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Biostatistics Advance Access originally published online on November 27, 2008
Biostatistics 2009 10(2):327-334; doi:10.1093/biostatistics/kxn039
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Statistical independence of the colocalized association signals for type 1 diabetes and RPS26 gene expression on chromosome 12q13

Vincent Plagnol*, Deborah J. Smyth, John A. Todd and David G. Clayton

Juveniles Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK, vincent.plagnol{at}cimr.cam.ac.uk

* To whom correspondence should be addressed.

Following the recent success of genome-wide association studies in uncovering disease-associated genetic variants, the next challenge is to understand how these variants affect downstream pathways. The most proximal trait to a disease-associated variant, most commonly a single nucleotide polymorphism (SNP), is differential gene expression due to the cis effect of SNP alleles on transcription, translation, and/or splicing gene expression quantitative trait loci (eQTL). Several genome-wide SNP–gene expression association studies have already provided convincing evidence of widespread association of eQTLs. As a consequence, some eQTL associations are found in the same genomic region as a disease variant, either as a coincidence or a causal relationship. Cis-regulation of RPS26 gene expression and a type 1 diabetes (T1D) susceptibility locus have been colocalized to the 12q13 genomic region. A recent study has also suggested RPS26 as the most likely susceptibility gene for T1D in this genomic region. However, it is still not clear whether this colocalization is the result of chance alone or if RPS26 expression is directly correlated with T1D susceptibility, and therefore, potentially causal. Here, we derive and apply a statistical test of this hypothesis. We conclude that RPS26 expression is unlikely to be the molecular trait responsible for T1D susceptibility at this locus, at least not in a direct, linear connection.

Keywords: Association studies; Gene expression; RPS26; T1D

Received June 19, 2008; revised August 5, 2008; revised September 12, 2008; revised September 25, 2008; accepted for publication October 17, 2008.


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