Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
21448234
TITLE
Genetic architecture of circulating lipid levels.
ABSTRACT
Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
DATE PUBLISHED
2011 Jul
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2011/03/30
entrez 2011/03/31 06:00
pubmed 2011/03/31 06:00
medline 2011/10/06 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Demirkan A Demirkan Ayşe A Genetic Epidemiology Unit, Department of Epidemiology and Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Amin N Amin Najaf N
Isaacs A Isaacs Aaron A
Jarvelin MR Jarvelin Marjo-Riitta MR
Whitfield JB Whitfield John B JB
Wichmann HE Wichmann Heinz-Erich HE
Kyvik KO Kyvik Kirsten O H M KO
Rudan I Rudan Igor I
Gieger C Gieger Christian C
Hicks AA Hicks Andrew A AA
Johansson Å Johansson Åsa
Hottenga JJ Hottenga Jouke-Jan JJ
Smith JJ Smith Johannes J JJ
Wild SH Wild Sarah H SH
Pedersen NL Pedersen Nancy L NL
Willemsen G Willemsen Gonneke G
Mangino M Mangino Massimo M
Hayward C Hayward Caroline C
Uitterlinden AG Uitterlinden André G AG
Hofman A Hofman Albert A
Witteman J Witteman Jacqueline J
Montgomery GW Montgomery Grant W GW
Pietiläinen KH Pietiläinen Kirsi H KH
Rantanen T Rantanen Taina T
Kaprio J Kaprio Jaakko J
Döring A Döring Angela A
Pramstaller PP Pramstaller Peter P PP
Gyllensten U Gyllensten Ulf U
de Geus EJ de Geus Eco J C EJ
Penninx BW Penninx Brenda W BW
Wilson JF Wilson James F JF
Rivadeneria F Rivadeneria Fernando F
Magnusson PK Magnusson Patrik K E PK
Boomsma DI Boomsma Dorret I DI
Spector T Spector Tim T
Campbell H Campbell Harry H
Hoehne B Hoehne Birgit B
Martin NG Martin Nicholas G NG
Oostra BA Oostra Ben A BA
McCarthy M McCarthy Mark M
Peltonen-Palotie L Peltonen-Palotie Leena L
Aulchenko Y Aulchenko Yurii Y
Visscher PM Visscher Peter M PM
Ripatti S Ripatti Samuli S
Janssens AC Janssens A Cecile J W AC
van Duijn CM van Duijn Cornelia M CM
ENGAGE CONSORTIUM
INVESTIGATORS
JOURNAL
VOLUME: 19
ISSUE: 7
TITLE: European journal of human genetics : EJHG
ISOABBREVIATION: Eur. J. Hum. Genet.
YEAR: 2011
MONTH: Jul
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-5438
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Eur J Hum Genet
COUNTRY: England
ISSNLINKING: 1018-4813
NLMUNIQUEID: 9302235
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
090532 Wellcome Trust United Kingdom
CZB/4/710 Chief Scientist Office United Kingdom
MC_U127561128 Medical Research Council United Kingdom
Chief Scientist Office United Kingdom
Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Female
Genome-Wide Association Study
Humans
Lipid Metabolism genetics
Lipids genetics
Male genetics
Metabolic Networks and Pathways genetics
Models, Genetic genetics
Phenotype genetics
Polymorphism, Single Nucleotide genetics
Quantitative Trait Loci genetics
Risk genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Lipids
OTHER ID's
OTHERID SOURCE
PMC3137496 NLM