Show simple item record

dc.contributor.authorAltshuler, David
dc.date.accessioned2015-04-27T13:30:30Z
dc.date.available2015-04-27T13:30:30Z
dc.date.issued2014-08
dc.date.submitted2014-06
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/96818
dc.description.abstractPeroxisome proliferator-activated receptor gamma (PPARG) is a master transcriptional regulator of adipocyte differentiation and a canonical target of antidiabetic thiazolidinedione medications. In rare families, loss-of-function (LOF) mutations in PPARG are known to cosegregate with lipodystrophy and insulin resistance; in the general population, the common P12A variant is associated with a decreased risk of type 2 diabetes (T2D). Whether and how rare variants in PPARG and defects in adipocyte differentiation influence risk of T2D in the general population remains undetermined. By sequencing PPARG in 19,752 T2D cases and controls drawn from multiple studies and ethnic groups, we identified 49 previously unidentified, nonsynonymous PPARG variants (MAF < 0.5%). Considered in aggregate (with or without computational prediction of functional consequence), these rare variants showed no association with T2D (OR = 1.35; P = 0.17). The function of the 49 variants was experimentally tested in a novel high-throughput human adipocyte differentiation assay, and nine were found to have reduced activity in the assay. Carrying any of these nine LOF variants was associated with a substantial increase in risk of T2D (OR = 7.22; P = 0.005). The combination of large-scale DNA sequencing and functional testing in the laboratory reveals that approximately 1 in 1,000 individuals carries a variant in PPARG that reduces function in a human adipocyte differentiation assay and is associated with a substantial risk of T2D.en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1410428111en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceNational Academy of Sciences (U.S.)en_US
dc.titleRare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetesen_US
dc.typeArticleen_US
dc.identifier.citationMajithia, A. R., J. Flannick, P. Shahinian, M. Guo, M.-A. Bray, P. Fontanillas, S. B. Gabriel, et al. “Rare Variants in PPARG with Decreased Activity in Adipocyte Differentiation Are Associated with Increased Risk of Type 2 Diabetes.” Proceedings of the National Academy of Sciences 111, no. 36 (August 25, 2014): 13127–13132.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorAltshuler, Daviden_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsMajithia, A. R.; Flannick, J.; Shahinian, P.; Guo, M.; Bray, M.-A.; Fontanillas, P.; Gabriel, S. B.; Rosen, E. D.; Altshuler, D.; Flannick, J.; Manning, A. K.; Hartl, C.; Agarwala, V.; Fontanillas, P.; Green, T.; Banks, E.; DePristo, M.; Poplin, R.; Shakir, K.; Fennell, T.; Njolstad, P. R.; Altshuler, D.; Burtt, N.; Gabriel, S.; Fuchsberger, C.; Kang, H. M.; Sim, X.; Ma, C.; Locke, A.; Blackwell, T.; Jackson, A.; Teslovich, T. M.; Stringham, H.; Chines, P.; Kwan, P.; Huyghe, J.; Tan, A.; Jun, G.; Stitzel, M.; Bergman, R. N.; Bonnycastle, L.; Tuomilehto, J.; Collins, F. S.; Scott, L.; Mohlke, K.; Abecasis, G.; Boehnke, M.; Strom, T.; Gieger, C.; Nurasyid, M. M.; Grallert, H.; Kriebel, J.; Ried, J.; Hrabe