TY - JOUR
T1 - Detailed metabolic and genetic characterization reveals new associations for 30 known lipid loci
AU - Tukiainen, Taru
AU - Kettunen, Johannes
AU - Kangas, Antti J.
AU - Lyytikäinen, Leo-Pekka
AU - Soininen, Pasi
AU - Sarin, Antti-Pekka
AU - Tikkanen, Emmi
AU - O'reilly, Paul F.
AU - Savolainen, Markku J.
AU - Kaski, Kimmo
AU - Pouta, Anneli
AU - Jula, Antti
AU - Lehtimäki, Terho
AU - Kähönen, Mika
AU - Viikari, Jorma
AU - Taskinen, Marja-Riitta
AU - Jauhiainen, Matti
AU - Eriksson, Johan G.
AU - Raitakari, Olli
AU - Salomaa, Veikko
AU - Järvelin, Marjo-Riitta
AU - Perola, Markus
AU - Palotie, Aarno
AU - Ala-Korpela, Mika
AU - Ripatti, Samuli
PY - 2012/3
Y1 - 2012/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84857684406&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddr581
DO - 10.1093/hmg/ddr581
M3 - Article
C2 - 22156771
AN - SCOPUS:84857684406
SN - 0964-6906
VL - 21
SP - 1444
EP - 1455
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 6
M1 - ddr581
ER -