Common variants at 30 loci contribute to polygenic dyslipidemia
Open accessAbstract
Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
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The observed association with AMD is likely caused by the functional variant rs10468017.
“Therefore, we concluded that the observed association with AMD is likely caused by this functional variant that has been identified in genetic studies of HDL levels ([25](#r25)).”
From Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( <i>LIPC</i> ) (2010) · cites this paper as [25]
The minor T allele of rs10468017 is associated with reduced LIPC expression and higher HDL.
“the minor allele T, previously associated with reduced LIPC expression and higher HDL”
From Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( <i>LIPC</i> ) (2010) · cites this paper as [25]
Genome-wide association studies have uncovered multiple loci associated with high levels of triglyceride.
“Finally, genome-wide association studies have uncovered multiple loci associated with high levels of triglyceride.150”
From Triglycerides and Cardiovascular Disease: A Scientific Statement From the American Heart Association (2011) · cites this paper as [150]
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- Authors
- Kathiresan, S., Willer, C. J., Peloso, G. M., Demissie, S., Musunuru, K., Schadt, E. E., Kaplan, L., Bennett, D., Li, Y., Tanaka, T., Voight, B. F., Bonnycastle, L. L., Jackson, A. U., Crawford, G., Surti, A., Guiducci, C., Burtt, N. P., Parish, S., Clarke, R., Zelenika, D., Kubalanza, K. A., Morken, M. A., Scott, L. J., Stringham, H. M., Galan, P., Swift, A. J., Kuusisto, J., Bergman, R. N., Sundvall, J., Laakso, M., Ferrucci, L., Scheet, P., Sanna, S., Uda, M., Yang, Q., Lunetta, K. L., Dupuis, J., de Bakker, P. I. W., O'Donnell, C. J., Chambers, J. C., Kooner, J. S., Hercberg, S., Meneton, P., Lakatta, E. G., Scuteri, A., Schlessinger, D., Tuomilehto, J., Collins, F. S., Groop, L., Altshuler, D., Collins, R., Lathrop, G. M., Melander, O., Salomaa, V., Peltonen, L., Orho-Melander, M., Ordovas, J. M., Boehnke, M., Abecasis, G. R., Mohlke, K. L., & Cupples, L. A.
- Affiliations
- Broad Institute (US)
- University of Michigan (US)
- Boston University (US)
- Massachusetts General Hospital (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- University of Oxford (GB)
- National Institutes of Health (US)
- Conservatoire National des Arts et Métiers (FR)
- University of Eastern Finland (FI)
- University of Southern California (US)
- National Research Council (IT)
- Imperial College London (GB)
- Hammersmith Hospital (GB)
- Inserm (FR)
- National Institute on Aging (US)
- Istituto Nazionale di Riposo e Cura per Anziani (IT)
- Lund University (SE)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Kathiresan, Sekar
- Abecasis, Gonçalo R
- Mohlke, Karen L
- Cupples, L Adrienne
- ORCID
- Kathiresan, Sekar
- Willer, Cristen J
- Peloso, Gina M
- Demissie, Serkalem
- Kaplan, Lee
- Bennett, Derrick
- Li, Yun
- Tanaka, Toshiko
- Voight, Benjamin F
- Bonnycastle, Lori L
- Jackson, Anne U
- Parish, Sarah
- Clarke, Robert
- Scott, Laura J
- Stringham, Heather M
- Galan, Pilar
- Kuusisto, Johanna
- Bergman, Richard N
- Laakso, Markku
- Ferrucci, Luigi
- Scheet, Paul
- Sanna, Serena
- Uda, Manuela
- Yang, Qiong
- Lunetta, Kathryn L
- Dupuis, Josée
- Chambers, John C
- Kooner, Jaspal S
- Meneton, Pierre
- Lakatta, Edward G
- Scuteri, Angelo
- Schlessinger, David
- Tuomilehto, Jaakko
- Collins, Francis S
- Groop, Leif
- Altshuler, David
- Collins, Rory
- Melander, Olle
- Salomaa, Veikko
- Peltonen, Leena
- Boehnke, Michael
- Abecasis, Gonçalo R
- Mohlke, Karen L
- Cupples, L Adrienne
- Venue
- Nature Genetics
- Published
- 2008-12-07
- Volume
- 41
- Issue
- 1
- Pages
- 56-65
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2881676
- OpenAlex
- W2105281057
- Cited by
- 1,364
- References
- 58
- Citations by year
- 2026: 13 · 2025: 23 · 2024: 37 · 2023: 40 · 2022: 41 · 2021: 51 · 2020: 52 · 2019: 57 · 2018: 64 · 2017: 70 · 2016: 69 · 2015: 77 · 2014: 112 · 2013: 106 · 2012: 123
- FWCI
- 81.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Wellcome Trust (089061)
- Cancer Research UK
- National Institute for Health and Care Research
- British Heart Foundation
- National Institutes of Health (n01hg065403-000, 5k23hl083102-02, n01hc25195-41-0-1)
- U.S. Public Health Service (53 K06 510)
- National Heart, Lung, and Blood Institute (K23-HL-083102, HL54776, U01HL084729, N01‐HC25195, HL-084729, N01-HC-025195, R01HL054776)
- National Human Genome Research Institute (Z01HG000024, HG02651, R01HG002651, N01 HG065403)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-072193, R01DK072193, U01DK062370, R56DK062370, R01DK029867, DK-062370, R01DK075030, P30DK040561, R01DK062370)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- LDL cholesterol, HDL cholesterol, triglycerides, lipoprotein concentration, genetic loci, common genetic variants, cardiovascular risk, ABCG8, ANGPTL4, HNF4α, lecithin:cholesterol acyltransferase, phospholipid transfer protein, hypercholesterolemia, hypertriglyceridemia
- MeSH terms
- Delta-5 Fatty Acid Desaturase, Adult, Alleles, Female, Gene Expression Regulation, Humans, Cholesterol, HDL, Cholesterol, LDL, Liver, Male, Middle Aged, Phenotype, RNA, Messenger, Syndrome, Triglycerides, Meta-Analysis as Topic, Reproducibility of Results, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Dyslipidemias, Genome-Wide Association Study
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