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Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes

Winckler, Wendy; Weedon, Michael N.; Graham, Robert R.; McCarrolll, Steven A.; Purcell, Shaun; Almgren, Peter LU ; Tuomi, Tiinamaija; Gaudet, Daniel; Bengtsson Boström, Kristina LU and Walker, Mark, et al. (2007) In Diabetes 56(3). p.685-693
Abstract
An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation irk the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, lpf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from... (More)
An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation irk the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, lpf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value < 0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values < 0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value < 10(-6) in > 15,000 samples. We combined these results with our previous studies on HNF4 alpha and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
56
issue
3
pages
685 - 693
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000244827500015
  • scopus:33847361938
ISSN
1939-327X
DOI
10.2337/db06-0202
language
English
LU publication?
yes
id
efabaa2d-a69d-4d03-9aa7-1c60c3226910 (old id 670514)
date added to LUP
2007-12-19 09:10:24
date last changed
2017-09-10 04:30:02
@article{efabaa2d-a69d-4d03-9aa7-1c60c3226910,
  abstract     = {An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation irk the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, lpf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value &lt; 0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values &lt; 0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value &lt; 10(-6) in &gt; 15,000 samples. We combined these results with our previous studies on HNF4 alpha and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.},
  author       = {Winckler, Wendy and Weedon, Michael N. and Graham, Robert R. and McCarrolll, Steven A. and Purcell, Shaun and Almgren, Peter and Tuomi, Tiinamaija and Gaudet, Daniel and Bengtsson Boström, Kristina and Walker, Mark and Hitman, Graham and Hattersley, Andrew T. and McCarthy, Mark I. and Ardlie, Kristin G. and Hirschhorn, Joel N. and Daly, Mark J. and Frayling, Timothy M. and Groop, Leif and Altshuler, David},
  issn         = {1939-327X},
  language     = {eng},
  number       = {3},
  pages        = {685--693},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes},
  url          = {http://dx.doi.org/10.2337/db06-0202},
  volume       = {56},
  year         = {2007},
}