TY - JOUR T1 - Novel Loci for Metabolic Networks and Multi-Tissue Expression Studies Reveal Genes for Atherosclerosis A1 - Inouye, Michael A1 - Ripatti, Samuli A1 - Kettunen, Johannes A1 - Lyytikäinen, Leo-Pekka A1 - Oksala, Niku A1 - Laurila, Pirkka-Pekka A1 - Kangas, Antti J. A1 - Soininen, Pasi A1 - Savolainen, Markku J. A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Perola, Markus A1 - Salomaa, Veikko A1 - Raitakari, Olli A1 - Lehtimäki, Terho A1 - Taskinen, Marja-Riitta A1 - Järvelin, Marjo-Riitta A1 - Ala-Korpela, Mika A1 - Palotie, Aarno A1 - de Bakker, Paul I. W. Y1 - 2012/08/16 N2 - Author Summary In this study, we aim to identify novel genetic variants for metabolism, characterize their effects on nearby genes, and show that the nearby genes are associated with metabolism and atherosclerosis. To discover new genetic variants, we use an alternative approach to traditional genome-wide association studies: we leverage the information in phenotype covariance to increase our statistical power. We identify variants at seven novel loci and then show that our top signals drive expression of nearby genes AQP9 and SERPINA1 in multiple tissues. We demonstrate that AQP9 and SERPINA1 gene expression, in turn, is associated with metabolite levels. Finally, we show that the genes are associated with atherosclerosis using mouse atherosclerotic lesion size (AQP9) as well as tissue from healthy human arteries and atherosclerotic plaques (AQP9 and SERPINA1). This study illustrates that multivariate analysis of correlated metabolites can boost power for gene discovery substantially. Further functional work will need to be performed to elucidate the biological role of SERPINA1 and AQP9 in atherosclerosis. JF - PLOS Genetics JA - PLOS Genetics VL - 8 IS - 8 UR - https://doi.org/10.1371/journal.pgen.1002907 SP - e1002907 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pgen.1002907 ER -