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

Lim, Elaine T.; Liu, Yangfan P.; Chan, Yingleong; Tuomi, Tiinamaija LU ; Karajamaki, AnnMari; Madsen, Erik; Altshuler, David M.; Raychaudhuri, Soumya; Groop, Leif LU and Fannick, Jason, et al. (2014) In American Journal of Human Genetics 95(5). p.509-520
Abstract
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... (More)
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. (Less)
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American Journal of Human Genetics
volume
95
issue
5
pages
509 - 520
publisher
Cell Press
external identifiers
  • wos:000344845000003
  • pmid:25439097
  • scopus:84920607541
ISSN
0002-9297
DOI
10.1016/j.ajhg.2014.09.015
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English
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7a1ddb72-8850-4738-bb60-280517a9a143 (old id 4865203)
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http://www.ncbi.nlm.nih.gov/pubmed/25439097?dopt=Abstract
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2015-01-07 10:32:56
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@article{7a1ddb72-8850-4738-bb60-280517a9a143,
  abstract     = {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.},
  author       = {Lim, Elaine T. and Liu, Yangfan P. and Chan, Yingleong and Tuomi, Tiinamaija and Karajamaki, AnnMari and Madsen, Erik and Altshuler, David M. and Raychaudhuri, Soumya and Groop, Leif and Fannick, Jason and Hirschhorn, Joel N. and Katsanis, Nicholas and Daly, Mark},
  issn         = {0002-9297},
  language     = {eng},
  number       = {5},
  pages        = {509--520},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {A Novel Test for Recessive Contributions to Complex Diseases Implicates Bardet-Biedl Syndrome Gene BBS10 in Idiopathic Type 2 Diabetes and Obesity},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2014.09.015},
  volume       = {95},
  year         = {2014},
}