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Leif Groop

Leif Groop

Principal investigator

Leif Groop

A Novel Test for Recessive Contributions to Complex Diseases Implicates Bardet-Biedl Syndrome Gene BBS10 in Idiopathic Type 2 Diabetes and Obesity

Author

  • Elaine T. Lim
  • Yangfan P. Liu
  • Yingleong Chan
  • Tiinamaija Tuomi
  • AnnMari Karajamaki
  • Erik Madsen
  • David M. Altshuler
  • Soumya Raychaudhuri
  • Leif Groop
  • Jason Fannick
  • Joel N. Hirschhorn
  • Nicholas Katsanis
  • Mark Daly

Summary, in English

Rare-variant association studies in common, complex diseases are customarily conducted under an additive risk model in both single-variant and burden testing. Here, we describe a method to improve detection of rare recessive variants in complex diseases termed RAFT (recessive-allele-frequency-based test). We found that RAFT outperforms existing approaches when the variant influences disease risk in a recessive manner on simulated data. We then applied our method to 1,791 Finnish individuals with type 2 diabetes (T2D) and 2,657 matched control subjects. In BBS10, we discovered a rare variant (c.1189A>G [p.Ile397Val]; rs202042386) that confers risk of T2D in a recessive state (p = 1.38 x 10(-6)) and would be missed by conventional methods. Testing of this variant in an established in vivo zebrafish model confirmed the variant to be pathogenic. Taken together, these data suggest that RAFT can effectively reveal rare recessive contributions to complex diseases overlooked by conventional association tests.

Department/s

  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2014

Language

English

Pages

509-520

Publication/Series

American Journal of Human Genetics

Volume

95

Issue

5

Document type

Journal article

Publisher

Cell Press

Topic

  • Medical Genetics

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 0002-9297