Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
Flannick J., Mercader JM., Fuchsberger C., Udler MS., Mahajan A., Wessel J., Teslovich TM., Caulkins L., Koesterer R., Barajas-Olmos F., Blackwell TW., Boerwinkle E., Brody JA., Centeno-Cruz F., Chen L., Chen S., Contreras-Cubas C., Córdova E., Correa A., Cortes M., DeFronzo RA., Dolan L., Drews KL., Elliott A., Floyd JS., Gabriel S., Garay-Sevilla ME., García-Ortiz H., Gross M., Han S., Heard-Costa NL., Jackson AU., Jørgensen ME., Kang HM., Kelsey M., Kim B-J., Koistinen HA., Kuusisto J., Leader JB., Linneberg A., Liu C-T., Liu J., Lyssenko V., Manning AK., Marcketta A., Malacara-Hernandez JM., Martínez-Hernández A., Matsuo K., Mayer-Davis E., Mendoza-Caamal E., Mohlke KL., Morrison AC., Ndungu A., Ng MCY., O'Dushlaine C., Payne AJ., Pihoker C., Broad Genomics Platform None., Post WS., Preuss M., Psaty BM., Vasan RS., Rayner NW., Reiner AP., Revilla-Monsalve C., Robertson NR., Santoro N., Schurmann C., So WY., Soberón X., Stringham HM., Strom TM., Tam CHT., Thameem F., Tomlinson B., Torres JM., Tracy RP., van Dam RM., Vujkovic M., Wang S., Welch RP., Witte DR., Wong T-Y., Atzmon G., Barzilai N., Blangero J., Bonnycastle LL., Bowden DW., Chambers JC., Chan E., Cheng C-Y., Cho YS., Collins FS., de Vries PS., Duggirala R., Glaser B., Gonzalez C., Gonzalez ME., Groop L., Kooner JS., Kwak SH., Laakso M., Lehman DM., Nilsson P., Spector TD., Tai ES., Tuomi T., Tuomilehto J., Wilson JG., Aguilar-Salinas CA., Bottinger E., Burke B., Carey DJ., Chan JCN., Dupuis J., Frossard P., Heckbert SR., Hwang MY., Kim YJ., Kirchner HL., Lee J-Y., Lee J., Loos RJF., Ma RCW., Morris AD., O'Donnell CJ., Palmer CNA., Pankow J., Park KS., Rasheed A., Saleheen D., Sim X., Small KS., Teo YY., Haiman C., Hanis CL., Henderson BE., Orozco L., Tusié-Luna T., Dewey FE., Baras A., Gieger C., Meitinger T., Strauch K., Lange L., Grarup N., Hansen T., Pedersen O., Zeitler P., Dabelea D., Abecasis G., Bell GI., Cox NJ., Seielstad M., Sladek R., Meigs JB., Rich SS., Rotter JI., DiscovEHR Collaboration None., CHARGE None., LuCamp None., ProDiGY None., GoT2D None., ESP None., SIGMA-T2D None., T2D-GENES None., AMP-T2D-GENES None., Altshuler D., Burtt NP., Scott LJ., Morris AP., Florez JC., McCarthy MI., Boehnke M.
Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.