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

Nat Genet
Authors
Keywords
Abstract

Genome 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 Publication
2013
Journal
Nat Genet
Volume
45
Issue
11
Pages
1380-5
Date Published
2013 Nov
ISSN
1546-1718
URL
DOI
10.1038/ng.2794
PubMed ID
24097065
PubMed Central ID
PMC4051627
Links
Grant list
R01 DK078616 / DK / NIDDK NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
5-T32-GM007748-33 / GM / NIGMS NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 2R01HL080494 / HL / NHLBI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 HL080494 / HL / NHLBI NIH HHS / United States
N01HC95170 / HL / NHLBI NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
Howard Hughes Medical Institute / United States
N01-HC-95171 / HC / NHLBI NIH HHS / United States
R01 HL084553 / HL / NHLBI NIH HHS / United States
6R01-NS 17950 / NS / NINDS NIH HHS / United States
N01-HC-95172 / HC / NHLBI NIH HHS / United States
N01HC95171 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
T32GM007753 / GM / NIGMS NIH HHS / United States
N01-HC-95170 / HC / NHLBI NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States
N01HC95172 / HL / NHLBI NIH HHS / United States