GWAS of lipids in Greenlanders finds association signals shared with Europeans and reveals an independent PCSK9 association signal
Perturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, trigly...
Published in: | European Journal of Human Genetics |
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Main Authors: | , , , , , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
2024
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Subjects: | |
Online Access: | https://portal.findresearcher.sdu.dk/da/publications/742ff7de-b9f1-4929-b920-fffb1a71e19d https://doi.org/10.1038/s41431-023-01485-8 https://findresearcher.sdu.dk/ws/files/255818891/s41431-023-01485-8.pdf |
Summary: | Perturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with lipid traits. Most of these loci were already known in Europeans, however, we found a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (β SD (SE) = −0.22 (0.03), p = 6.5 × 10 −12 ) and total cholesterol (−0.17 (0.03), p = 1.1 × 10 −8 ) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance. [Figure not available: see fulltext.]. |
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