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Exploration of weighting schemes based on allele frequency and annotation for weighted burden association analysis of complex phenotypes

Curtis, D; (2022) Exploration of weighting schemes based on allele frequency and annotation for weighted burden association analysis of complex phenotypes. Gene , 809 , Article 146039. 10.1016/j.gene.2021.146039. Green open access

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Abstract

Weighted burden analysis can incorporate variants with different frequencies and annotations into a combined test for association between a gene and a phenotype. However there has not been a systematic exploration of which weighting schemes provide maximum power to detect association. Here we assess different weighting schemes using a number of genes for which exome-wide evidence of association with common phenotypes was obtained in 200,000 exome-sequenced UK Biobank participants. We find that there are marked differences in optimal weighting schemes between genes, both with respect to allele frequency and to annotation, implying that there is no "one-size-fits-all" scheme which is generally optimal. It seems helpful to weight rare variants more highly than common ones, to give loss of function variants higher weights than protein-altering variants and to assign higher weights to protein-altering variants predicted to have more severe effects. However with the data currently available it does not seem possible to make more specific recommendations. This research has been conducted using the UK Biobank Resource.

Type: Article
Title: Exploration of weighting schemes based on allele frequency and annotation for weighted burden association analysis of complex phenotypes
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.gene.2021.146039
Publisher version: https://doi.org/10.1016/j.gene.2021.146039
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Association, Exome, Loss of function, Nonsynonymous, Rare variant
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/10139274
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