title: Detailed metabolic and genetic characterization reveals new associations for 30 known lipid loci.
abstract: Almost 100 genetic loci are known to affect serum cholesterol and triglyceride levels. For many of these loci, the biological function and causal variants remain unknown. We performed an association analysis of the reported 95 lipid loci against 216 metabolite measures, including 95 measurements on lipids and lipoprotein subclasses, obtained via serum nuclear magnetic resonance metabolomics and four enzymatic lipid traits in 8330 individuals from Finland. The genetic variation in the loci was investigated using a dense set of 440 807 directly genotyped and imputed variants around the previously identified lead single nucleotide polymorphisms (SNPs). For 30 of the 95 loci, we identified new metabolic or genetic associations (P < 5 × 10(-8)). In the majority of the loci, the strongest association was to a more specific metabolite measure than the enzymatic lipids. In four loci, the smallest high-density lipoprotein measures showed effects opposite to the larger ones, and 14 loci had associations beyond the individual lipoprotein measures. In 27 loci, we identified SNPs with a stronger association than the previously reported markers and 12 loci harboured multiple, statistically independent variants. Our data show considerable diversity in association patterns between the loci originally identified through associations with enzymatic lipid measures and reveal association profiles of far greater detail than from routine clinical lipid measures. Additionally, a dense marker set and a homogeneous population allow for detailed characterization of the genetic association signals to a resolution exceeding that achieved so far. Further understanding of the rich variability in genetic effects on metabolites provides insights into the biological processes modifying lipid levels.
authors.affiliation: Institute for Molecular Medicine Finland FIMM, Helsinki University Hospital, FI-00014 University of Helsinki, Helsinki, Finland.
authors.forename: Taru
authors.initials: T
authors.lastname: Tukiainen
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Kangas
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Sarin
authors.forename: Emmi
authors.initials: E
authors.lastname: Tikkanen
authors.forename: Paul F
authors.initials: PF
authors.lastname: O'Reilly
authors.forename: Markku J
authors.initials: MJ
authors.lastname: Savolainen
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kaski
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Jorma
authors.initials: J
authors.lastname: Viikari
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.forename: Olli
authors.initials: O
authors.lastname: Raitakari
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Mika
authors.initials: M
authors.lastname: Ala-Korpela
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D005260:Female; D005387:Finland / Q000453:epidemiology; D005500:Follow-Up Studies; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism*; D008137:Longitudinal Studies; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D055432:Metabolomics; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors
chemical_list: D008074:Lipoproteins