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

Anders Albrechtsen, Niels Grarup, Y Li, Thomas Hempel Sparsø, G Tian, H Cao, T Jiang, S Y Kim, T Korneliussen, Q Li, C Nie, R Wu, Line Skotte, A P Morris, C Ladenvall, S Cauchi, A Stančáková, G Andersen, A Astrup, Karina BanasikA J Bennett, L 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, J M Justesen, K Kristiansen, J Kuusisto, M Lajer, O Lantieri, W Li, Hong Liang, Q Liao, A A Nielsen, C Christensen, I Brandslund, D.E.S.I.R. Study Group

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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.
Udgave nummer2
Sider (fra-til)298-310
Antal sider13
StatusUdgivet - 2013

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