Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes
Majithia AR., Flannick J., Shahinian P., Guo M., Bray M-A., Fontanillas P., Gabriel SB., Rosen ED., Altshuler D., 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., Nurasyid MM., Grallert H., Kriebel J., Ried J., Hrabé 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 CN., Wilson JG., O'Donnell CJ., Kathiresan S., Hirschhorn J., Seidman JG., Gabriel S., Seidman C., Altshuler D., Williams AL., Jacobs SBR., Macías HM., Chagoya AH., Churchhouse C., Luna CM., Ortíz HG., Vázquez MJG., Burtt NP., Estrada K., Mercader JM., Ripke S., Manning AK., Neale B., Stram DO., López JCF., Hidalgo SR., Delfín IA., Hernández AM., Cruz FC., Caamal EM., Monsalve CR., Andrade SI., Córdova E., Arellano ER., Soberón X., Villalpando MEG., Monroe K., Wilkens L., Kolonel LN., Le Marchand L., Riba L., Sánchez MLO., Guillén RR., Bautista IC., Torres MR., Hernández LLM., Sáenz T., Gómez D., Alvirde U., Onofrio RC., Brodeur WM., Gage D., Murphy J., Franklin J., Mahan S., Ardlie K., Crenshaw AT., Winckler W., Fennell T., MacArthur DG., Altshuler D., Florez JC., Haiman CA., Henderson BE., Salinas CAA., Villalpando CG., Orozco L., Luna TT., 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., Williams AGD., Duggirala R., Dupuis J., Dyer T., Feng S., Tajes JF., 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 I-S., Huyghe JR., Ikram K., Jablonski KA., Kim YJ., Jun G., Kato N., Kim J., King CR., Kooner J., Kwon M-S., Im HK., Laakso M., Lam KK-Y., 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 MCY., Nicolae D., Oh S., Palmer N., Park T., Pollin TI., Prokopenko I., Reich D., Rivas MA., Scott LJ., Seielstad M., Cho YS., Tai E-S., 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 J-Y., Zawistowski M., Zeggini E., Zhang W., Zöllner S.
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.