Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.
Dastani Z., Hivert M-F., Timpson N., Perry JRB., Yuan X., Scott RA., Henneman P., Heid IM., Kizer JR., Lyytikäinen L-P., Fuchsberger C., Tanaka T., Morris AP., Small K., Isaacs A., Beekman M., Coassin S., Lohman K., Qi L., Kanoni S., Pankow JS., Uh H-W., Wu Y., Bidulescu A., Rasmussen-Torvik LJ., Greenwood CMT., Ladouceur M., Grimsby J., Manning AK., Liu C-T., Kooner J., Mooser VE., Vollenweider P., Kapur KA., Chambers J., Wareham NJ., Langenberg C., Frants R., Willems-Vandijk K., Oostra BA., Willems SM., Lamina C., Winkler TW., Psaty BM., Tracy RP., Brody J., Chen I., Viikari J., Kähönen M., Pramstaller PP., Evans DM., St Pourcain B., Sattar N., Wood AR., Bandinelli S., Carlson OD., Egan JM., Böhringer S., van Heemst D., Kedenko L., Kristiansson K., Nuotio M-L., Loo B-M., Harris T., Garcia M., Kanaya A., Haun M., Klopp N., Wichmann H-E., Deloukas P., Katsareli E., Couper DJ., Duncan BB., Kloppenburg M., Adair LS., Borja JB., DIAGRAM+ Consortium None., MAGIC Consortium None., GLGC Investigators None., MuTHER Consortium None., Wilson JG., Musani S., Guo X., Johnson T., Semple R., Teslovich TM., Allison MA., Redline S., Buxbaum SG., Mohlke KL., Meulenbelt I., Ballantyne CM., Dedoussis GV., Hu FB., Liu Y., Paulweber B., Spector TD., Slagboom PE., Ferrucci L., Jula A., Perola M., Raitakari O., Florez JC., Salomaa V., Eriksson JG., Frayling TM., Hicks AA., Lehtimäki T., Smith GD., Siscovick DS., Kronenberg F., van Duijn C., Loos RJF., Waterworth DM., Meigs JB., Dupuis J., Richards JB., Voight BF., Scott LJ., Steinthorsdottir V., Dina C., Welch RP., Zeggini E., Huth C., Aulchenko YS., Thorleifsson G., McCulloch LJ., Ferreira T., Grallert H., Amin N., Wu G., Willer CJ., Raychaudhuri S., McCarroll SA., Hofmann OM., Segrè AV., van Hoek M., Navarro P., Ardlie K., Balkau B., Benediktsson R., Bennett AJ., Blagieva R., Boerwinkle E., Bonnycastle LL., Boström KB., Bravenboer B., Bumpstead S., Burtt NP., Charpentier G., Chines PS., Cornelis M., Crawford G., Doney ASF., Elliott KS., Elliott AL., Erdos MR., Fox CS., Franklin CS., Ganser M., Gieger C., Grarup N., Green T., Griffin S., Groves CJ., Guiducci C., Hadjadj S., Hassanali N., Herder C., Isomaa B., Jackson AU., Johnson PRV., Jørgensen T., Kao WHL., Kong A., Kraft P., Kuusisto J., Lauritzen T., Li M., Lieverse A., Lindgren CM., Lyssenko V., Marre M., Meitinger T., Midthjell K., Morken MA., Narisu N., Nilsson P., Owen KR., Payne F., Petersen A-K., Platou C., Proença C., Prokopenko I., Rathmann W., Rayner NW., Robertson NR., Rocheleau G., Roden M., Sampson MJ., Saxena R., Shields BM., Shrader P., Sigurdsson G., Sparsø T., Strassburger K., Stringham HM., Sun Q., Swift AJ., Thorand B., Tichet J., Tuomi T., van Dam RM., van Haeften TW., van Herpt T., van Vliet-Ostaptchouk JV., Walters GB., Weedon MN., Wijmenga C., Witteman J., Bergman RN., Cauchi S., Collins FS., Gloyn AL., Gyllensten U., Hansen T., Hide WA., Hitman GA., Hofman A., Hunter DJ., Hveem K., Laakso M., Morris AD., Palmer CNA., Rudan I., Sijbrands E., Stein LD., Tuomilehto J., Uitterlinden A., Walker M., Watanabe RM., Abecasis GR., Boehm BO., Campbell H., Daly MJ., Hattersley AT., Pedersen O., Barroso I., Groop L., Sladek R., Thorsteinsdottir U., Wilson JF., Illig T., Froguel P., van Duijn CM., Stefansson K., Altshuler D., Boehnke M., McCarthy MI., Soranzo N., Wheeler E., Glazer NL., Bouatia-Naji N., Mägi R., Randall J., Elliott P., Rybin D., Dehghan A., Hottenga JJ., Song K., Goel A., Lajunen T., Doney A., Cavalcanti-Proença C., Kumari M., Timpson NJ., Zabena C., Ingelsson E., An P., O'Connell J., Luan J., Elliott A., McCarroll SA., Roccasecca RM., Pattou F., Sethupathy