학술논문
Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
Document Type
article
Author
Albrechtsen, A; Grarup, N; Li, Y; Sparsø, T; Tian, G; Cao, H; Jiang, T; Kim, SY; Korneliussen, T; Li, Q; Nie, C; Wu, R; Skotte, L; Morris, AP; Ladenvall, C; Cauchi, S; Stančáková, A; Andersen, G; Astrup, A; Banasik, K; Bennett, AJ; Bolund, L; Charpentier, G; Chen, Y; Dekker, JM; Doney, ASF; Dorkhan, M; Forsen, T; Frayling, TM; Groves, CJ; Gui, Y; Hallmans, G; Hattersley, AT; He, K; Hitman, GA; Holmkvist, J; Huang, S; Jiang, H; Jin, X; Justesen, JM; Kristiansen, K; Kuusisto, J; Lajer, M; Lantieri, O; Li, W; Liang, H; Liao, Q; Liu, X; Ma, T; Ma, X; Manijak, MP; Marre, M; Mokrosiński, J; Morris, AD; Mu, B; Nielsen, AA; Nijpels, G; Nilsson, P; Palmer, CNA; Rayner, NW; Renström, F; Ribel-Madsen, R; Robertson, N; Rolandsson, O; Rossing, P; Schwartz, TW; Slagboom, PE; Sterner, M; D.E.S.I.R. Study Group; Tang, M; Tarnow, L; the DIAGRAM Consortium; Tuomi, T; van’t Riet, E; van Leeuwen, N; Varga, TV; Vestmar, MA; Walker, M; Wang, B; Wang, Y; Wu, H; Xi, F; Yengo, L; Yu, C; Zhang, X; Zhang, J; Zhang, Q; Zhang, W; Zheng, H; Zhou, Y; Altshuler, D; ‘t Hart, LM; Franks, PW; Balkau, B; Froguel, P; McCarthy, MI; Laakso, M; Groop, L; Christensen, C; Brandslund, I
Source
Diabetologia. 56(2)
Subject
Language
Abstract
Aims/hypothesisHuman 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.MethodsThe 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/interpretationWe 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.