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Leif Groop

Leif Groop

Principal investigator

Leif Groop

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

Author

  • Jason Flannick
  • Valeriya Lyssenko
  • Leif Groop
  • Peter Nilsson
  • Michael Boehnke

Summary, in English

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.

Department/s

  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health
  • Internal Medicine - Epidemiology
  • History of Medicine

Publishing year

2019

Language

English

Pages

71-76

Publication/Series

Nature

Volume

570

Issue

7759

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Endocrinology and Diabetes
  • Medical Genetics

Keywords

  • Mus

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Internal Medicine - Epidemiology

ISBN/ISSN/Other

  • ISSN: 0028-0836