Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
| Title: | Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls |
|---|---|
| Authors: | 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 BJ; Koistinen HA; Kuusisto J; Leader JB; Linneberg A; Liu CT; 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; 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 TY; Atzmon G; Barzilai N; Blangero J; Bonnycastle LL; Bowden DW; Chambers JC; Chan E; Cheng CY; 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 JY; 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; Altshuler D; Burtt NP; Scott LJ; Morris AP; Florez JC; McCarthy MI; Boehnke M |
| Publication Year: | 2019 |
| Collection: | Free University of Bozen-Bolzano (UNIBZ): BIA (Bozen-Bolzano Institutional Archive) |
| Description: | 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. ; open |
| Document Type: | article in journal/newspaper |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 0028-0836 |
| Relation: | http://dx.doi.org/10.1038/s41586-019-1231-2; https://bia.unibz.it/handle/10863/12039 |
| DOI: | 10.1038/s41586-019-1231-2 |
| Availability: | https://doi.org/10.1038/s41586-019-1231-2; https://bia.unibz.it/handle/10863/12039 |
| Rights: | open access, http://creativecommons.org/licenses/by/4.0/ ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: | edsbas.CA68E35 |
| Database: | BASE |