Empirically determined baseline masking strategies and other considerations for gene-level burden tests

Nature Genetics 2026 Open access

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Authors: T M Nguyen, Ryan Koesterer, Poeya Haydarlou, Peter Dornbos, Satoshi Yoshiji, Alex Llamas, Dongkeun Jang, Patrick Smadbeck, Annie Moriondo, Quy Hoang, Oliver Ruebenacker, Connie R. Bezzina
+4 more Patrick Ellinor, Sean J. Jurgens, Noël P. Burtt, Jason Flannick
DOI: 10.1038/s41588-026-02597-9
Cited by: 1
References: 68

Abstract

Rare-variant association studies typically perform gene-level tests in which coding variants are filtered (or 'masked') and aggregated based on functional annotation and allele frequency. Through a systematic literature review, we cataloged 664 masks used across 234 studies and found that masking strategies (that is, sets of masks) rarely repeat across studies and are rarely justified. To quantify their impact on association results, we applied all previously employed strategies to 54 traits within 189,947 UK Biobank exomes. Here we find that the number of significant associations greatly depends on the masking strategy (ranging from 58 to 2,523 associations), which is a key reason for the modest overlap (

Fields of Study & Subjects

Genetic Associations and Epidemiology Genomics and Rare Diseases Genetic Syndromes and Imprinting

Publication details

Journal / source
Nature Genetics
Publisher
Springer Science and Business Media LLC
Volume
58
Issue
6
Pages
1226–1236
Publication date
8 May 2026
Language
EN