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Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):13127-32. doi: 10.1073/pnas.1410428111. Epub 2014 Aug 25.

Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes.

Collaborators (264)

Flannick J, Manning AK, Hartl C, Agarwala V, Fontanillas P, Green T, Banks E, DePristo M, Poplin R, Shakir K, Fennell T, Njølstad PR, Altshuler D, Burtt N, Gabriel S, Fuchsberger C, Kang HM, Sim X, Ma C, Locke A, Blackwell T, Jackson A, Teslovich TM, Stringham H, Chines P, Kwan P, Huyghe J, Tan A, Jun G, Stitzel M, Bergman RN, Bonnycastle L, Tuomilehto J, Collins FS, Scott L, Mohlke K, Abecasis G, Boehnke M, Strom T, Gieger C, Müller-Nurasyid M, Grallert H, Kriebel J, Ried J, de Angelis MH, 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, Newton-Cheh C, Wilson JG, O'Donnell CJ, Kathiresan S, Hirschhorn J, Seidman JG, Gabriel S, Seidman C, Altshuler D, Williams AL, Jacobs SB, Moreno-Macías H, Huerta-Chagoya A, Churchhouse C, Márquez-Luna C, García-Ortíz H, Gómez-Vázquez MJ, Burtt NP, Ripke S, Manning AK, Neale B, Stram DO, Fernández-López JC, Romero-Hidalgo S, Aguilar-Delfín I, Martínez-Hernández A, Centeno-Cruz F, Mendoza-Caamal E, Revilla-Monsalve C, Islas-Andrade S, Córdova E, Rodríguez-Arellano E, Soberón X, González-Villalpando ME, Monroe K, Wilkens L, Kolonel LN, Marchand LL, Riba L, Ordóñez-Sánchez ML, Rodríguez-Guillén R, Cruz-Bautista I, Rodríguez-Torres M, Muñoz-Hernández LL, Sáenz T, Gómez D, Alvirde U, Onofrio RC, Brodeur WM, Gage D, Murphy J, Franklin J, Mahan S, Ardlie K, Crenshaw AT, Winckler W, Altshuler D, Florez JC, Haiman CA, Henderson BE, Aguilar-Salinas CA, González-Villalpando C, Orozco L, Tusié-Luna T, Abecasis G, Almeida M, Altshuler D, Asimit JL, Atzmon G, Barber M, Beer NL, Bell GI, Below J, Blackwell T, Blangero J, Boehnke M, Bowden DW, Burtt N, Chambers J, Chen H, Chen P, Chines PS, Choi S, Churchhouse C, Cingolani P, Cornes BK, Cox N, Day-Williams AG, Duggirala R, Dupuis J, Dyer T, Feng S, Fernandez-Tajes J, Ferreira T, Fingerlin TE, Flannick J, Florez J, Fontanillas P, Frayling TM, Fuchsberger C, Gamazon ER, Gaulton K, Ghosh S, Gloyn A, Grossman RL, Grundstad J, Hanis C, Heath A, Highland H, Hirokoshi M, Huh IS, Huyghe JR, Ikram K, Jablonski KA, Jun YJ, Kato N, Kim J, King C, Kooner J, Kwon MS, Im HK, Laakso M, Lam KK, Lee J, Lee S, Lee S, Lehman DM, Li H, Lindgren CM, Liu X, Livne OE, Locke AE, Mahajan A, Maller JB, Manning AK, Maxwell TJ, Mazoure A, McCarthy MI, Meigs JB, Min B, Mohlke KL, Morris A, Musani S, Nagai Y, Ng MC, Nicolae D, Oh S, Palmer N, Park T, Pollin TI, Prokopenko I, Reich D, Rivas MA, Scott LJ, Seielstad M, Cho YS, Tai ES, Sim X, Sladek R, Smith P, Tachmazidou I, Teslovich TM, Torres J, Trubetskoy V, Willems SM, Williams AL, Wilson JG, Wiltshire S, Won S, Wood AR, Xu W, Teo YY, Yoon J, Lee JY, Zawistowski M, Zeggini E, Zhang W, Zöllner S, Estrada K, Mercader J, MacArthur D.

Author information

1
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142; Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114; Department of Medicine, Harvard Medical School, Boston, MA 02115;
2
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142;
3
Department of Genetics, Harvard Medical School, Boston, MA 02115;
4
Department of Medicine, Harvard Medical School, Boston, MA 02115; Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02115; and.
5
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142; Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114; Department of Medicine, Harvard Medical School, Boston, MA 02115; Department of Genetics, Harvard Medical School, Boston, MA 02115; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 altshuler@molbio.mgh.harvard.edu.

Erratum in

  • Proc Natl Acad Sci U S A. 2014 Nov;11;111(45):16225. Estrada, Karol [added]; Mercader, Josep [added]; MacArthur, Daniel [added].

Abstract

Peroxisome 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.

PMID:
25157153
PMCID:
PMC4246964
DOI:
10.1073/pnas.1410428111
[Indexed for MEDLINE]
Free PMC Article

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