GWAS of lipids in Greenlanders finds association signals shared with Europeans and reveals an independent PCSK9 association signal.

Autor: Senftleber NK; Clinical Research, Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark.; Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Andersen MK; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jørsboe E; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom.; Nuffield Department of Population Health, University of Oxford, Oxford, UK., Stæger FF; Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Nøhr AK; Center for Clinical Data Science, Department of Clinical Medicine, Aalborg University and Research, Education, and Innovation, Aalborg University Hospital, Aalborg, Denmark., Garcia-Erill G; Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Meisner J; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Santander CG; Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Balboa RF; Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Gilly A; Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany., Bjerregaard P; Centre for Public Health in Greenland, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark., Larsen CVL; Centre for Public Health in Greenland, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.; Greenland Center for Health Research, Institute for Health and Nature, University of Greenland, Nuuk, Greenland., Grarup N; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jørgensen ME; Clinical Research, Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark.; Centre for Public Health in Greenland, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.; Steno Diabetes Center Greenland, Nuuk, Greenland., Zeggini E; Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.; Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Munich, Germany., Moltke I; Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark. ida@binf.ku.dk., Hansen T; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. torben.hansen@sund.ku.dk., Albrechtsen A; Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark. albrecht@binf.ku.dk.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Feb; Vol. 32 (2), pp. 215-223. Date of Electronic Publication: 2023 Oct 30.
DOI: 10.1038/s41431-023-01485-8
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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