Rare variants in
PPARG
with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes
Authors: Majithia Amit R. , Flannick Jason , Shahinian Peter , Guo Michael , Bray Mark-Anthony , Fontanillas Pierre , Gabriel Stacey B. ,   GoT2D Consortium,   NHGRI JHS/FHS Allelic Spectrum Project,   SIGMA T2D Consortium,   T2D-GENES Consortium, Rosen Evan D. , Altshuler David , Flannick Jason , Manning Alisa K. , Hartl Christopher , Agarwala Vineeta , Fontanillas Pierre , Green Todd , Banks Eric , DePristo Mark , Poplin Ryan , Shakir Khalid , Fennell Timothy , Njølstad Pål R. , Altshuler David , Burtt Noël , Gabriel Stacey , Fuchsberger Christian , Kang Hun Min , Sim Xueling , Ma Clement , Locke Adam , Blackwell Thomas , Jackson Anne , Teslovich Tanya M. , Stringham Heather , Chines Peter , Kwan Phoenix , Huyghe Jeroen , Tan Adrian , Jun Goo , Stitzel Michael , Bergman Richard N. , Bonnycastle Lori , Tuomilehto Jaakko , Collins Francis S. , Scott Laura , Mohlke Karen , Abecasis Gonçalo , Boehnke Michael , Strom Tim , Gieger Christian , Nurasyid Martina Müller , Grallert Harald , Kriebel Jennifer , Ried Janina , Hrabé de Angelis Martin , Huth Cornelia , Meisinger Christa , Peters Annette , Rathmann Wolfgang , Strauch Konstantin , Meitinger Thomas , Kravic Jasmina , Algren Peter , Ladenvall Claes , Toumi Tiinamaija , Isomaa Bo , Groop Leif , Gaulton Kyle , Moutsianas Loukas , Rivas Manny , Pearson Richard , Mahajan Anubha , Prokopenko Inga , Kumar Ashish , Perry John , Howie Bryan , van de Bunt Martijn , Small Kerrin , Lindgren Cecilia , Lunter Gerton , Robertson Neil , Rayner William , Morris Andrew , Buck David , Hattersley Andrew , Spector Tim , McVean Gil , Frayling Tim , Donnelly Peter , McCarthy Mark , Gupta Namrata , Taylor Herman , Fox Ervin , Cheh Christopher Newton , Wilson James G , O'Donnell Christopher J , Kathiresan Sekar , Hirschhorn Joel , Seidman J.G. , Gabriel Stacey , Seidman Christine , Altshuler David , Williams Amy L. , Jacobs Suzanne B. R. , Macías Hortensia Moreno , Chagoya Alicia Huerta , Churchhouse Claire , Luna Carla Márquez , Ortíz Humberto García , Vázquez María José Gómez , Burtt Noël P. , Estrada Karol , Mercader Josep M. , Ripke Stephan , Manning Alisa K. , Neale Benjamin , Stram Daniel O. , López Juan Carlos Fernández , Hidalgo Sandra Romero , Delfín Irma Aguilar , Hernández Angélica Martínez , Cruz Federico Centeno , Caamal Elvia Mendoza , Monsalve Cristina Revilla , Andrade Sergio Islas , Córdova Emilio , Arellano Eunice Rodríguez , Soberón Xavier , Villalpando María Elena González , Monroe Kristine , Wilkens Lynne , Kolonel Laurence N. , Le Marchand Loic , Riba Laura , Sánchez María Luisa Ordóñez , Guillén Rosario Rodríguez , Bautista Ivette Cruz , Torres Maribel Rodríguez , Hernández Linda Liliana Muñoz , Sáenz Tamara , Gómez Donají , Alvirde Ulices , Onofrio Robert C. , Brodeur Wendy M. , Gage Diane , Murphy Jacquelyn , Franklin Jennifer , Mahan Scott , Ardlie Kristin , Crenshaw Andrew T. , Winckler Wendy , Fennell Timothy , MacArthur Daniel G. , Altshuler David , Florez Jose C. , Haiman Christopher A. , Henderson Brian E. , Salinas Carlos A. Aguilar , Villalpando Clicerio González , Orozco Lorena , Luna Teresa Tusié , Abecasis Gonçalo , Almeida Marcio , Altshuler David , Asimit Jennifer L. , Atzmon Gil , Barber Mathew , Beer Nicola L. , Bell Graeme I. , Below Jennifer , Blackwell Tom , Blangero John , Boehnke Michael , Bowden Donald W. , Burtt Noël , Chambers John , Chen Han , Chen Peng , Chines Peter S. , Choi Sungkyoung , Churchhouse Claire , Cingolani Pablo , Cornes Belinda K. , Cox Nancy , Williams Aaron G. Day , Duggirala Ravindranath , Dupuis Josée , Dyer Thomas , Feng Shuang , Tajes Juan Fernandez , Ferreira Teresa , Fingerlin Tasha E. , Flannick Jason , Florez Jose , Fontanillas Pierre , Frayling Timothy M. , Fuchsberger Christian , Gamazon Eric R. , Gaulton Kyle , Ghosh Saurabh , Gloyn Anna , Grossman Robert L. , Grundstad Jason , Hanis Craig , Heath Allison , Highland Heather , Hirokoshi Momoko , Huh Ik-Soo , Huyghe Jeroen R. , Ikram Kamran , Jablonski Kathleen A. , Kim Young Jin , Jun Goo , Kato Norihiro , Kim Jayoun , King C. Ryan , Kooner Jaspal , Kwon Min-Seok , Im Hae Kyung , Laakso Markku , Lam Kevin Koi-Yau , Lee Jaehoon , Lee Selyeong , Lee Sungyoung , Lehman Donna M. , Li Heng , Lindgren Cecilia M. , Liu Xuanyao , Livne Oren E. , Locke Adam E. , Mahajan Anubha , Maller Julian B. , Manning Alisa K. , Maxwell Taylor J. , Mazoure Alexander , McCarthy Mark I. , Meigs James B. , Min Byungju , Mohlke Karen L. , Morris Andrew , Musani Solomon , Nagai Yoshihiko , Ng Maggie C.Y. , Nicolae Dan , Oh Sohee , Palmer Nicholette , Park Taesung , Pollin Toni I. , Prokopenko Inga , Reich David , Rivas Manuel A. , Scott Laura J. , Seielstad Mark , Cho Yoon Shin , Tai E-Shyong , Sim Xueling , Sladek Robert , Smith Philip , Tachmazidou Ioanna , Teslovich Tanya M. , Torres Jason , Trubetskoy Vasily , Willems Sara M. , Williams Amy L. , Wilson James G. , Wiltshire Steven , Won Sungho , Wood Andrew R. , Xu Wang , Teo Yik Ying , Yoon Joon , Lee Jong-Young , Zawistowski Matthew , Zeggini Eleftheria , Zhang Weihua , Zöllner Sebastian 
Published: August 2014

Significance

Genome sequencing of individuals in the population reveals new mutations in almost every protein coding gene; interpreting the consequence of these mutations for human health and disease remains challenging. We sequenced the gene
PPARG
, a target of antidiabetic drugs, in nearly 20,000 individuals with and without type 2 diabetes (T2D). We identified 49 previously unidentified protein-altering mutations, characterized their cellular function in human cells, and discovered that nine of these mutations cause loss-of-function (LOF). The individuals who carry these nine LOF mutations have a sevenfold increased risk of T2D, whereas individuals carrying mutations we classify as benign have no increased risk of T2D.