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A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance
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Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
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Metadata
- Authors
- Manning, A. K., Hivert, M.-F., Scott, R. A., Grimsby, J. L., Bouatia-Naji, N., Chen, H., Rybin, D., Liu, C.-T., Bielak, L. F., Prokopenko, I., Amin, N., Barnes, D., Cadby, G., Hottenga, J.-J., Ingelsson, E., Jackson, A. U., Johnson, T., Kanoni, S., Ladenvall, C., Lagou, V., Lahti, J., Lecoeur, C., Liu, Y., Martinez-Larrad, M. T., Montasser, M. E., Navarro, P., Perry, J. R. B., Rasmussen-Torvik, L. J., Salo, P., Sattar, N., Shungin, D., Strawbridge, R. J., Tanaka, T., van Duijn, C. M., An, P., de Andrade, M., Andrews, J. S., Aspelund, T., Atalay, M., Aulchenko, Y., Balkau, B., Bandinelli, S., Beckmann, J. S., Beilby, J. P., Bellis, C., Bergman, R. N., Blangero, J., Boban, M., Boehnke, M., Boerwinkle, E., Bonnycastle, L. L., Boomsma, D. I., Borecki, I. B., Böttcher, Y., Bouchard, C., Brunner, E., Budimir, D., Campbell, H., Carlson, O., Chines, P. S., Clarke, R., Collins, F. S., Corbatón-Anchuelo, A., Couper, D., de Faire, U., Dedoussis, G. V., Deloukas, P., Dimitriou, M., Egan, J. M., Eiriksdottir, G., Erdos, M. R., Eriksson, J. G., Eury, E., Ferrucci, L., Ford, I., Forouhi, N. G., Fox, C. S., Franzosi, M. G., Franks, P. W., Frayling, T. M., Froguel, P., Galan, P., de Geus, E., Gigante, B., Glazer, N. L., Goel, A., Groop, L., Gudnason, V., Hallmans, G., Hamsten, A., Hansson, O., Harris, T. B., Hayward, C., Heath, S., Hercberg, S., Hicks, A. A., Hingorani, A., Hofman, A., Hui, J., Hung, J., Jarvelin, M.-R., Jhun, M. A., Johnson, P. C. D., Jukema, J. W., Jula, A., Kao, W. H., Kaprio, J., Kardia, S. L. R., Keinanen-Kiukaanniemi, S., Kivimaki, M., Kolcic, I., Kovacs, P., Kumari, M., Kuusisto, J., Kyvik, K. O., Laakso, M., Lakka, T., Lannfelt, L., Lathrop, G. M., Launer, L. J., Leander, K., Li, G., Lind, L., Lindstrom, J., Lobbens, S., Loos, R. J. F., Luan, J., Lyssenko, V., Mägi, R., Magnusson, P. K. E., Marmot, M., Meneton, P., Mohlke, K. L., Mooser, V., Morken, M. A., Miljkovic, I., Narisu, N., O'Connell, J., Ong, K. K., Oostra, B. A., Palmer, L. J., Palotie, A., Pankow, J. S., Peden, J. F., Pedersen, N. L., Pehlic, M., Peltonen, L., Penninx, B., Pericic, M., Perola, M., Perusse, L., Peyser, P. A., Polasek, O., Pramstaller, P. P., Province, M. A., Räikkönen, K., Rauramaa, R., Rehnberg, E., Rice, K., Rotter, J. I., Rudan, I., Ruokonen, A., Saaristo, T., Sabater-Lleal, M., Salomaa, V., Savage, D. B., Saxena, R., Schwarz, P., Seedorf, U., Sennblad, B., Serrano-Rios, M., Shuldiner, A. R., Sijbrands, E. J. G., Siscovick, D. S., Smit, J. H., Small, K. S., Smith, N. L., Smith, A. V., Stančáková, A., Stirrups, K., Stumvoll, M., Sun, Y. V., Swift, A. J., Tönjes, A., Tuomilehto, J., Trompet, S., Uitterlinden, A. G., Uusitupa, M., Vikström, M., Vitart, V., Vohl, M.-C., Voight, B. F., Vollenweider, P., Waeber, G., Waterworth, D. M., Watkins, H., Wheeler, E., Widen, E., Wild, S. H., Willems, S. M., Willemsen, G., Wilson, J. F., Witteman, J. C. M., Wright, A. F., Yaghootkar, H., Zelenika, D., Zemunik, T., Zgaga, L., DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, The Multiple Tissue Human Expression Resource (MUTHER) Consortium, Wareham, N. J., McCarthy, M. I., Barroso, I., Watanabe, R. M., Florez, J. C., Dupuis, J., Meigs, J. B., & Langenberg, C.
- Venue
- Nature Genetics
- Published
- 2012-05-13
- Volume
- 44
- Issue
- 6
- Pages
- 659-669
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2093362931
- Cited by
- 827
- References
- 84
- FWCI
- 36.14
- Type
- journal article
- Language
- en
- Open access
- green
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.