Epistasis in sporadic Alzheimer's disease

Combarros, Onofre; Cortina-Borja, Mario; Smith, A. David; Lehmann, Donald J.

doi:10.1016/j.neurobiolaging.2007.11.027

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Volume 30, Issue 9 , Pages 1333-1349, September 2009

Epistasis in sporadic Alzheimer's disease

Onofre Combarros
- Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla University Hospital (University of Cantabria), 39008 Santander, Spain
Mario Cortina-Borja
- Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK
A. David Smith
- Oxford Project To Investigate Memory and Ageing (OPTIMA), Oxford Centre for Gene Function, University Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford OX1 3QB, UK
Donald J. Lehmann
- Oxford Project To Investigate Memory and Ageing (OPTIMA), Oxford Centre for Gene Function, University Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford OX1 3QB, UK
- Corresponding author.

Received 16 July 2007; received in revised form 30 November 2007; accepted 30 November 2007. published online 18 January 2008.

Abstract

The traditional approach in case-control association studies, to evaluate candidate genes individually, either single markers or haplotypes, has had limited success. The multifactorial nature of complex diseases suggests the alternative of examining gene–gene interactions (epistasis) within biological networks.

We have used synergy factor analysis to assess over 100 claims of epistasis in sporadic Alzheimer's disease (AD), in networks involving, e.g. cholesterol, β-amyloid, inflammation and oxidative stress. We found 27 gene–gene interactions that were significantly associated with AD. In most of these the main effect of one of the genes was so small that it would probably have been missed by the traditional locus-by-locus approach. There are questions, however, about the quality of replication studies: about sample sizes, about homogeneity, characterization and matching of sample sets, and about the statistical methods commonly used to assess interactions.

Meta-analyses could now be conducted of the four interactions that have been sufficiently replicated, all involving APOE4: ACT −17AA; BACE1 exon5 GG; IL6 −174C; BCHE K. Only that between BACE1 exon5 GG and APOE4 has so far been consistently replicated.

We conclude that epistasis is a crucial feature of complex diseases, that its study is a promising approach to the genetics of AD and that larger and more rigorous studies are needed to establish interactions.

Keywords: Polymorphism, Genetic network, Antagonism, Heterogeneity, Metabolism