations are often context-specific [8][9][10][11][12][13][14][15][16]. For example, the Immune Variation project identified eQTLs in monocytederived dendritic cells and human CD4+ T lymphocytes with different effects in response to in vitro stimulation and polarization [13,17].…”

Section: Introductionmentioning

confidence: 99%

Fast and powerful statistical method for context-specific QTL mapping in multi-context genomic studies

Lü

Thompson

et al. 2021

Preprint

View full text Add to dashboard Cite

Recent studies suggest that context-specific eQTLs underlie genetic risk factors for complex diseases. However, methods for identifying them are still nascent, limiting their comprehensive characterization and downstream interpretation of disease-associated variants. Here, we introduce FastGxC, a method to efficiently and powerfully map context-specific eQTLs by leveraging the correlation structure of multi-context studies. We first show via simulations that FastGxC is orders of magnitude more powerful and computationally efficient than previous approaches, making previously year-long computations possible in minutes. We next apply FastGxC to bulk multi-tissue and single-cell RNA-seq data sets to produce the most comprehensive tissue- and cell-type-specific eQTL maps to date. We then validate these maps by establishing that context-specific eQTLs are enriched in corresponding functional genomic annotations. Finally, we examine the relationship between context-specific eQTLs and human disease and show that FastGxC context-specific eQTLs provide a three-fold increase in precision to identify relevant tissues and cell types for GWAS variants than standard eQTLs. In summary, FastGxC enables the construction of context-specific eQTL maps that can be used to understand the context-specific gene regulatory mechanisms underlying complex human diseases.

show abstract

“…On the other hand, recent empirical work on within-family disease risk prediction showed that the reduction in accuracy is at most modest (Lello et al, 2020), and within-siblings-GWAS yielded similar results to unrelated-GWAS for most physiological traits (Howe et al, 2021). Additionally, accuracy in non-European populations is rapidly improving due to the establishment of national biobanks in non-European countries (Koyama et al, 2020;Vujkovic et al, 2020) and improvement in methods for transferring scores into non-European populations (Amariuta et al, 2020;Cai et al, 2021). Either way, the analytical results presented in this paper are formulated generally as a function of the achievable accuracy 2 , and as such, users can substitute values relevant to their specific target population and disease.…”

Section: Discussionmentioning

confidence: 99%

Utility of polygenic embryo screening for disease depends on the selection strategy

Lencz

Backenroth

Green

et al. 2020

Preprint

View full text Add to dashboard Cite

As of 2019, polygenic risk scores have been utilized to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. In this short report, we demonstrate that a strong determinant of the potential utility of such screening is the selection strategy employed, a factor that has not been previously studied. Minimal risk reduction is expected if only extremely high-scoring embryos are excluded, whereas risk reductions are substantially greater if the lowest-scoring embryo (for a given disease) is selected. We systematically examined the relative contributions of the variance explained by the score, the number of embryos, the disease prevalence, and the parental scores on the utility of screening. We discuss the results in the context of relative vs absolute risk, as well as the potential ethical concerns raised by such procedures.

show abstract

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

Cited by 151 publications

References 63 publications

The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models

The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models

Fast and powerful statistical method for context-specific QTL mapping in multi-context genomic studies

Utility of polygenic embryo screening for disease depends on the selection strategy

Contact Info

Product

Resources

About