Scientific Publications

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

Publication TypeJournal Article
AuthorsFlannick, J., Beer NL, Bick AG, Agarwala V., Molnes J., Gupta N., Burtt NP, Florez JC, Meigs JB, Taylor H., Lyssenko V., Irgens H., Fox E., Burslem F., Johansson S., Brosnan MJ, Trimmer JK, Newton-Cheh C., Tuomi T., Molven A., Wilson JG, O'Donnell CJ, Kathiresan S., Hirschhorn JN, Njølstad PR, Rolph T., Seidman JG, Gabriel S., Cox DR, Seidman CE, Groop L., and Altshuler D.
AbstractGenome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders 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 estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (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.
Year of Publication2013
JournalNature genetics
Volume45
Issue11
Pages1380-5
Date Published (YYYY/MM/DD)2013/11/01
ISSN Number1061-4036
DOI10.1038/ng.2794
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/24097065?dopt=Abstract