Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes
Leif Groop, Mark I. McCarthy, Evan D. Rosen, Gonçalo R. Abecasis, David Reich, Robert C. Onofrio, Sohee Oh, Han Chen, Clement Ma, Francis S. Collins, Nancy J. Cox, Michael Boehnke, Benjamin M. Neale, Julian Maller, James B. Meigs, Josée Dupuis, Eric Banks, Timothy R. Fennell, Karol Estrada, Mark A. DePristo, Jason Flannick, Namrata Gupta, Lorena Orozco, Ryan Poplin, Manuel A. Rivas, Khalid Shakir, José C. Florez, Sekar Kathiresan, Jaakko Tuomilehto, Daniel G. MacArthur, Vineeta Agarwala, Stephan Ripke, Laurence N. Kolonel, Loı̈c Le Marchand, Christopher A. Haiman, Scott Mahan, Humberto Garcia‐Ortíz, Angélica Martínez‐Hernández, Emilio J. Córdova, Federico Centeno-Cruz, Carlos A. Aguilar‐Salinas, Sungho Won, John B. Chambers, Christine E. Seidman, Daniel O. Stram, J G Seidman, Wanghong Xu, Ashish Kumar, Toni I. Pollin, Anne Jackson, Lori L. Bonnycastle, Heather M. Stringham, Laura J. Scott, Richard N. Bergman, Karen L. Mohlke, Graeme I. Bell, Kristin Ardlie, Loukas Moutsianas, Jennifer Franklin, Diane Gage, Martin Hrabě de Angelis, Tim D. Spector, Gil McVean, Annette Peters, Thomas Meitinger, Martijn van de Bunt, Anna L. Gloyn, Brian E. Henderson, Yik Ying Teo, Jaspal S. Kooner, Robert L. Grossman, Allison P. Heath, Gil Atzmon, Taesung Park, Peter Donnelly, Bryan Howie, Tom Blackwell, Christian Fuchsberger, Goo Jun, Gerton Lunter, Claire Churchhouse, Christopher Hartl, Eleftheria Zeggini, Cecilia M. Lindgren, Pierre Fontanillas, John R. B. Perry, Christa Meisinger, Wolfgang Rathmann, Alicia Huerta‐Chagoya, Josep M. Mercader, Matthew Zawistowski, Sebastian Zöllner, Adam E. Locke, Jason Torres, Eric R. Gamazon, Hae Kyung Im, E Shyong Tai, John Blangero, Donald W. Bowden, Thomas W. Blackwell, Stacey Gabriel, James Wilson, Saurabh Ghosh, Tim M. Strom, Wendy Winckler, Timothy M. Frayling, Andrew T. Hattersley, Sungyoung Lee, David Altshuler, Joel N. Hirschhorn, Dan L. Nicolae, Teresa Ferreira, Andrew R. Wood, Harald Grallert, Konstantin Strauch, Christian Gieger, Robert Sladek, Claes Ladenvall, Iksoo Huh, Michael L. Stitzel, Mark Seielstad, Todd J. Green, David Buck, Pablo Cingolani, Craig L. Hanis, Christopher J. O’Donnell, Young Jin Kim, Jennifer L. Asimit, Laura Riba, Kathleen A. Jablonski, Anubha Mahajan, Janina S. Ried, Weihua Zhang, Markku Laakso, Andrew Crenshaw, Kerrin S. Small, Pål R. Njølstad, Wendy Brodeur, Sandra Romero‐Hidalgo, Xavier Soberón, Ravindranath Duggirala, Yoon Shin Cho, Jong‐Young Lee, Donna M. Lehman, Maggie C. Y. Ng, M. Revilla, Noël P. Burtt, Solomon K. Musani, Herman A. Taylor, Xuanyao Liu, Thomas D. Dyer, Ervin R. Fox, Christopher R. King, Richard D. Pearson, Heather M. Highland, Belinda K. Cornes, Nicola L. Beer, Suzanne B.R. Jacobs, Bo Isomaa, Jasmina Kravić, Tanya M. Teslovich, Peter S. Chines, Martina Müller‐Nurasyid, Juan Fernández Tajes, Jeroen R. Huyghe, Jennifer E. Below, Peng Chen, Tasha E. Fingerlin, Selyeong Lee, Taylor J. Maxwell, Yoshihiko Nagai, Joon Yoon, Phoenix Kwan, Jennifer Kriebel, Jacquelyn Murphy, Cornelia Huth, Michael H. Guo, Jason Grundstad, Neil Robertson, Amy L. Williams, Linda Liliana Muñóz-Hernández, Tamara Sáenz, Donají Gómez, Ulices Alvirde, Irma Aguilar-Delfín, Kristine R. Monroe, Ioanna Tachmazidou, Stacey Gabriel, Mark‐Anthony Bray, Steven Wiltshire, Marcio Almeida, Sungkyoung Choi, Jayoun Kim, Oren E. Livne, Norihiro Kato, Amit R. Majithia, Peter Shahinian, NHGRI JHS/FHS Allelic Spectrum Project, Alisa K. Manning, Pierre Fontanillas, Hun Min Kang, Xueling Sim, Adrian Y. Tan, Peter Algren, Tiinamaija Toumi, Kyle Gaulton, Manny Rivas, Inga Prokopenko, W Rayner, Andrew H. Morris, Christopher Newton Cheh, Hortensia Moreno Macías, C Luna, María José Gómez Vázquez, Juan Carlos Fernández López, Elvia Mendoza Caamal, Sergio Islas Andrade, Martha Eunice Rodríguez-Arellano, María Elena González Villalpando, Lynne Wilkens, María Luisa Ordóñez Sánchez, Rosario Rodríguez Guillén, Ivette Cruz Bautista, Maribel Rodríguez Torres, Clicerio González Villalpando, Teresa Tusie Luna, Mathew Barber, Aaron G. Day Williams, Shuang Feng, Momoko Hirokoshi, Kamran Ikram, Minseok Kwon, Kevin Lam, Jaehoon Lee, Heng Li, Alexander Mazoure, Byungju Min, Nicholette Palmer, Philip Smith, Vasily Trubetskoy, Sara M. Willems, James G. Wilson
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.