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Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes

Flannick, Jason; Beer, Nicola L.; Bick, Alexander G.; Agarwala, Vineeta; Molnes, Janne; Gupta, Namrata; Burtt, Noel P.; Florez, Jose C.; Meigs, James B. and Taylor, Herman, et al. (2013) In Nature Genetics 45(11). p.1380-1380
Abstract
Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1-7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates8-12. We sequenced seven genes for maturity-onset diabetes of the young (MODY) 13 in well-phenotyped population samples14,15 (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from... (More)
Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1-7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates8-12. We sequenced seven genes for maturity-onset diabetes of the young (MODY) 13 in well-phenotyped population samples14,15 (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases. (Less)
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@article{f4684b0b-bc16-4476-9d54-fb01b02f9155,
  abstract     = {Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1-7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates8-12. We sequenced seven genes for maturity-onset diabetes of the young (MODY) 13 in well-phenotyped population samples14,15 (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.},
  author       = {Flannick, Jason and Beer, Nicola L. and Bick, Alexander G. and Agarwala, Vineeta and Molnes, Janne and Gupta, Namrata and Burtt, Noel P. and Florez, Jose C. and Meigs, James B. and Taylor, Herman and Lyssenko, Valeriya and Irgens, Henrik and Fox, Ervin and Burslem, Frank and Johansson, Stefan and Brosnan, M. Julia and Trimmer, Jeff K. and Newton-Cheh, Christopher and Tuomi, Tiinamaija and Molven, Anders and Wilson, James G. and O'Donnell, Christopher J. and Kathiresan, Sekar and Hirschhorn, Joel N. and Njolstad, Pal R. and Rolph, Tim and Seidman, J. G. and Gabriel, Stacey and Cox, David R. and Seidman, Christine E. and Groop, Leif and Altshuler, David},
  issn         = {1546-1718},
  language     = {eng},
  number       = {11},
  pages        = {1380--1380},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes},
  url          = {http://dx.doi.org/10.1038/ng.2794},
  volume       = {45},
  year         = {2013},
}