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

In English

Författare

  • Jason Flannick
  • Nicola L. Beer
  • Alexander G. Bick
  • Vineeta Agarwala
  • Janne Molnes
  • Namrata Gupta
  • Noel P. Burtt
  • Jose C. Florez
  • James B. Meigs
  • Herman Taylor
  • Valeriya Lyssenko
  • Henrik Irgens
  • Ervin Fox
  • Frank Burslem
  • Stefan Johansson
  • M. Julia Brosnan
  • Jeff K. Trimmer
  • Christopher Newton-Cheh
  • Tiinamaija Tuomi
  • Anders Molven
  • James G. Wilson
  • Christopher J. O'Donnell
  • Sekar Kathiresan
  • Joel N. Hirschhorn
  • Pal R. Njolstad
  • Tim Rolph
  • J. G. Seidman
  • Stacey Gabriel
  • David R. Cox
  • Christine E. Seidman
  • Leif Groop
  • David Altshuler
Visa allt

Summary, in English

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.

Publiceringsår

2013

Språk

Engelska

Sidor

1380-1380

Publikation/Tidskrift/Serie

Nature Genetics

Volym

45

Issue

11

Dokumenttyp

Artikel i tidskrift

Förlag

Nature Publishing Group

Ämne

  • Endocrinology and Diabetes

Status

Published

Forskningsgrupp

  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Övrigt

  • ISSN: 1546-1718