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

, ; Flannick, Jason; Lyssenko, Valeriya LU ; Groop, Leif LU ; Nilsson, Peter LU and Boehnke, Michael (2019) In Nature 570(7759). p.71-76
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... (More)
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. © 2019, The Author(s), under exclusive licence to Springer Nature Limited. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Mus
in
Nature
volume
570
issue
7759
pages
6 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85066251977
ISSN
0028-0836
DOI
10.1038/s41586-019-1231-2
language
English
LU publication?
yes
id
a103c3ae-8efd-49b4-b46e-00911b9ecff8
date added to LUP
2019-06-18 09:08:52
date last changed
2019-10-15 07:08:02
@article{a103c3ae-8efd-49b4-b46e-00911b9ecff8,
  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. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.},
  author       = {,  and Flannick, Jason and Lyssenko, Valeriya and Groop, Leif and Nilsson, Peter and Boehnke, Michael},
  issn         = {0028-0836},
  keyword      = {Mus},
  language     = {eng},
  number       = {7759},
  pages        = {71--76},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls},
  url          = {http://dx.doi.org/10.1038/s41586-019-1231-2},
  volume       = {570},
  year         = {2019},
}