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PMID: 24097065 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 45 ·No. 11 ·2013-11-00 ·Pages 1380-5

Flannick 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, Altshuler D

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.

MeSH Terms
Adult Base Sequence Basic Helix-Loop-Helix Transcription Factors/genetics Chromosome Mapping Diabetes Mellitus, Type 2/genetics Female Genetic Predisposition to Disease Genetic Variation Germinal Center Kinases Hepatocyte Nuclear Factor 1-alpha/genetics Hepatocyte Nuclear Factor 1-beta/genetics Hepatocyte Nuclear Factor 4/genetics Homeodomain Proteins/genetics Humans Male Middle Aged Phenotype Protein Serine-Threonine Kinases/genetics Risk Sequence Analysis, DNA Trans-Activators/genetics Young Adult
Chemicals
Basic Helix-Loop-Helix Transcription Factors Germinal Center Kinases HNF1A protein, human HNF1B protein, human HNF4A protein, human Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 4 Homeodomain Proteins NEUROD1 protein, human Trans-Activators pancreatic and duodenal homeobox 1 protein Hepatocyte Nuclear Factor 1-beta Protein Serine-Threonine Kinases
Authors & Affiliations
32 authors, click to expand affiliations / ORCID
Flannick Jason
1] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [4].
Beer Nicola L
Bick Alexander G
Agarwala Vineeta
Molnes Janne
Gupta Namrata
Burtt Noël P
Florez Jose C
Meigs James B
Taylor Herman
Lyssenko Valeriya
Irgens Henrik
Fox Ervin
Burslem Frank
Johansson Stefan
Brosnan M Julia
Trimmer Jeff K
Newton-Cheh Christopher
Tuomi Tiinamaija
Molven Anders
Wilson James G
O'Donnell Christopher J
Kathiresan Sekar
Hirschhorn Joel N
Njølstad Pål R ORCID
Rolph Tim
Seidman J G
Gabriel Stacey
Cox David R
Seidman Christine E
Groop Leif
Altshuler David
Supplementary Concepts
Mason-Type Diabetes (Disease)
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2794
Published
2013-11-00
Epub
2013-00-06
Pages
1380-5
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC4051627
Subset
IM
Grants
NHGRI NIH HHS · U54 HG003067 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · T32 GM007753 · United States
NHLBI NIH HHS · R01 HL080494 · United States
NHLBI NIH HHS · N01HC95170 · United States
NIDDK NIH HHS · K24 DK080140 · United States
NINDS NIH HHS · 6R01-NS 17950 · United States
NHLBI NIH HHS · N01-HC-95172 · United States
NIGMS NIH HHS · T32GM007753 · United States
NHLBI NIH HHS · N01HC95172 · United States
NIDDK NIH HHS · R01 DK078616 · United States
NHLBI NIH HHS · N02-HL-6-4278 · United States
NIGMS NIH HHS · 5-T32-GM007748-33 · United States
NHLBI NIH HHS · N01-HC-25195 · United States
NINDS NIH HHS · R01 NS017950 · United States
NHLBI NIH HHS · R01 2R01HL080494 · United States
NHLBI NIH HHS · N01-HC-95171 · United States
NHLBI NIH HHS · R01 HL084553 · United States
NHLBI NIH HHS · N01HC95171 · United States
NHLBI NIH HHS · N01HC25195 · United States
NHLBI NIH HHS · N01-HC-95170 · United States
NIGMS NIH HHS · T32 GM007748 · United States
External Links
PubMed source DOI: 10.1038/ng.2794 PMC Full Text View journal details
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