Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls

, Jason Flannick (Lead / Corresponding author), Josep M. Mercader, Christian Fuchsberger, Miriam S. Udler, Anubha Mahajan, Jennifer Wessel, Tanya M. Teslovich, Lizz Caulkins, Ryan Koesterer, Francisco Barajas-Olmos, Thomas W. Blackwell, Eric Boerwinkle, Jennifer A. Brody, Federico Centeno-Cruz, Ling Chen, Siying Chen, Cecilia Contreras-Cubas, Emilio Córdova, Adolfo CorreaMaria Cortes, Ralph A. DeFronzo, Lawrence Dolan, Kimberly L. Drews, Amanda Elliott, James S. Floyd, Stacey Gabriel, Maria Eugenia Garay-Sevilla, Humberto García-Ortiz, Myron Gross, Sohee Han, Nancy L. Heard-Costa, Anne U. Jackson, Marit E. Jørgensen, Hyun Min Kang, Megan Kelsey, Bong-Jo Kim, Heikki A. Koistinen, Johanna Kuusisto, Joseph B. Leader, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Valeriya Lyssenko, Alisa K. Manning, Anthony Marcketta, Juan Manuel Malacara-Hernandez, Andrew D. Morris, Colin N. A. Palmer, Laura J. Scott, Andrew P. Morris

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Abstract

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.

Original languageEnglish
Pages (from-to)71-76
Number of pages6
JournalNature
Volume570
Issue number7759
Early online date22 May 2019
DOIs
Publication statusPublished - Jun 2019

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    , Flannick, J., Mercader, J. M., Fuchsberger, C., Udler, M. S., Mahajan, A., Wessel, J., Teslovich, T. M., Caulkins, L., Koesterer, R., Barajas-Olmos, F., Blackwell, T. W., Boerwinkle, E., Brody, J. A., Centeno-Cruz, F., Chen, L., Chen, S., Contreras-Cubas, C., Córdova, E., ... Morris, A. P. (2019). Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature, 570(7759), 71-76. https://doi.org/10.1038/s41586-019-1231-2