Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

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Anders Albrechtsen, Niels Grarup, Y. Li, Thomas Hempel Sparsø, G. Tian, H. Cao, T. Jiang, S.Y. Kim, Thorfinn Sand Korneliussen, Q. Li, C. Nie, R. Wu, Line Skotte, A.P. Morris, C. Ladenvall, S. Cauchi, A. Stancáková, G. Andersen, Arne Astrup, Karina Banasik & 86 others A.J. Bennett, Lars Bolund, G. Charpentier, Y. Chen, J.M. Dekker, A.S.F. Doney, M. Dorkhan, T. Forsen, T.M. Frayling, C.J. Groves, Y. Gui, G. Hallmans, A.T. Hattersley, K. He, G.A. Hitman, J. Holmkvist, S. Huang, H. Jiang, X. Jin, Johanne Marie Justesen, Karsten Kristiansen, J. Kuusisto, M. Lajer, O. Lantieri, W. Li, H. Liang, Q. Liao, X. Liu, T. Ma, X. Ma, M.P. Manijak, M. Marre, Jacek Mokrosinski, A.D. Morris, B. Mu, A.A. Nielsen, G. Nijpels, P. Nilsson, C.N.A. Palmer, N.W. Rayner, F. Renström, Rasmus Ribel-Madsen, N. Robertson, O. Rolandsson, P. Rossing, Thue W. Schwartz, P.E. Slagboom, M. Sterner, M. Tang, L. Tarnow, T. Tuomi, E. Van't Riet, N. van Leeuwen, T.V. Varga, Marie Aare Vestmar, M. Walker, B. Wang, Y. Wang, H. Wu, F. Xi, L. Yengo, C. Yu, X. Zhang, J. Zhang, Q. Zhang, W. Zhang, H. Zheng, Y. Zhou, D. Altshuler, L.M. 't Hart, P.W. Franks, B. Balkau, P. Froguel, M.I. McCarthy, M. Laakso, L. Groop, C. Christensen, I. Brandslund, T. Lauritzen, D.R. Witte, A. Linneberg, Torben Jørgensen, Torben Hansen, Jun Wang, Rasmus Nielsen, Oluf Pedersen

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p¿1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p¿=¿8.5¿×¿10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p¿=¿1.2¿×¿10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p¿=¿8.2¿×¿10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Original languageEnglish
Issue number2
Pages (from-to)298-310
Number of pages13
Publication statusPublished - 2013

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