Document Detail


Genome-wide association scan allowing for epistasis in type 2 diabetes.
MedLine Citation:
PMID:  21133856     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In the presence of epistasis multilocus association tests of human complex traits can provide powerful methods to detect susceptibility variants. We undertook multilocus analyses in 1924 type 2 diabetes cases and 2938 controls from the Wellcome Trust Case Control Consortium (WTCCC). We performed a two-dimensional genome-wide association (GWA) scan using joint two-locus tests of association including main and epistatic effects in 70,236 markers tagging common variants. We found two-locus association at 79 SNP-pairs at a Bonferroni-corrected P-value = 0.05 (uncorrected P-value = 2.14 × 10⁻¹¹). The 79 pair-wise results always contained rs11196205 in TCF7L2 paired with 79 variants including confirmed variants in FTO, TSPAN8, and CDKAL1, which are associated in the absence of epistasis. However, the majority (82%) of the 79 variants did not have compelling single-locus association signals (P-value = 5 × 10⁻⁴). Analyses conditional on the single-locus effects at TCF7L2 established that the joint two-locus results could be attributed to single-locus association at TCF7L2 alone. Interaction analyses among the peak 80 regions and among 23 previously established diabetes candidate genes identified five SNP-pairs with case-control and case-only epistatic signals. Our results demonstrate the feasibility of systematic scans in GWA data, but confirm that single-locus association can underlie and obscure multilocus findings.
Authors:
Jordana T Bell; Nicholas J Timpson; N William Rayner; Eleftheria Zeggini; Timothy M Frayling; Andrew T Hattersley; Andrew P Morris; Mark I McCarthy
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-12-06
Journal Detail:
Title:  Annals of human genetics     Volume:  75     ISSN:  1469-1809     ISO Abbreviation:  Ann. Hum. Genet.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-16     Completed Date:  2011-02-03     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0416661     Medline TA:  Ann Hum Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  10-9     Citation Subset:  IM    
Copyright Information:
© 2010 The Authors Annals of Human Genetics © 2010 Blackwell Publishing Ltd/University College London.
Affiliation:
Wellcome Trust Centre for Human Genetics, University of Oxford, UK. jordana@well.ox.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Diabetes Mellitus, Type 2 / genetics*
Epistasis, Genetic*
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Polymorphism, Single Nucleotide
Transcription Factor 7-Like 2 Protein / genetics
Grant Support
ID/Acronym/Agency:
076113//Wellcome Trust; 088885//Wellcome Trust; G0600705//Medical Research Council; WT081682/Z/06/Z//Wellcome Trust; WT088885/Z/09/Z//Wellcome Trust
Chemical
Reg. No./Substance:
0/TCF7L2 protein, human; 0/Transcription Factor 7-Like 2 Protein
Comments/Corrections

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