Improving the informativeness of Mendelian disease-derived pathogenicity scores for common disease

Samuel S. Kim (), Kushal K. Dey, Omer Weissbrod, Carla Márquez-Luna, Steven Gazal and Alkes L. Price ()
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Samuel S. Kim: Massachusetts Institute of Technology
Kushal K. Dey: Harvard T.H. Chan School of Public Health
Omer Weissbrod: Harvard T.H. Chan School of Public Health
Carla Márquez-Luna: Icahn School of Medicine at Mount Sinai
Steven Gazal: Harvard T.H. Chan School of Public Health
Alkes L. Price: Harvard T.H. Chan School of Public Health

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Despite considerable progress on pathogenicity scores prioritizing variants for Mendelian disease, little is known about the utility of these scores for common disease. Here, we assess the informativeness of Mendelian disease-derived pathogenicity scores for common disease and improve upon existing scores. We first apply stratified linkage disequilibrium (LD) score regression to evaluate published pathogenicity scores across 41 common diseases and complex traits (average N = 320K). Several of the resulting annotations are informative for common disease, even after conditioning on a broad set of functional annotations. We then improve upon published pathogenicity scores by developing AnnotBoost, a machine learning framework to impute and denoise pathogenicity scores using a broad set of functional annotations. AnnotBoost substantially increases the informativeness for common disease of both previously uninformative and previously informative pathogenicity scores, implying that Mendelian and common disease variants share similar properties. The boosted scores also produce improvements in heritability model fit and in classifying disease-associated, fine-mapped SNPs. Our boosted scores may improve fine-mapping and candidate gene discovery for common disease.

Date: 2020
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DOI: 10.1038/s41467-020-20087-2

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