Integration of rare expression outlier-associated variants improves polygenic risk prediction

Smail, Craig; Ferraro, Nicole M.; Hui, Qin; Durrant, Matthew G.; Aguirre, Matthew; Tanigawa, Yosuke; Keever-Keigher, Marissa R.; Rao, Abhiram; Justesen, Johanne Marie; Li, Xin; Gloudemans, Michael J.; Assimes, Themistocles L.; Kooperberg, Charles; Reiner, Alexander P.; Huang, Jie; O’Donnell, Christopher J.; Sun, Yan V.; Rivas, Manuel A.; Montgomery, S

doi:10.1016/j.ajhg.2022.04.015

Cited by 15 publications

(8 citation statements)

References 39 publications

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“… 43 , 44 , 45 , 46 , 47 , 48 , 49 It supports a unified framework where multi-omics functional signals can inform prioritization of genetic variation across the entire frequency spectrum, such that the incorporation of rare variants into common variant frameworks such as polygenic risk scoring could improve stratification of patient risks. 3 An important consideration when predicting disease risk using Watershed posteriors on rare variants, however, is the relevant genetic regulatory context. Our current model was trained using multi-omics data collected from blood samples from healthy donors, which may serve as a reasonable background for immunological traits and the two neuropsychiatric diseases we considered (AD and SCZ).…”

Section: Discussionmentioning

confidence: 99%

“…The ability of transcriptome data to enhance prioritization of rare variants with effects on diseases and traits 3 is presumably due to those effects propagating through the regulatory cascade to protein levels and cellular functions. Prior work has shown that common variants associated with changes in gene expression can have effects on ribosome and protein levels, although those effects are significantly reduced at the protein level.…”

Section: Introductionmentioning

confidence: 99%

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The functional impact of rare variation across the regulatory cascade

Li,

Ferraro,

Strober

et al. 2023

Cell Genomics

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The functional impact of rare variation across the regulatory cascade

Li,

Ferraro,

Strober

et al. 2023

Cell Genomics

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“…Aberrant underexpression of tumor suppressor genes and aberrant overexpression of oncogenes are hallmarks of oncogenesis 1,2 . Moreover, aberrant gene expression is a frequent cause of rare inheritable disorders 3–8 and contributes to risks for common disease-associated traits 9 .…”

Section: Mainmentioning

confidence: 99%

Aberrant expression prediction across human tissues

Hölzlwimmer,

Lindner,

Wagner

et al. 2023

Preprint

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Despite the frequent implication of aberrant gene expression in diseases, algorithms predicting aberrantly expressed genes of an individual are lacking. To address this need, we compiled an aberrant expression prediction benchmark covering 8.2 million rare variants from 633 individuals across 48 tissues. While not geared toward aberrant expression, the deleteriousness score CADD and the loss-of-function predictor LOFTEE showed mild predictive ability (1-1.5% average precision). Leveraging these and further variant annotations, we next trained AbExp, a model that yielded 10% average precision by combining in a tissue-specific fashion expression variability with variant effects on isoforms and on aberrant splicing. Integrating expression measurements from clinically accessible tissues led to another two-fold improvement. Furthermore, we show on UK Biobank blood traits that performing rare variant association testing using the continuous and tissue-specific AbExp variant scores instead of LOFTEE variant burden increases gene discovery sensitivity and enables improved phenotype predictions.

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“…Lali et al (2021) were able to develop a rare variant genetic risk score which was able to identify 1.5% of people with a risk of early for coronary artery disease even when adjusting for Mendelian genes, clinical risk factors and common genetic variants. A recent study showed that PRSs based on common genetic variants for obesity, and the risk of severe obesity and early bariatric surgery, was enhanced by incorporating rare variants associated with significant gene expression changes (which they termed expression outliers), highlighting the potential utility of combining common and rare genetic variants in PRSs (Smail et al, 2022).…”

Section: The Future Of Polygenic Risk Scoresmentioning

confidence: 99%

Polygenic risk scores: An overview from bench to bedside for personalised medicine

2022

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Since the first polygenic risk score (PRS) in 2007, research in this area has progressed significantly. The increasing number of SNPs that have been identified by large scale GWAS analyses has fuelled the development of a myriad of PRSs for a wide variety of diseases and, more recently, to PRSs that potentially identify differential response to specific drugs. PRSs constitute a composite genomic biomarker and potential applications for PRSs in clinical practice encompass risk prediction and disease screening, early diagnosis, prognostication, and drug stratification to improve efficacy or reduce adverse drug reactions. Nevertheless, to our knowledge, no PRSs have yet been adopted into routine clinical practice. Beyond the technical considerations of PRS development, the major challenges that face PRSs include demonstrating clinical utility and circumnavigating the implementation of novel genomic technologies at scale into stretched healthcare systems. In this review, we discuss progress in developing disease susceptibility PRSs across multiple medical specialties, development of pharmacogenomic PRSs, and future directions for the field.

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Integration of rare expression outlier-associated variants improves polygenic risk prediction

Cited by 15 publications

References 39 publications

The functional impact of rare variation across the regulatory cascade

The functional impact of rare variation across the regulatory cascade

Aberrant expression prediction across human tissues

Polygenic risk scores: An overview from bench to bedside for personalised medicine

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