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

Am J Hum Genet. 2014 Nov 6;95(5):509-20. doi: 10.1016/j.ajhg.2014.09.015. Epub 2014 Oct 16.


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 × 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Chaperonins
  • Diabetes Mellitus, Type 2 / genetics*
  • Finland
  • Gene Frequency
  • Genes, Recessive / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods*
  • Group II Chaperonins / genetics*
  • Humans
  • Likelihood Functions
  • Models, Genetic*
  • Obesity / genetics*
  • Odds Ratio
  • Zebrafish


  • BBS10 protein, human
  • Chaperonins
  • Group II Chaperonins