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

Albrechtsen, A., Grarup, N., Li, Y., Sparso, T., Tian, G., Cao, H., Jiang, T., Kim, S. Y., Korneliussen, T., Li, Q., Nie, C., Wu, R., Skotte, L., Morris, A. P., Ladenvall, C., Cauchi, S., Stancakova, A., Andersen, G., Astrup, A., Banasik, K., Bennett, A. J., Bolund, L., Charpentier, G., Chen, Y., Dekker, J. M., Doney, A. S. F., Dorkhan, M., Forsen, T., Frayling, T. M., Groves, C. J., Gui, Y., Hallmans, G., Hattersley, A. T., He, K., Hitman, G. A., Holmkvist, J., Huang, S., Jiang, H., Jin, X., Justesen, J. M., Kristiansen, K., Kuusisto, J., Lajer, M., Lantieri, O., Li, W., Liang, H., Liao, Q., Liu, X., Ma, T., Ma, X., Manijak, M. P., Marre, M., Mokrosinski, J., Morris, A. D., Mu, B., Nielsen, A. A., Nijpels, G., Nilsson, P., Palmer, C. N. A., Rayner, N. W., Renstrom, F., Ribel-Madsen, R., Robertson, N., Rolandsson, O., Rossing, P., Schwartz, T. W., Slagboom, P. E., Sterner, M., Tang, M., Tarnow, L., Tuomi, T., van't Riet, E., van Leeuwen, N., Varga, T. V., Vestmar, M. A., 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, L. M., Franks, P. W., Balkau, B., Froguel, P., McCarthy, M. I., Laakso, M., Groop, L., Christensen, C., Brandslund, I., Lauritzen, T., Witte, D. R., Linneberg, A., Jorgensen, T., Hansen, T., Wang, J., Nielsen, R. and Pedersen, O. (2013) Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia, 56 2: 298-310. doi:10.1007/s00125-012-2756-1


Author Albrechtsen, A.
Grarup, N.
Li, Y.
Sparso, T.
Tian, G.
Cao, H.
Jiang, T.
Kim, S. Y.
Korneliussen, T.
Li, Q.
Nie, C.
Wu, R.
Skotte, L.
Morris, A. P.
Ladenvall, C.
Cauchi, S.
Stancakova, A.
Andersen, G.
Astrup, A.
Banasik, K.
Bennett, A. J.
Bolund, L.
Charpentier, G.
Chen, Y.
Dekker, J. M.
Doney, A. S. F.
Dorkhan, M.
Forsen, T.
Frayling, T. M.
Groves, C. J.
Gui, Y.
Hallmans, G.
Hattersley, A. T.
He, K.
Hitman, G. A.
Holmkvist, J.
Huang, S.
Jiang, H.
Jin, X.
Justesen, J. M.
Kristiansen, K.
Kuusisto, J.
Lajer, M.
Lantieri, O.
Li, W.
Liang, H.
Liao, Q.
Liu, X.
Ma, T.
Ma, X.
Manijak, M. P.
Marre, M.
Mokrosinski, J.
Morris, A. D.
Mu, B.
Nielsen, A. A.
Nijpels, G.
Nilsson, P.
Palmer, C. N. A.
Rayner, N. W.
Renstrom, F.
Ribel-Madsen, R.
Robertson, N.
Rolandsson, O.
Rossing, P.
Schwartz, T. W.
Slagboom, P. E.
Sterner, M.
Tang, M.
Tarnow, L.
Tuomi, T.
van't Riet, E.
van Leeuwen, N.
Varga, T. V.
Vestmar, M. A.
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, L. M.
Franks, P. W.
Balkau, B.
Froguel, P.
McCarthy, M. I.
Laakso, M.
Groop, L.
Christensen, C.
Brandslund, I.
Lauritzen, T.
Witte, D. R.
Linneberg, A.
Jorgensen, T.
Hansen, T.
Wang, J.
Nielsen, R.
Pedersen, O.
Title Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
Journal name Diabetologia   Check publisher's open access policy
ISSN 0012-186X
1432-0428
Publication date 2013-02-01
Year available 2012
Sub-type Article (original research)
DOI 10.1007/s00125-012-2756-1
Open Access Status Not yet assessed
Volume 56
Issue 2
Start page 298
End page 310
Total pages 13
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
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/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case–control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans.

Results
Exome sequencing identified 70,182 polymorphisms with MAF >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.
Keyword Exome sequencing
Genetic epidemiology
Genetics
Lipids
Next-generation sequencing
Obesity
Type 2 diabetes
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 5263
G0000649
GR072960
RP-PG-0310-1002
G0000934
ENGAGE: HEALTH-F4-2007-201413
2006.00.060
Dnr-349-2006-6589
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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