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

作者：Lim Elaine T^*; Liu Yangfan P; Chan Yingleong; Tiinamaija Tuomi; Karajamaki AnnMari; Madsen Erik; Altshuler David M; Raychaudhuri Soumya; Groop Leif; Fannick Jason; Hirschhorn Joel N; Katsanis Nicholas; Daly Mark J

来源：American Journal of Human Genetics, 2014, 95(5): 509-520.

DOI：10.1016/j.ajhg.2014.09.015

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%26gt;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.

• 出版日期2014-11-6