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Analysis of 200 000 exome-sequenced UK Biobank subjects illustrates the contribution of rare genetic variants to hyperlipidaemia

Curtis, D; (2021) Analysis of 200 000 exome-sequenced UK Biobank subjects illustrates the contribution of rare genetic variants to hyperlipidaemia. Journal of Medical Genetics 10.1136/jmedgenet-2021-107752. (In press). Green open access

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Abstract

Background: A few genes have previously been identified in which very rare variants can have major effects on lipid levels. / Methods: Weighted burden analysis of rare variants was applied to exome sequenced UK Biobank subjects with hyperlipidaemia as the phenotype, of whom 44 054 were designated cases and 156 578 controls, with the strength of association characterised by the signed log 10 p value (SLP). / Results: With principal components included as covariates there was a tendency for genes on the X chromosome to produce strongly negative SLPs, and this was found to be due to the fact that rare X chromosome variants were identified less frequently in men than women. The test performed well when both principal components and sex were included as covariates and strongly implicated LDLR (SLP=50.08) and PCSK9 (SLP=−10.42) while also highlighting other genes previously found to be associated with lipid levels. Variants classified by SIFT as deleterious have on average a twofold effect and their cumulative frequency is such that they are present in approximately 1.5% of the population. / Conclusion: These analyses shed further light on the way that genetic variation contributes to risk of hyperlipidaemia and in particular that there are very many protein-altering variants which have on average moderate effects and whose effects can be detected when large samples of exome-sequenced subjects are available. This research has been conducted using the UK Biobank Resource.

Type: Article
Title: Analysis of 200 000 exome-sequenced UK Biobank subjects illustrates the contribution of rare genetic variants to hyperlipidaemia
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1136/jmedgenet-2021-107752
Publisher version: https://doi.org/10.1136/jmedgenet-2021-107752
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.
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/10128857
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