P., Ariyurek Y., Barter P., Beilby JP., Ben-Shlomo Y., Bergmann S., Bochud M., Bonnefond A., Borch-Johnsen K., Böttcher Y., Brunner E., Bumpstead SJ., Chen Y-DI., Chines P., Clarke R., Coin LJM., Cooper MN., Crisponi L., Day INM., de Geus EJC., Delplanque J., Fedson AC., Fischer-Rosinsky A., Forouhi NG., Franzosi MG., Galan P., Goodarzi MO., Graessler J., Grundy S., Gwilliam R., Hallmans G., Hammond N., Han X., Hartikainen A-L., Hayward C., Heath SC., Hercberg S., Hillman DR., Hingorani AD., Hui J., Hung J., Kaakinen M., Kaprio J., Kesaniemi YA., Kivimaki M., Knight B., Koskinen S., Kovacs P., Kyvik KO., Lathrop GM., Lawlor DA., Le Bacquer O., Lecoeur C., Li Y., Mahley R., Mangino M., Martínez-Larrad MT., McAteer JB., McPherson R., Meisinger C., Melzer D., Meyre D., Mitchell BD., Mukherjee S., Naitza S., Neville MJ., Orrù M., Pakyz R., Paolisso G., Pattaro C., Pearson D., Peden JF., Pedersen NL., Pfeiffer AFH., Pichler I., Polasek O., Posthuma D., Potter SC., Pouta A., Province MA., Rayner NW., Rice K., Ripatti S., Rivadeneira F., Rolandsson O., Sandbaek A., Sandhu M., Sanna S., Sayer AA., Scheet P., Seedorf U., Sharp SJ., Shields B., Sigurðsson G., Sijbrands EJG., Silveira A., Simpson L., Singleton A., Smith NL., Sovio U., Swift A., Syddall H., Syvänen A-C., Tönjes A., Uitterlinden AG., van Dijk KW., Varma D., Visvikis-Siest S., Vitart V., Vogelzangs N., Waeber G., Wagner PJ., Walley A., Ward KL., Watkins H., Wild SH., Willemsen G., Witteman JCM., Yarnell JWG., Zelenika D., Zethelius B., Zhai G., Zhao JH., Zillikens MC., DIAGRAM Consortium None., GIANT Consortium None., Global B Pgen Consortium None., Borecki IB., Meneton P., Magnusson PKE., Nathan DM., Williams GH., Silander K., Bornstein SR., Schwarz P., Spranger J., Karpe F., Shuldiner AR., Cooper C., Serrano-Ríos M., Lind L., Palmer LJ., Hu FB., Franks PW., Ebrahim S., Marmot M., Kao WHL., Pramstaller PP., Wright AF., Stumvoll M., Hamsten A., Procardis Consortium None., Buchanan TA., Valle TT., Rotter JI., Penninx BWJH., Boomsma DI., Cao A., Scuteri A., Schlessinger D., Uda M., Ruokonen A., Jarvelin M-R., Peltonen L., Mooser V., Sladek R., MAGIC investigators None., GLGC Consortium None., Musunuru K., Smith AV., Edmondson AC., Stylianou IM., Koseki M., Pirruccello JP., Chasman DI., Johansen CT., Fouchier SW., Peloso GM., Barbalic M., Ricketts SL., Bis JC., Feitosa MF., Orho-Melander M., Melander O., Li X., Li M., Cho YS., Go MJ., Kim YJ., Lee J-Y., Park T., Kim K., Sim X., Ong RT-H., Croteau-Chonka DC., Lange LA., Smith JD., Ziegler A., Zhang W., Zee RYL., Whitfield JB., Thompson JR., Surakka I., Spector TD., Smit JH., Sinisalo J., Scott J., Saharinen J., Sabatti C., Rose LM., Roberts R., Rieder M., Parker AN., Pare G., O'Donnell CJ., Nieminen MS., Nickerson DA., Montgomery GW., McArdle W., Masson D., Martin NG., Marroni F., Lucas G., Luben R., Lokki M-L., Lettre G., Launer LJ., Lakatta EG., Laaksonen R., Kyvik KO., König IR., Khaw K-T., Kaplan LM., Johansson Å., Janssens ACJW., Igl W., Hovingh GK., Hengstenberg C., Havulinna AS., Hastie ND., Harris TB., Haritunians T., Hall AS., Groop LC., Gonzalez E., Freimer NB., Erdmann J., Ejebe KG., Döring A., Dominiczak AF., Demissie S., Deloukas P., de Faire U., Crawford G., Chen Y-DI., Caulfield MJ., Boekholdt SM., Assimes TL., Quertermous T., Seielstad M., Wong TY., Tai E-S., Feranil AB., Kuzawa CW., Taylor HA., Gabriel SB., Holm H., Gudnason V., Krauss RM., Ordovas JM., Munroe PB., Kooner JS., Tall AR., Hegele RA., Kastelein JJP., Schadt EE., Strachan DP., Reilly MP., Samani NJ., Schunkert H., Cupples LA., Sandhu MS., Ridker PM., Rader DJ., Kathiresan S.
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.