4.5 Article

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

期刊

JOURNAL OF MEDICAL GENETICS
卷 59, 期 6, 页码 597-604

出版社

BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2021-107752

关键词

human genetics; point mutation; sequence analysis; DNA

资金

  1. BBSRC [BB/R01356X/1]
  2. BBSRC [BB/R01356X/1] Funding Source: UKRI

向作者/读者索取更多资源

Rare variants in genes, particularly on the X chromosome, have been found to have major effects on lipid levels. The study demonstrated the importance of including principal components and sex as covariates in genetic analysis, and identified significant associations with genes like LDLR and PCSK9. Variants classified as deleterious by SIFT were found to have a twofold effect and are present in approximately 1.5% of the population, highlighting their impact on hyperlipidaemia risk.
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.

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