de Angelis, M.; Huth, C.; Meisinger, C.; Peters, A.; Rathmann, W.; Strauch, K.; Meitinger, T.; Kravic, J.; Algren, P.; Ladenvall, C.; Toumi, T.; Isomaa, B.; Groop, L.; Gaulton, K.; Moutsianas, L.; Rivas, M.; Pearson, R.; Mahajan, A.; Prokopenko, I.; Kumar, A.; Perry, J.; Howie, B.; van de Bunt, M.; Small, K.; Lindgren, C.; Lunter, G.; Robertson, N.; Rayner, W.; Morris, A.; Buck, D.; Hattersley, A.; Spector, T.; McVean, G.; Frayling, T.; Donnelly, P.; McCarthy, M.; Gupta, N.; Taylor, H.; Fox, E.; Cheh, C. N.; Wilson, J. G.; O'Donnell, C. J.; Kathiresan, S.; Hirschhorn, J.; Seidman, J. G.; Gabriel, S.; Seidman, C.; Altshuler, D.; Williams, A. L.; Jacobs, S. B. R.; Macias, H. M.; Chagoya, A. H.; Churchhouse, C.; Luna, C. M.; Ortiz, H. G.; Vazquez, M. J. G.; Burtt, N. P.; Estrada, K.; Mercader, J. M.; Ripke, S.; Manning, A. K.; Neale, B.; Stram, D. O.; Lopez, J. C. F.; Hidalgo, S. R.; Delfin, I. A.; Hernandez, A. M.; Cruz, F. C.; Caamal, E. M.; Monsalve, C. R.; Andrade, S. I.; Cordova, E.; Arellano, E. R.; Soberon, X.; Villalpando, M. E. G.; Monroe, K.; Wilkens, L.; Kolonel, L. N.; Le Marchand, L.; Riba, L.; Sanchez, M. L. O.; Guillen, R. R.; Bautista, I. C.; Torres, M. R.; Hernandez, L. L. M.; Saenz, T.; Gomez, D.; Alvirde, U.; Onofrio, R. C.; Brodeur, W. M.; Gage, D.; Murphy, J.; Franklin, J.; Mahan, S.; Ardlie, K.; Crenshaw, A. T.; Winckler, W.; Fennell, T.; MacArthur, D. G.; Altshuler, D.; Florez, J. C.; Haiman, C. A.; Henderson, B. E.; Salinas, C. A. A.; Villalpando, C. G.; Orozco, L.; Luna, T. T.; Abecasis, G.; Almeida, M.; Altshuler, D.; Asimit, J. L.; Atzmon, G.; Barber, M.; Beer, N. L.; Bell, G. I.; Below, J.; Blackwell, T.; Blangero, J.; Boehnke, M.; Bowden, D. W.; Burtt, N.; Chambers, J.; Chen, H.; Chen, P.; Chines, P. S.; Choi, S.; Churchhouse, C.; Cingolani, P.; Cornes, B. K.; Cox, N.; Williams, A. G. D.; Duggirala, R.; Dupuis, J.; Dyer, T.; Feng, S.; Tajes, J. F.; Ferreira, T.; Fingerlin, T. E.; Flannick, J.; Florez, J.; Fontanillas, P.; Frayling, T. M.; Fuchsberger, C.; Gamazon, E. R.; Gaulton, K.; Ghosh, S.; Gloyn, A.; Grossman, R. L.; Grundstad, J.; Hanis, C.; Heath, A.; Highland, H.; Hirokoshi, M.; Huh, I.-S.; Huyghe, J. R.; Ikram, K.; Jablonski, K. A.; Kim, Y. J.; Jun, G.; Kato, N.; Kim, J.; King, C. R.; Kooner, J.; Kwon, M.-S.; Im, H. K.; Laakso, M.; Lam, K. K.-Y.; Lee, J.; Lee, S.; Lee, S.; Lehman, D. M.; Li, H.; Lindgren, C. M.; Liu, X.; Livne, O. E.; Locke, A. E.; Mahajan, A.; Maller, J. B.; Manning, A. K.; Maxwell, T. J.; Mazoure, A.; McCarthy, M. I.; Meigs, J. B.; Min, B.; Mohlke, K. L.; Morris, A.; Musani, S.; Nagai, Y.; Ng, M. C. Y.; Nicolae, D.; Oh, S.; Palmer, N.; Park, T.; Pollin, T. I.; Prokopenko, I.; Reich, D.; Rivas, M. A.; Scott, L. J.; Seielstad, M.; Cho, Y. S.; Tai, E.-S.; Sim, X.; Sladek, R.; Smith, P.; Tachmazidou, I.; Teslovich, T. M.; Torres, J.; Trubetskoy, V.; Willems, S. M.; Williams, A. L.; Wilson, J. G.; Wiltshire, S.; Won, S.; Wood, A. R.; Xu, W.; Teo, Y. Y.; Yoon, J.; Lee, J.-Y.; Zawistowski, M.; Zeggini, E.; Zhang, W.; Zollner, S.en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-7250-4107
mit.licensePUBLISHER_POLICYen_US
mit.metadata.statusComplete


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record