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Investigation of Recessive Effects of Coding Variants on Common Clinical Phenotypes in Exome-Sequenced UK Biobank Participants

Curtis, David; (2024) Investigation of Recessive Effects of Coding Variants on Common Clinical Phenotypes in Exome-Sequenced UK Biobank Participants. Human Heredity , 89 (1) pp. 1-7. 10.1159/000537771. Green open access

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Abstract

INTRODUCTION: Previous studies have demonstrated effects of rare coding variants on common, clinically relevant phenotypes although the additive burden of these variants makes only a small contribution to overall trait variance. Although recessive effects of individual homozygous variants have been studied, little work has been done to elucidate the impact of rare coding variants occurring together as compound heterozygotes. METHODS: In this study, attempts were made to identify pairs of variants likely to be occurring as compound heterozygotes using 200,000 exome-sequenced subjects from the UK Biobank. Pairs of variants, which were seen together in the same subject more often than would be expected by chance, were excluded as it was assumed that these might be present in the same haplotype. Attention was restricted to variants with minor allele frequency ≤0.05 and to those predicted to alter amino acid sequence or prevent normal gene expression. For each gene, compound heterozygotes were assigned scores based on the rarity and predicted functional consequences of the constituent variants and the scores were used in a logistic regression analysis to test for association with hypertension, hyperlipidaemia, and type 2 diabetes. RESULTS: No statistically significant associations were observed and the results conformed to the distribution, which would be expected under the null hypothesis. The average number of apparently compound heterozygous subjects for each gene was only 282.2. CONCLUSION: It seems difficult to detect an effect of compound heterozygotes on the risk of these phenotypes. Even if recessive effects from compound heterozygotes do occur, they would only affect a small number of people and overall would not make a substantial contribution to phenotypic variance. This research has been conducted using the UK Biobank Resource.

Type: Article
Title: Investigation of Recessive Effects of Coding Variants on Common Clinical Phenotypes in Exome-Sequenced UK Biobank Participants
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.1159/000537771
Publisher version: http://dx.doi.org/10.1159/000537771
Language: English
Additional information: © 2024 The Author(s). Published by S. Karger AG, Basel. This article is licensed under the Creative Commons Attribution 4.0 International License (CC BY) (http://www.karger.com/Services/ OpenAccessLicense).
Keywords: Exome, Recessive effects, Compound heterozygote
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/10191621
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