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Human Molecular Genetics Advance Access published online on March 16, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl058
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© The Author 2006. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received December 7, 2005
Revised February 8, 2006
Accepted March 9, 2006

Article

Two-dimensional genome scan identifies novel epistatic loci for essential hypertension

Jordana T. Bell 1, Chris Wallace 2, Richard Dobson 2, Steven Wiltshire 3, Charles Mein 2, Janine Pembroke 2, Morris Brown 4, David Clayton 4, Nilesh Samani 5, Anna Dominiczak 6, John Webster 7, G Mark Lathrop 8, John Connell 6, Patricia Munroe 2, Mark Caulfield 2, and Martin Farrall 1 *

1 Department of Cardiovascular Medicine, University of Oxford, Oxford OX3 7BN, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
2 Barts and The London School of Medicine and Dentistry, London EC1M 6BQ, UK
3 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
4 Clinical Pharmacology and the Cambridge Institute of Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK
5 Cardiology Group, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK
6 Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow G11 6NT, UK
7 Medicine and Therapeutics, Aberdeen Royal Infirmary, Aberdeen AB9 2ZB, UK
8 Centre National de Genotypage, Evry, Paris 91057, France

* To whom correspondence should be addressed.
Martin Farrall, E-mail: mfarrall{at}well.ox.ac.uk


  Abstract

It is well established that gene interactions influence common human diseases, but to date linkage studies have been constrained to searching for single genes across the genome. We applied a novel approach to uncover significant gene-gene interactions in a systematic two-dimensional (2D) genome scan of essential hypertension. The study cohort comprised 2076 affected sib-pairs and 66 affected half-sib-pairs from the BRItish Genetics of HyperTension study. Extensive simulations were used to establish significance thresholds in the context of 2D genome scans. Our analyses found significant and suggestive evidence for loci on chromosomes 5, 9, 11, 15, 16, and 19 that influence hypertension when gene-gene interactions are taken into account (5q13.1 and 11q22.1, two-locus lod score = 5.72; 5q13.1 and 19q12, two-locus lod score = 5.35; 9q22.3 and 15q12, two-locus lod score = 4.80; 16p12.3 and 16q23, two-locus lod score = 4.50). For each significant and suggestive pairwise interaction, the two-locus genetic model that best fitted the data was determined. Regions that were not detected using single-locus linkage analysis were identified in the 2D scan as contributing significant epistatic effects. This approach has discovered novel loci for hypertension and offers a unique potential to use existing data to uncover novel regions involved in complex human diseases.


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