A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity

Elaine T. Lim*, Yangfan P. Liu, Yingleong Chan, Tuomi Tiinamaija, Ann Mari Käräjämäki, Erik Madsen, David M. Altshuler, Soumya Raychaudhuri, Leif Groop, Jason Flannick, Joel N. Hirschhorn, Elias Nicholas Katsanis, Mark J. Daly

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Rare-variant association studies in common, complex diseases are customarily conducted under an additive risk model in both singlevariant 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 RAFToutperforms existing approaches when the variant influences disease risk in a recessive manner on simulated ata. We then applied our method to 1,791 Finnish individuals ith 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 × 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.

Original languageEnglish (US)
Pages (from-to)509-520
Number of pages12
JournalAmerican journal of human genetics
Volume95
Issue number5
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Lim, E. T., Liu, Y. P., Chan, Y., Tiinamaija, T., Käräjämäki, A. M., Madsen, E., Altshuler, D. M., Raychaudhuri, S., Groop, L., Flannick, J., Hirschhorn, J. N., Katsanis, E. N., & Daly, M. J. (2014). A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity. American journal of human genetics, 95(5), 509-520. https://doi.org/10.1016/j.ajhg.2014.09.015