Weighted burden analysis of rare coding variants in 470,000 exome-sequenced UK Biobank participants characterises effects on hyperlipidaemia risk

AbstractA previous study of 200,000 exome-sequenced UK Biobank participants investigating the association between rare coding variants and hyperlipidaemia had implicated four genes,LDLR,PCSK9,APOC3 andIFITM5, at exome-wide significance. In addition, a further 43 protein-coding genes were significant with an uncorrectedp value of<0.001. Exome sequence data has become available for a further 270,000 participants and weighted burden analysis to test for association with hyperlipidaemia was carried out in this sample for the 47 genes highlighted by the previous study. There was no evidence to implicateIFITM5 butLDLR,PCSK9,APOC3,ANGPTL3,ABCG5 andNPC1L1 were all statistically significant after correction for multiple testing. These six genes were also all exome-wide significant in the combined sample of 470,000 participants. Variants impairing function ofLDLR andABCG5 were associated with increased risk whereas variants in the other genes were protective. Variant categories associated with large effect sizes are cumulatively very rare and the main benefit of this kind of study seems to be to throw light on the molecular mechanisms impacting hyperlipidaemia risk, hopefully supporting attempts to develop improved therapies.

Source: Journal of Human Genetics - March 7, 2024 Category: Genetics & Stem Cells Source Type: research