TY - JOUR

T1 - Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls

AU - Flannick, Jason

AU - Mercader, Josep M

AU - Fuchsberger, Christian

AU - Udler, Miriam S

AU - Mahajan, Anubha

AU - Wessel, Jennifer

AU - Teslovich, Tanya M

AU - Caulkins, Lizz

AU - Koesterer, Ryan

AU - Barajas-Olmos, Francisco

AU - Blackwell, Thomas W

AU - Boerwinkle, Eric

AU - Brody, Jennifer A

AU - Centeno-Cruz, Federico

AU - Chen, Ling

AU - Chen, Siying

AU - Contreras-Cubas, Cecilia

AU - Córdova, Emilio

AU - Correa, Adolfo

AU - Cortes, Maria

AU - DeFronzo, Ralph A

AU - Dolan, Lawrence

AU - Drews, Kimberly L

AU - Elliott, Amanda

AU - Floyd, James S

AU - Gabriel, Stacey

AU - Garay-Sevilla, Maria Eugenia

AU - García-Ortiz, Humberto

AU - Gross, Myron

AU - Han, Sohee

AU - Heard-Costa, Nancy L

AU - Jackson, Anne U

AU - Jørgensen, Marit E

AU - Kang, Hyun Min

AU - Kelsey, Megan

AU - Kim, Bong-Jo

AU - Koistinen, Heikki A

AU - Kuusisto, Johanna

AU - Leader, Joseph B

AU - Linneberg, Allan

AU - Liu, Ching-Ti

AU - Liu, Jianjun

AU - Lyssenko, Valeriya

AU - Manning, Alisa K

AU - Marcketta, Anthony

AU - Witte, Daniel R

AU - Loos, Ruth J F

AU - Grarup, Niels

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Broad Genomics Platform

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

KW - Animals

KW - Case-Control Studies

KW - Decision Support Techniques

KW - Diabetes Mellitus, Type 2/genetics

KW - Exome/genetics

KW - Female

KW - Gene Frequency

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Whole Exome Sequencing

U2 - 10.1038/s41586-019-1231-2

DO - 10.1038/s41586-019-1231-2

M3 - Journal article

C2 - 31118516

VL - 570

SP - 71

EP - 76

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7759

ER -