Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
(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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https://lup.lub.lu.se/record/a103c3ae-8efd-49b4-b46e-00911b9ecff8
- author
- Flannick, Jason ; Lyssenko, Valeriya LU ; Groop, Leif LU ; Nilsson, Peter LU and Boehnke, Michael
- author collaboration
- organization
- publishing date
- 2019
- 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
- pmid:31118516
- ISSN
- 0028-0836
- DOI
- 10.1038/s41586-019-1231-2
- language
- English
- LU publication?
- yes
- additional info
- Export Date: 18 June 2019
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- a103c3ae-8efd-49b4-b46e-00911b9ecff8
- date added to LUP
- 2019-06-18 09:08:52
- date last changed
- 2024-05-14 12:56:08
@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 = {{Flannick, Jason and Lyssenko, Valeriya and Groop, Leif and Nilsson, Peter and Boehnke, Michael}},
issn = {{0028-0836}},
keywords = {{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}},
doi = {{10.1038/s41586-019-1231-2}},
volume = {{570}},
year = {{2019}},
}